Publications

Valina O et al. (2024) Transfus Med; online ahead of print:
Validation of the Sysmex XN analyser and Blood Bank mode for the quality and safety of donor blood and transfusion products.

Summary:
The XN analyser, equipped with a Blood Bank mode, demonstrated reliable performance when used for CBC blood donor evaluation and assessment of end blood products' quality (RBC, HCT, HGB, PLT) and safety (rWBC, rRBC and residual PLT) compared against manual method using counting chamber.

Rabcuka J et al. (2022) Acta Haematol; 6(18): 5415:
Metabolic reprogramming under hypoxic storage preserves faster oxygen unloading from stored red blood cells.

Summary:
In this study, relative to standard blood bank storage protocols, hypoxic storage preserves faster O2 unloading from red blood cells in RBC units stored up to 35 days. The effect correlated with Sysmex XN RBC side-scatter (RET-RBC-Z) from RET channel.

Arisawa F et al. (2021) Sysmex J Int; 31(2): 18:
Evaluation of the Blood Bank mode Software of Sysmex XN-1000 Hematology Analyzer for Counting Residual Red Blood Cells and Platelets in Platelet concentrates, and Residual White Blood Cells in Leucocyte-Reduced Whole Blood

Summary:
The study investigated Blood Bank mode (XN-1000) analytical performance of rRBC (0-5000/µL), rWBC (0-30/µL) with standard blood components counting methods and the PLT correlation with XS-1000i. The authors suggested due to the comparable results that it is possible to measure rRBC, rWBC, and platelet counts for quality control in one sample using the Blood Bank mode.

Bell S et al. (2021) Transfus Med 31(2): 94:
Comparison of four methods to measure haemoglobin concentrations in whole blood donors (COMPARE): A diagnostic accuracy study.

Summary:
Four haemoglobin measurement methods in 21.840 blood donors recruited from 10 NHSBT centres in England were investigated against reference (XN analyser). The proportion of donors who would have been inappropriately bled ranged from 2.2% to 18.9%. The proportion of donors who would have been deferred incorrectly with haemoglobin concentration above the minimum threshold ranged from 0.1% to 20.3%.

Residual Red Blood Cells

Cavagnetto C et al. (2021) Transfusion; 61(2): e258:
Residual red cells in blood components: A multisite study of fully automated enumeration using a hematology analyzer.

Summary:
In this study, the Blood Bank mode was tested at multiple sites and showed very good performance characteristics, with an LoD/LoQ of 6 RBC/µL and excellent linear correlation between expected and observed values in spiking experiments. Moreover, in a batch of routine manufactured blood components the Blood Bank mode identified all residual RBC contaminated samples correctly.

Residual White Blood Cells

Genicco A et al. (2023) La Rivista Italiana della Medicina di Laboratorio; 19(1): 30:
Verification of leukocyte contamination in leucodepleted blood components using Blood Bank mode of Sysmex XN-1000 haematology analyzer.

Summary:
The authors found that the residual WBC counting methods ADAM and the XN Blood Bank mode had an agreement of 100% for K2EDTA samples. Both methods exhibited excellent linearity and precision results and adequate limit of quantification values. The bias between XN BB mode and ADAM increased slightly over storage time. Performance of residual RBC count on XN BB mode was in agreement with results published by Cavagnetto et al. in 2021.

Blanco RA et al. (2020) Transfusion; 60(1): 155:
The use of a hematology analyzer with a new generation of software as an alternative to flow cytometry for enumerating residual white blood cells in blood components.

Summary:
In this study, the performance of the XN Blood Bank (BB) mode for residual WBC (rWBC) enumeration in blood components was analysed. In platelet, plasma and RBC components spiked with WBC, the BB mode demonstrated a LOQ of 2 WBC/μL and an excellent concordance with flow cytometry (FC) results. In components obtained from a routine blood bank, the BB mode successfully identified leukodepletion failures and met the guideline criteria of 90% of tested components containing less than 1x10^6 rWBC/unit, which was in agreement with FC results.

Mack S et al. (2020) Transfusion; 60(1): 4:
Component residual white blood cell counting made easy?

Summary:
A short review on required detection levels for blood products in US and Europe, and currently used methods on residual white blood cell counting. An outlook is given based on the publication by Blanco et al. how XN-Series analysers could increase the efficiency and reduce costs in blood banks in the future.

Lagerberg JW et al. (2020) Transfusion; 60(10): 2456:
Improved accuracy in counting residual white blood cells in red cell concentrates using new blood bank mode software of SYSMEX XN-1000 hematology analyzer.

Summary:
The authors re-calculated their results with the updated XN software for Blood Bank mode and observed a very good linear fit between expected and observed values for residual WBC in red cell concentrates (RCC). The previous underestimation of residual WBC in RCC (Blanco RA et al.) was solved with the updated XN software (XN IPU SW 22.15).

Download Literature List Blood Bank Mode
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Body Fluids

Cerebrospinal Fluid (CSF)

Buoro S et al. (2018) Int J Lab Hematol; 40(1):26:
Two-site evaluation of the diagnostic performance of the Sysmex XN Body Fluid (BF) module for cell count and differential in Cerebrospinal Fluid.

Summary:
In this study, the XN-BF mode provides rapid and accurate counts of cerebrospinal fluid samples in clinically relevant ranges. The authors considered it as a good alternative to conventional microscopic analysis.

Fleming C et al. (2015) Clin Chem Lab Med; 54(1):e19:
Liposomal interference on Sysmex XN-series body fluid mode.

Summary:
Liposomal particles from DepoCyt chemotherapy treatment may be misclassified as polymorphonuclear cells by the XN-BF mode (software version 18). The authors worked together with Sysmex to develop an alert, available from software version 20.

Li A et al. (2014) Scand J Clin Lab Invest; 74(8):673:
Automated white blood cell counts in cerebrospinal fluid using the body fluid mode on the platform Sysmex XE-5000.

Summary:
Quote: 'In the present study, we found that the open body fluid mode of the Sysmex XE-5000 was a favourable method for determination of WBC counts and for differentiation between MNCs and PMNs, compared to manual counting.'

Zur B et al. (2012) Cen Eur Neurosurg; 73:93:
Evaluation of 2 Hematology Analyzers in Body Fluid Mode versus Flow Cytometry Immunophenotyping of Mainly Neurosurgical Cerebrospinal Fluid Samples.

Summary:
Quote: ’Determination of CSF cells with the XE-5000 is presently the best automated method for counting leukocytes of blood-stained CSF.’

Zimmermann M et al. (2011) Int J Lab Hematol; 33:629:
Automated vs. manual cerebrospinal fluid cell counts: a work and cost analysis comparing the Sysmex XE-5000 and the Fuchs-Rosenthal manual counting chamber.

Summary:
The authors found that using the XE-5000 for automated counting in CSF is trustworthy especially for severely pathological cell counts, but also for counts below this. The study demonstrates specific and significant savings in terms of time and money (about 6 times).

Boer K et al. (2009) Clin Biochem; 42:684:
Evaluation of the XE-5000 for the automated analysis of blood cells in cerebrospinal fluid.

Summary:
In this study, most patients were classified correctly using the XE-5000 which is thus suitable for automated quantification of white blood cells in CSF in a defined diagnostic setting.

General Body Fluids

Van Laer C et al. (2023) J Lab Med; 47(6): 257:
Performance evaluation of the automated body fluid analysis of the new Sysmex XR haematology analyser.

Summary:
The Body Fluid modes of the XR-Series and XN-Series analysers were compared in 392 measurements (86 CSF, 77 peritoneal, 78 pleural, 89 synovial and 62 bronchoalveolar lavage fluids). The correlation coefficients between the two analysers were excellent for the majority of diagnostic and research parameters (r > 0.9) and the flagging rate of 'WBC Abn Scattergram' was comparable.

Evren E et al. (2022) Turk J Biochem; 48(1):19:
Cell counting chamber vs. Sysmex XN-1000 for determining white blood cell count and differentiation for body fluids.

Summary:
The authors found a very strong correlation (r ≥ 0.90, p<0.0001) for the WBC count, MN%, and PMN% obtained by the XN-1000 BF mode compared to the manual counting chamber for synovial fluid (n=92), CSF (n=78), and peritoneal fluid (n=22). In method comparison XN-1000 showed acceptable performance, in this study.

Ivady G et al. (2022) Ann Clin Lab Sci; 52(2):314:
Comparative Evaluation of Body Fluid Analysis by Sysmex XN Hematology Analyzers, CellaVision, Manual Microscopy and Multicolor Flow Cytometry.

Summary:
In this study, ascitic fluid and CSF samples have been analysed with XN-1000 and XN-2000 BF modes, manual microscopy, digital imaging analysis (DM96) and immunophenotyping. An excellent correlation between the analysers and imaging methods were found and only samples suspicious for the presence of malignant cells must be evaluated manually in this laboratory.

Yamatani K et al. (2019) Int J Lab Hematol; 41(6): e134:
Performance evaluation of the Sysmex DI‐60 overview application for tumor cell detection in body fluid samples.

Summary:
The study aims to evaluate the Sysmex DI-60 instrument for the detection of malignant tumour cells in a range of different body fluid in comparison with manual microscopy and the XN-Series BF mode. The authors conclude that the DI-60 overview analysis allows faster screening of malignant cells with accuracy comparable to manual microscopy.

Favresse J et al. (2018) Int J Lab Hematol; 40(2):e28:
Characterization of Candida spp. interference on the Sysmex XN-1000 body fluid mode.

Summary:
In this study, the presence of yeast interferes with WBC and TC counts, and in a less extend with HF count, when measuring body fluids on the XN-1000. Quote: ‘Therefore, the assessment of the typical “blue surfboard pattern” is also useful to identify the presence of yeast as it is important for laboratory specialists to report their presence.’ The absence of the flag “WBC abn Scattergram” does not proof that there are no interferences.

Cho YU et al. (2018) Int J Lab Hematol; 40(3):258:
Validation of reflex testing rules and establishment of a new workflow for body fluid cell analysis using a Sysmex XN-550 automatic hematology analyzer.

Summary:
The XN-550 was evaluated for body fluid analysis and the authors conclude that the XN-550 is a suitable alternative to manual body fluid analysis. In addition, several laboratory-specific cytospin review criteria were established, resulting in significant workflow improvements.

Seghezzi M et al. (2017) Clin Chim Acta; 473:133:
Preliminary evaluation of UF-5000 Body Fluid Mode for automated cerebrospinal fluid cell counting.

Summary:
The present study found a good agreement of the UF-5000 BF mode with manual chamber count for the parameters RBC, TNC, WBC (PMN/MN). The diagnostic performance was excellent especially in samples with few cells (RBC <1,000 cells/µL, WBC <20 cells/µL) as well as low LoB, LoD, LoQ and good linearity for CSF samples.

Tanaka M et al. (2016) Sysmex J Int; 26 (1):
Performance evaluation of the XN-550 Automated Hematology Analyzer body Fluid Mode — Considerations for Operational Conditions for Cell Counting with Cerebrospinal and Synovial Fluids —.

Summary:
The authors found good performance of the body fluid mode on XN-L compared to manual microscopy and on XN-9000 for cerebrospinal and synovial fluid samples.

Fleming C et al. (2015) Clin Chem Lab Med; 53(11):1689:
Clinical relevance and contemporary methods for counting blood cells in body fluids suspected of inflammatory disease.

Summary:
Excellent review on body fluid analysis. Several different analysers were compared, including the XE-5000, XN-Series and UF-Series.

Cho YU et al. (2015) Int J Lab Hematol; 37(3):346:
Body fluid cellular analysis using the Sysmex XN-2000 automatic hematology analyzer: focusing on malignant samples.

Summary:
It was found that cell counts obtained from the XN-2000 body fluid mode were comparable to counts obtained from microscopy. The authors recommend that samples with highly fluorescent cells (HF-BF) should be further analysed.

Fleming C et al. (2012) Clin Chem Med Lab; 50:1791:
Validation of the body fluid module on the new Sysmex XN-1000 for counting blood cells in cerebrospinal fluid and other body fluids.

Summary:
"The BF module on the XN-1000 is a suitable tool for fast and accurate quantification of WBC (differential) and RBC counts in CSF and other BFs in a diagnostic setting."

De Jonge R et al. (2010) Clin Chem Lab Med; 48:665:
Evaluation of the new body fluid mode on the Sysmex XE-5000 for counting leukocytes and erythrocytes in cerebrospinal fluid and other body fluids.

Summary:
In this study , the body fluid mode on the Sysmex XE-5000 offers rapid and accurate RBC and WBC (differential) counts in clinically relevant concentration ranges in CSF and other body fluids.

Paris A et al. (2010) Int J Lab Hematol; 32:539:
Performance evaluation of the body fluid mode on the platform Sysmex XE-5000 series automated hematology analyzer.

Summary:
Quote: ‘The agreement between the automated method and the manual reference showed high correlation, with Pearson correlation coefficients greater than 0.9 for all types of body fluids. We also demonstrate that the automated body fluid analysis on the XE-5000 is an acceptable alternative to the microscopic reference method as far as ascitic fluid, peritoneal dialysis fluid, SF or PF are concerned.’

Riedl JA et al. (2010) J Clin Pathol; 63:538:
Automated morphological analysis of cells in body fluids by the digital microscopy system DM96.

Summary:
The 24 h available DM96 body fluid module reliably and accurately preclassifies five main cell categories in cytospin slides with a low CV and an agreement of 90% as compared with highly trained technicians, thereby contributing to quality improvement.

Other Body Fluids

Haslacher H et al. (2021) Int J Lab Hematol; 43(4):O176:
Adequate scattergram interpretation increases the reliability of automated polymorphonuclear (pmn) cell counts from ascitic fluid of patients with liver cirrhosis.

Summary:
In this study, polymorphonuclear cell count on both, XN-BF and manual differentials compared well in ascitic fluid samples. Automated PMN counts were overestimated among samples with the lowest microscopic counts and the extend of the difference was linked to scattergram patterns indicating misclassification of cells. These findings emphasise the importance of visual validation of the WBC scattergram.

Pearson L et al. (2020) J Appl Lab Med; 6(3):679:
Reliability of Total Nucleated Cell Counts in the Setting of Hip Arthroplasty.

Summary:
The authors introduced that metallosis following total hip arthroplasty is a risk for spurious total nucleated cell counts measured by automated methods in synovial fluid. This study confirms automated methods as generally reliable for analysis of synovial fluid. Xn-bf flagged all but one of the samples in the metallosis group for manual verification of the results.

Deirmengian CA et al. (2020) J Arthroplasty; 35(6S):S304:
False-Positive Automated Synovial Fluid White Blood Cell Counting Is a Concern for Both Hip and Knee Arthroplasty Aspirates.

Summary:
In a retrospectively reviewed cohort of 44,824 synovial fluid samples from an arthroplasty the rate of false-positive automated WBC counts >3,000 cells/mL, which were corrected by a manual count to a value <3,000 cells/mL, was 4.4% for fluid from native knees, 10.1% for fluid from total knee arthroplasties and 34.3% for fluid from total hip arthroplasties.

Saadalla A et al. (2020) Clin Chim Acta; 510:416:
Evaluation of automated synovial fluid total cell count and percent polymorphonuclear leukocytes on a Sysmex XN-1000 analyzer for identifying patients at risk of septic arthritis.

Summary:
The authors suggest cut-offs on Sysmex XN-BF (TC-BF > 10,000 cells/μL and PMN% > 60%) that minimise differences between automated and manual cell counts and allow rapid automated reporting in the vast majority of septic arthritis cases.

Wong-Arteta J et al. (2019) Clin Chim Acta; 499:115:
High fluorescence cell count in pleural fluids for malignant effusion screening.

Summary:
From the perspective of a clinical workflow, the study evaluated the use of HF-BF [#] in pleural fluids for screening for malignancies. A previously published cut-off of ≥17 cells/μL for HF-BF was confirmed also considering the absence of heart failure and low respiratory infection, resulting in a sensitivity of 87% and specificity of 97%.

Favresse J et al. (2019) Int J Lab Hematol; 42(3):e92:
Utility of the XN‐1000 research mode for leukocytes counting in ascitic and pleural fluids

Summary:
The study results confirm the good performance of the XN-BF mode for ascitic and pleural fluids for total cell count (TC-BF), polymorphonuclear (PMN) and mononuclear (MN) cells. Additionally, research parameters for neutrophils, lymphocytes, monocytes and high fluorescent cells have a good performance especially when malignant cells containing samples are excluded.

Xu W et al. (2017) Medicine (Baltimore); 96(27):e7433:
Evaluation of Sysmex XN-1000 hematology analyzer for cell count and screening of malignant cells of serous cavity effusion.

Summary:
In this study, the analysis of serous fluid on the XN-BF mode showed good comparability with microscopy. High fluorescence cells (HF-BF) count correlated with the presence of malignant cells.

Seghezzi M et al. (2016) Clin Chem Acta; 462:41:
Optimization of Cellular analysis of Synovial Fluids by optical microscopy and automated count using the Sysmex XN Body Fluid Mode.

Summary:
The authors found an excellent performance for the XN-BF mode.

Bottini PV et al. (2015) Int J Lab Hematol; 37(2):e16:
Comparison between automated and microscopic analysis in body fluids cytology.

Summary:
The authors describe a performance evaluation of the XE-5000 body fluid mode for peritoneal and serous fluids. A good correlation between the XE-5000 and microscopy was found as well as good precision and low carryover.

Labaere D et al. (2015) Int J Lab Hematol; 37(5):715:
Detection of malignant cells in serous body fluids by counting high-fluorescent cells on the Sysmex XN-2000 hematology analyzer.

Summary:
Analysis of serous fluids on the XN-2000 performed in this study showed that the absence of highly fluorescent body fluid (HF-BF) cells can be used to exclude suspected malignant samples: The negative predictive value was 92 % at a cut-off value of 2.1 % and 95 % at a cut-off value of 17/µl.

Lippi G et al. (2013) J Lab Autom 2013; 18(3):240:
Evaluation of the Fully Automated Hematological Analyzer Sysmex XE-5000 for Flow Cytometric Analysis of Peritoneal Fluid.

Summary:
This evaluation of the XE-5000 for peritoneal fluid analysis showed excellent performance for all analysed parameters. The performance of the XE-5000 was slightly better than that of the XE-2100.

De Jonge R et al. (2006) Clin Chem Med Lab; 44:1367:
Automated analysis of pleural fluid total and differential leukocyte counts with the Sysmex XE-2100.

Summary:
The authors found that total and differential leukocyte counts in pleural fluid can be reliably determined with the XE-2100 with some limitations.

De Jonge R et al. (2004) Rheumatol; 43:170:
Automated counting of white blood cells in synovial fluid.

Summary:
In this study, the XE-2100 determined the number of leukocytes in the synovial fluid more accurately and faster reliably compared to manual counting. The authors suggested that this could improve the low confidence clinicians currently have in these results.

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COVID-19

Attention - Please consider the following when assessing the literature regarding COVID-19 (SARS-CoV-2 infection)

Please consider the following when assessing the literature regarding COVID-19 (SARS-CoV-2 infection):
COVID-19 is an emerging, rapidly evolving pandemic.
Available literature is changing quickly and studies summarised here may not represent the latest status of knowledge. Please consider that conclusions of articles of this list may be based on low sample numbers or manuscripts that are not peer-reviewed yet (pre-prints).

Original articles

Jha B et al. (2023) Int J Lab Hematol; 45(3): 282:
Value of new advanced hematological parameters in early prediction of severity of COVID-19.

Summary:
In this prospective observational study the intensive care infection score (ICIS) and the COVID-19 prognostic score showed similar performance in identifying critical illness in a cohort of COVID-19 positive patients (AUC 0.778 and 0.781). All EIP (except for NEUT-GI) exhibited significant differences in critically ill versus non critical patients and RE-LYMP# was found as independent risk factor.

Martens R et al. (2021) Clin Chem Lab Med; 59(4): 783:
Hemocytometric characteristics of COVID-19 patients with and without cytokine Storm syndrome on the Sysmex XN-10 hematology analyzer.

Summary:
The study’s results on the haemocytometric characteristics of COVID-19 patients revealed that a cytokine-storm syndrome was associated with higher AS-LYMPH, RE-MONO and monocyte fluorescence.

Dennison D et al. (2021) Int J Infect Dis; 106: 155:
Circulating activated neutrophils in COVID-19: An independent predictor for mechanical ventilation and death.

Summary:
The authors found that in multivariable regression analyses NEUT-RI (OR = 1.22) was a statistically significant predictor at admission for a later need of mechanical ventilation and death in COVID-19 positive patients among others. NEUT-RI cut-off value for mechanical ventilation was 52 FI (44% sensitivity, 88% specificity; AUC= 0.67).

Kilercik M et al. (2021) PloS ONE; 16(8) e0254073:
A new haematocytometric index: Predicting severity and mortality risk value in COVID-19 patients.

Summary:
This retrospective analysis of 97 COVID-19 positive patients identified monocyte-to-neutrophil ratio (MNR), MCV, RDW, and PLT as independent risk factors for mortality. A mortality risk score comprised of MNR, neutrophil-to-lymphocyte ratio (NLR), RDW, and PLT achieved an AUC of 0.91 and a specificity of 0.94.

Boulanger M et al. (2021) Am J Med; 134(8): 1029:
Peripheral Plasma Cells Associated with Mortality Benefit in Severe COVID-19: A Marker of Disease Resolution.

Summary:
This multicentric study investigated the association of plasma cells (HFLC) in peripheral blood of severe COVID-19 patients for morbidity. Retrospective analysis showed that patients exhibiting plasma cells were more likely to develop severe disease but also had a reduced risk of death. In most patients plasma cells appeared after progression to severe disease and, thus, will not serve as an early marker for severe disease.

Cohen A et al. (2021) J Thromb Thrombolysis; 52(3): 708:
Immature platelets in patients with Covid‑19: association with disease severity.

Summary:
In this study of patients with COVID-19 patients (56 mild cases, 80 severe) showed that immature platelet parameters (IPF, IPF# and maximal IPF#) were elevated in severe disease. Maximal IPF# was an independent prognostic factor for prolonged hospitalisation length.

Incir S et al. (2021) Turk J Biochem; 46(4): 359:
Immature platelet fraction: is a novel early predictive marker for disease severity in patients with Covid-19 pneumonia?

Summary:
This study of COVID-19 patients (110 non-severe cases, 44 severe) showed that IPF at admission was higher in severe disease. IPF was an independent predictor for disease severity with an AUC of 0.88 at a cut-off of > 9.5% (sensitivity 69.5% and specificity 92.4%).

Urrechaga E et al. (2021) Scand J Clin Lab Invest; 81(5): 394:
Leukocyte differential and reactive lymphocyte counts from Sysmex XN analyzer in the evaluation of SARS-CoV-2 infection.

Summary:
This prospective observational study aimed to assess the diagnostic performance in distinguishing SARS-CoV-2 infections from other viral or bacterial infections in emergency room (ER) patients presenting with fever. NLR > 3.3 and RE-LYMP >0.6% correctly distinguished 95.6% of SARS-CoV-2 infection patients in the validation group (bacterial and viral infected ER patients).

Osman J et al. (2020) Br J Haematol; 190(5): 718:
Rapid Screening of COVID-19 Patients by White Blood Cells Scattergrams, a Study on 381 Patients.

Summary:
The authors of this study investigated a specific pattern of WDF scattergram, the “sandglass shape” pattern of lymphocyte population in a cohort of 381 patients. It exhibited a sensitivity and specificity of 85.9% and 83.5% for identifying COVID-19 infection, respectively.

Yip CYC et al. (2020) Br J Haematol; 190(1): 33:
Temporal changes in immune blood cell parameters in COVID‐19 infection and recovery from severe infection.

Summary:
According to the results of this study, the authors indicate that CBC including extended parameters about activated lymphocytes may be a valuable tool to triage patients with COVID-19. AS-LYMP%L (as a percentage of lymphocytes) yielded the best area under the receiver operating characteristic curve for predicting severe disease.

Wang Z et al. (2020) Br J Haematol; 190(2): e76:
High-fluorescent lymphocytes are increased in patients with COVID-19.

Summary:
This retrospective analysis of patients from the epicentre of the COVID-19 outbreak in Wuhan, China showed that while lymphocyte (L) counts were progressively decreased as disease severity increased, high-fluorescent lymphocyte (HFL) count and HFL/L ratio were increased in mild and severe cases compared to healthy controls.

Zhang C et al. (2020) Chem Lab Med; 58(7): 1152:
Decreased "WBC*LYM" was observed in SARS-CoV-2-infected patients from a fever clinic in Wuhan.

Summary:
Retrospective CBC+DIFF data analysis from a fever clinic in Wuhan from February 2020 (mid-Corona-pandemic in China) to evaluate the diagnostic value of haematologic parameters in suspected COVID-19 patients. The combination parameter of WBC and LYM (WBC*LYM) showed the best performance data for the quick evaluation of the patients disease severity and whether the patient is likely to have COVID-19 or not.

Foy B et al. (2020) JAMA Netw Open; 3(9): e2022058:
Association of Red Blood Cell Distribution Width With Mortality Risk in Hospitalized Adults With SARS-CoV-2 Infection.

Summary:
A retrospective analysis from four US hospitals associated an elevated red cell distribution width (RDW) at admission and an increasing RDW during hospitalisation with increased mortality risk in COVID-19 patients, and identified RDW as an independent mortality risk factor.

Rolla R et al. (2020) Int J Lab Hematol; 43(1): e5:
Reduced activity of B lymphocytes, recognised by Sysmex XN-2000™ haematology analyser, predicts mortality in patients with coronavirus disease 2019.

Summary:
In this study, the antibody-synthesizing lymphocyte count (AS-LYMP#) together with age, C-reactive protein (CRP) and creatinine level was identified by the authors of this study as an independent predictor of in-hospital mortality in COVID-19 patients.

Lapic I et al. (2020) Int J Lab Hematol; 43(2): e64:
Cell population data: Could a routine hematology analyzer aid in the differential diagnosis of COVID-19.

Summary:
This letter to the editor describes the detailed analysis of cell population data (CPD) from an XN-1000 in COVID-19 and non-COVID-19 patients. CBC parameters do not present with significant differences. The CPD parameters present with significant differences, with the most pronounced the elevated LY-WZ.

Urrechaga E et al. (2020) Clin Chem Lab Med; 59(2): e57:
Complete blood counts and cell population data from Sysmex XN analyser in the detection of SARS-CoV-2 infection.

Summary:
This letter to the editor describes a categorisation of patients with infection/fever into distinct groups based on statistical analyses of complete blood count and cell population data (CPD) from an XN analyser. 93.5% of COVID-19 patients and 100% of non-COVID-19 patients were correctly classified. The authors suggested a flag for COVID-19 infection, based on the neutrophil-to-lymphocyte ratio (NLR) and CPD values.

Santotoribio J et al. (2020) Clin. Lab; 66(9):
Evaluation of Routine Blood Tests for Diagnosis of Suspected Coronavirus Disease 2019.

Summary:
This descriptive diagnostic study evaluated several routine blood tests for the diagnosis of COVID-19 at hospital admission. Lymphocytes, eosinophils, ferritin, LDH, D-dimer and hsCRP were included in the diagnostic criteria that identified suspected COVID-19 patients with a sensitivity of 91% and a specificity of 47%.

Cohen A et al. (2020) J Thromb Thrombolysis; 30: 1:
Immature platelets in patients hospitalized with Covid-19.

Summary:
Patients with COVID-19 have increased immature platelets parameters (IPF, IPF#) compared to stable patients with cardiovascular risk factors. As the disease progresses IPF and IPF# are increased also compared to acute myocardial infarction patients.

Linssen J et al. (2020) Elife; 9: e63195;:
A novel haemocytometric COVID-19 prognostic score developed and validated in an observational
multicentre European hospital-based study.

Summary:
The intention of the prognostic score is to support the management of COVID-19 patients. In this study, score values generated within the first three days of hospital admission could predict clinical severity in COVID-19 patients over the next two weeks. The score performance was shown to be superior to single parameters or parameter ratios.

Review articles

Khartabil TA et al. (2020) Crit Rev Clin Lab Sci; 57(6): 415:
A summary of the diagnostic and prognostic value of hemocytometry markers in COVID-19 patients.

Nokhostin F et al. (2020) J Adv Med Biomed Res; 28(128): 171:
Evaluation of Prognostic/Diagnostic Value of Hematological Markers in the Detection of Inflammation in Coronavirus Disease: A Review Study.

Single case reports

ZHANG B et al. (2020) PLOS ONE. 15(7): e0235458:
Clinical characteristics of 82 cases of death from COVID-19.

Gérard D et al. (2020) Br J Haematol; 189(5): 845:
SARS-CoV-2: A New Aetiology for Atypical Lymphocytes.

Fan BE et al. (2020) Am J Hematol; 95(6): 723:
COVID-19 and mycoplasma pneumoniae coinfection.

Foldes D et al. (2020) Am J Hematol; 95(7): 861:
Plasmacytoid lymphocytes in SARS-CoV-2 infection (Covid-19).

Mitra A et al. (2020) Am J Hematol; 95(8): 999:
Leukoerythroblastic Reaction in a Patient With COVID-19 Infection.

Download Literature List COVID-19
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Clinical Flow Cytometry

General

Salvia R et al. (2024) OSF Preprints. 2024 Feb 28. Web.:
Clinical Utility of the XF-1600 Flow Cytometer for MRD Assessment in Multiple Myeloma.

Summary:
This study presents a standardized and a reproducible panel for MRD detection of multiple myeloma patients in the XF-1600. It shows a strong correlation between the MRD assessment in the XF-1600 versus DxFlex and Navios EX Flow Cytometers from Beckman Coulter.

Ward R et al. (2023) Int J Lab Hematol. 2023 Dec 19. doi: 10.1111/ijlh.14219. Epub ahead of print.:
Can Metrological Traceability for Lymphocyte Subsets be achieved: A Technical Assessment of the Sysmex XF-1600.

Summary:
This study compared a bead-based technique (BD Multitest™ 6-colour TBNK assay using Trucount™ tubes on a BD FACSLyric flow cytometer) with a volumetric method on the Sysmex XF-1600 flow cytometer using Exbio Kombitest 6-colour TBNK reagent. A high degree of correlation was found for results from both methodologies and observed bias was within the limits of clinical acceptability for all populations. The authors conclude that the metrologically traceable lymphocyte subset absolute counts produced by the Sysmex XF-1600 are robust within clinically required limits.

Download Literature List Clinical Flow Cytometry
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Life Science

Breast cancer - Sentinel lymph node analysis by OSNA

PEÑA KB et al. (2021) Genes:
Total Tumor Load of mRNA Cytokeratin 19 in the Sentinel Lymph Node as a Predictive Value of Axillary Lymphadenectomy in Patients with Neoadjuvant Breast Cancer

Summary:
OSNA is a highly sensitive, specific and reproducible diagnostic method applicable also for the analysis of sentinel lymph nodes after neo-adjuvant chemotherapy. Moreover, the Total Tumour Load assessed by OSNA can help predicting the probability of additional axillary metastases.

VIEITES B et al. (2021) Clinical and Translational Oncology:
Predictive and prognostic value of total tumor load in sentinel lymph nodes in breast cancer patients after neoadjuvant treatment using one-step nucleic acid amplification: the NEOVATTL study

Summary:
Results of this study support the intraoperative use of OSNA in breast cancer patients treated with neo-adjuvant systemic therapy. A Total Tumour Load (TTL) cut-off of 250 CK-19 mRNA copies/µl predicts non-SLN involvement (NPV = 99%). A TTL value > 25.000 CK-19 mRNA copies/µl showed prognostic value and was associated with a higher risk of disease recurrence.

ALGARA LÓPEZ M et al. (2020) Radiation Oncology:
OPTimizing Irradiation through Molecular Assessment of Lymph node (OPTIMAL): a randomized open label trial

Summary:
Standardising radiotherapy treatment of breast cancer patients with few metastatic lymph nodes is crucial due to the lack of consensus. The OPTIMAL study aims to demonstrate the non-inferiority of incidental irradiation compared to intentional irradiation of axillary nodes in terms of survival of breast cancer patients with limited involvement of sentinel lymph nodes according to OSNA.

HINTZEN KFH et al. (2020) Surgical Oncology:
Molecular analysis of sentinel lymph nodes in patients with breast cancer using one-step nucleic acid amplification (OSNA): Does not lead to overtreatment in the current era of de-escalating axillary management

Summary:
Being a highly sensitive technique, OSNA detects more micrometastases in sentinel lymph nodes than standard histology but does not lead to overtreatment with more axillary dissections or irradiation.

CUFFOLO G et al. (2020) The Breast Journal:
One-step nucleic acid amplification CK19 copy number for sentinel node biopsy in breast cancer: Identification of new cutoffs to predict nonsentinel axillary node involvement

Summary:
Among the different potential cut-offs for OSNA investigated, the Total Tumour Load (TTL) allowed the most accurate prediction of non-sentinel lymph nodes (SLN).

PIÑERO-MADRONA A et al. (2020) Breast Cancer Research and Treatment:
External validation of a prognostic model based on total tumor load of sentinel lymph node for early breast cancer patients

Summary:
A nomogram based on total tumour load in the SLN determined by OSNA, age and the number of risk factors allows to predict probability of 5-year disease-free survival in breast cancer patients.

FOUGO JL et al. (2020) Surgical Oncology:
Sentinel node total tumour load as a predictive factor for non-sentinel node status in early breast cancer patients - The PORTTLE study

Summary:
The Total Tumour Load (TTL) can predict metastatic non-sentinel lymph nodes and together with other patient and tumour features might support intra-operative decision on further axillary dissection.

SHIMAZU K et al. (2019) Anticancer Research:
One-step nucleic acid amplification can identify sentinel node-negative breast cancer patients with excellent prognosis

Summary:
Patients treated with endocrine therapy alone and having negative SLN determined by OSNA show significantly better prognosis than patients pN0 by histology undergoing the same treatment.

SHIMAZU K et al. (2018) Annals of Surgical Oncology:
Intraoperative Nomograms, Based on One-Step Nucleic Acid Amplification, for Prediction of Non-sentinel Node Metastasis and Four or More Axillary Node Metastases in Breast Cancer Patients with Sentinel Node Metastasis

Summary:
An intraoperative nomogram including the Total Tumour Load (TTL) determined by OSNA can predict non-sentinel lymph node involvement and four or more axillary lymph node metastases. Such tool might support surgical and therapeutic decision-making.

BRITO MJ (2018) Acta Medica Portuguesa:
Molecular Staging of Patients with Colon Cancer. The C-Closer-II Study: A Multicentre Study in Portugal

Summary:
Molecular examination of lymph nodes by OSNA allows a more accurate staging of patients with colorectal cancer and standardizes nodal assessment. In this study, 28.8% of patients with histologically negative lymph nodes were found to have metastatic lymph nodes using OSNA

Fung V. et al. (2017) Molecular and Clinical Oncology:
Intraoperative prediction of the two axillary lymph node macrometastases threshold in patients with breast cancer using a one-step nucleic acid cytokeratin-19 amplification assay

Summary:
“OSNA identifies a TTL threshold value where, in the presence of involved SLNs, ALND may be avoided. This technique offers objective confidence in adopting conservative management of the axilla in patients with SLN macrometastases.”

Peg V. et al. (2017) The Breast:
Role of total tumour load of sentinel lymph node on survival in early breast cancer patients

Summary:
“SLN TTL permits the differentiation between two patient groups in terms of DFS and OS, independently of axillary staging (pN), age and tumour characteristics (size, grade, lymphovascular invasion). This new data confirms the clinical value of low axillary involvement and could partially replace the information that staging of the entire axilla provides in patients on whom no axillary lymph node dissection is performed.”

Terrenato I. et al. (2017) PLoS One:
A cut-off of 2150 cytokeratin 19 mRNA copy number in sentinel lymph node may be a powerful predictor of non-sentinel lymph node status in breast cancer patients

Summary:
“Logistic regression models indicated that the cut-off of 2150 copies better discriminates patients with node negative or positive in comparison with the conventional OSNA cut-off (p<0.0001). This cut-off identifies false positive and false negative cases and true-positive and true negative cases very efficiently, and therefore better identifies which patients really need an ALND and which patients can avoid one. This is why we suggest that the negative cut-off should be raised from 250 to 2150. Furthermore, we propose that for patients with a copy number that ranges between 2150 and 5000, there should be a multidisciplinary discussion concerning the clinical and bio-morphological features of primary breast cancer before any decision is taken on whether to perform an ALND or not.”

Di Filippo F et al. (2016) Journal of Experimental & Clinical Cancer Research:
Elaboration of a nomogram to predict nonsentinel node status in breast cancer patients with positive sentinel node, intraoperatively assessed with one step nucleic amplification: Retrospective and validation phase

Summary:
”The results of the study confirm that OSNA nomogram may help surgeons make an intraoperative decision on whether to perform ALND or not in case of positive sentinel nodes, and the patient to accept this decision based on a reliable estimation on the true percentage of NSN involvement. The use of this nomogram achieves two main gools: 1) the choice of the right treatment during the operation, 2) to avoid for the patient a second surgery procedure.”

Parada D. et al. (2016) Molecular and Clinical Oncology:
Intraoperative molecular analysis of sentinel lymph nodes following neoadjuvant chemotherapy in patients with clinical node negative breast cancer: An institutional study

Summary:
“The OSNA assay is a highly sensitive, specific and reproducible diagnostic technique that can be used to analyse SLNs following NAC. The total tumoral load may assist with predicting additional non SLN metastases.”

Espinosa-Bravo M. et al. (2016) The Breast:
Intraoperative assessment of sentinel lymph node by one-step nucleic acid amplification in breast cancer patients after neoadjuvant treatment reduces the need for a second surgery for axillary lymph node dissection

Summary:
The accurate and standardized intraoperative SLN analysis by OSNA decreases the need of a second surgery in 18.5% of breast cancer patients with a positive SLN after neoadjuvant therapy.

Shimazu K. et al. (2016) Surgery Today:
Clinical significance of breast cancer micrometastasis in the sentinel lymph node

Summary:
The OSNA method shows the benefit of reproducibility among different institutions and the capability of analysing a whole lymph node in only 30-40 minutes.

Kubota M et al. (2016) Molecular and Clinical Oncology:
One-step nucleic acid amplification assay for intraoperative prediction of advanced axillary lymph node metastases in breast cancer patients with sentinel lymph node metastasis

Summary:
The Total Tumour Load (TTL) determined by OSNA analysis can predict further axillary lymph node metastases in breast cancer patients. The TTL can be assessed intra-operatively, thus it can be used during surgery to determine the need for axillary lymph node dissection.

Banerjee SM et al. (2016) European Journal of Surgical Oncology:
The use of one-step nucleic acid amplification (OSNA) and tumour related factors in the treatment of axillary breast cancer: A predictive model

Summary:
A predictive model combining Total Tumour Load (TTL) determined by OSNA analysis with lymphovascular invasion can identify breast cancer patients who require additional axillary treatment, i.e. axillary lymph node dissection or other adjuvant measures.

Vieites B. et al. (2016) Histopathology:
CK19 expression in breast tumours and lymph node metastasis after neoadjuvant therapy

Summary:
The expression of CK19 protein is preserved after neoadjuvant therapy. This indicates that OSNA is a suited approach for lymph node analysis also upon neoadjuvant treatment.

Bernet L. et al. (2015) Revista de Senología y Patología Mamaria:
A multiparametric predictive model of axillary status in patients with breast cancer: total tumoral load and molecular signature. A multicenter study

Summary:
“The inclusion of PM in the multivariate model improved the AUC, especially when the total number of sentinel nodes were included. Differences were observed in the impact of the CTT among the different molecular profiles subtypes.”

Di Filippo F. et al. (2015) Journal of Experimental & Clinical Cancer Research:
Elaboration of a nomogram to predict non sentinel node status in breast cancer patients with positive sentinel node, intra-operatively assessed with one step nucleic acid amplification method

Summary:
The nomogram described by Di Filippo et al. is a very useful tool for predicting non-SLN status in breast cancer patients with positive SLNs assessed intra-operatively by OSNA.

Piñero-Madrona A. et al. (2014) The Breast:
Tumoral load quantification of positive sentinel lymph nodes in breast cancer to predict more than two involved nodes

Summary:
In this study, the OSNA result clearly correlates with the risk of having two or more metastatic non-SLNs in breast cancer patients.

Rubio IT. et al. (2014) Breast Cancer Research and Treatment:
Nomogram including the total tumoral load in the sentinel nodes assessed by one-step nucleic acid amplification as a new factor for predicting nonsentinel lymph node metastasis in breast cancer patients

Summary:
The nomogram described by Rubio et al. incorporates the Total Tumour Load (TTL) assessed by OSNA and can be used to predict non-SLN positivity. This useful tool can support clinicians in decision-making.

Deambrogio C. et al. (2014) Journal of Clinical Pathology:
A new clinical cut-off of cytokeratin 19 mRNA copy number in sentinel lymph node better identifies eligible for axillary lymph node dissection in breast cancer

Summary:
The CK19 mRNA copy number represents a useful tool to predict the probability of nodal involvement and thus, it can be applied for the selection of patients in which axillary lymph node dissection could be recommended due to the high risk of further axillary lymph node metastases.

Klingler S. et al. (2013) Annals of Oncology:
Using one-step nucleic acid amplification (OSNA) for intraoperative detection of lymph node metastasis in breast cancer patients avoids second surgery and accelerates initiation of adjuvant therapy

Summary:
The intraoperative SLN analysis by OSNA reduces the need of a second surgery in breast cancer patients and allows a prompt initiation of adjuvant therapy.

Espinosa-Bravo M. et al. (2013) European Journal of Surgical Oncology:
Prediction of non-sentinel lymph node metastasis in early breast cancer by assessing total tumoral load in the sentinel lymph node by molecular assay

Summary:
Intraoperatively assessed Total Tumour load (TTL) in SLNs of clinically node negative breast cancer patients predicts for further non-SLN metastasis. TTL helps decision-making on performing or not axillary lymph node dissection.

Osako T. et al. (2013) European Journal of Cancer:
Sentinel node tumour burden quantified based on cytokeratin 19 mRNA copy number predicts non-sentinel node metastases in breast cancer: molecular whole-node analysis of all removed nodes

Summary:
The CK19 mRNA copy number determined by OSNA predicts non-SLN metastases. This study further support the predictive value of the OSNA result.

Osako T et al. (2013) British Journal of Cancer:
Molecular detection of lymph node metastasis in breast cancer patients treated with preoperative systemic chemotherapy: a prospective multicentre trial using the one-step nucleic acid amplification assay

Summary:
“The OSNA assay can detect the residual tumour burden as accurately as conventional pathology, although chemotherapy-induced histological changes are present.”

Navarro-Cecilia J. et al. (2013) European Journal of Surgical Oncology:
Intraoperative sentinel node biopsy by one-step nucleic acid amplification (OSNA) avoids axillary lymphadenectomy in women with breast cancer treated with neoadjuvant chemotherapy

Summary:
The OSNA result can predict the axillary status with a high accuracy also in clinically node negative patients at initial presentation who underwent neoadjuvant therapy.

Peg V. et al. (2013) Breast Cancer Research and Treatment:
Intraoperative molecular analysis of total tumor load in sentinel lymph node: a new predictor of axillary status in early breast cancer patients

Summary:
The Total Tumour Load (TTL) determined by OSNA is an independent predictor of the nodal status and can support clinicians in personalising surgical treatment.

Sagara Y. et al. (2013) Journal of Breast Cancer:
Clinical application of the one-step nucleic acid amplification method to detect sentinel lymph node metastasis in breast cancer

Summary:
The OSNA assay allows the accurate analysis of SLN and the prediction of non-SLN metastases. Moreover, applying this technique reduces pathologist’s workload.

Helimann T. et al. (2013) Journal of Cancer Research and Clinical Oncology:
Intra-operative use of one-step nucleic acid amplification (OSNA) for detection of the tumor load of sentinel lymph nodes in breast cancer patients

Summary:
OSNA is a very useful tool for supporting intra-operative decision-making about further axillary surgery, thus reducing the risk of second surgeries. Moreover, the CK19 copy number allows the prediction of further lymph node involvement and might help to find adequate adjuvant treatment options.

Ohi Y. et al. (2012) British Journal of Cancer:
Whole sentinel lymph node analysis by a molecular assay predicts axillary node status in breast cancer

Summary:
The CK19 mRNA copy number in the SLN is the most significant predictor of non-SLN involvement.

Le Frère-Belda MA. et al. (2012) International Journal of Cancer:
Diagnostic performance of one-step nucleic acid amplification for intraoperative sentinel node metastasis detection in breast cancer patients

Summary:
The OSNA method shows a higher sensitivity than intraoperative histological evaluation, and thus its use possibly leads to a decrease of the number of women who require a second surgical procedure for axillary lymph node dissection.

Cserni G. (2012) Journal of Clinical Pathology:
Intraoperative analysis of sentinel lymph nodes in breast cancer by one-step nucleic acid amplification

Summary:
Cserni et al. describes in this review current literature and concerns related to the OSNA method.

Castellano I. et al. (2012) Annals of Surgery:
Reliability of whole sentinel lymph node analysis by one-step nucleic acid amplification for intraoperative diagnosis of breast cancer metastases

Summary:
Whole SLN analysis by OSNA provides objective and reproducible results that help treatment decision making and accurate characterisation of SLN staging.

Godey F. et al. (2012) Journal of Breast Cancer Research and Treatment:
Sentinel lymph node analysis in breast cancer: contribution of one-step nucleic acid amplification (OSNA)

Summary:
The intraoperative analysis of SLN by OSNA enables the surgeon to perform, when necessary, axillary lymph node dissection during the same procedure.

Bernet L. et al. (2011) Histopathology:
Diagnosis of the sentinel lymph node in breast cancer: a reproducible molecular method: a multicentric Spanish study

Summary:
OSNA is a very sensitive, specific and reproducible method that enables standardisation of the SLN diagnostic procedure.

Snook KL. et al. (2011) British Journal of Surgery:
Multicentre evaluation of intraoperative molecular analysis of sentinel lymph nodes in breast carcinoma

Summary:
OSNA allows accurate intraoperative evaluation of SLN and show excellent concordance with histology. This promising approach will become the standard method for analysis of SLN and axillary LNs.

Schem C. et al. (2009) Virchows Archiv:
One-step nucleic acid amplification – a molecular method for the detection of lymph node metastases in breast cancer patients; results of the German study group

Summary:
OSNA is a reliable and standardized tool for the intraoperative detection of lymph node metastases and its adoption may lead to a benefit for the patients since unnecessary second surgeries are avoided.

Visser M. et al. (2008) International Journal of Cancer:
Intra-operative rapid diagnostic method based on CK19 mRNA expression for the detection of lymph node metastases in breast cancer

Summary:
OSNA enables whole lymph node analysis and therefore, sampling errors, which are related to histological techniques, are avoided. Moreover, the automated procedure leads to a high degree of standardization and objectivity.

Tsujimoto M. et al. (2007) Clinical Cancer Research:
One-step nucleic acid amplification for intraoperative detection of lymph node metastasis in breast cancer patients

Summary:
CK19 mRNA copy number cut-off values enable to distinguish among macrometastasis, micrometastasis, and non-metastasis. The clinical findings indicate that the OSNA assay is a useful intraoperative detection method for the detection of lymph node metastasis in breast cancer patients.

CALPROTECTIN MEASUREMENT FOR IBD DIAGNOSIS AND MONITORING

MÉRIDA F.J. ET AL. (2020) Annals of Clinical & Laboratory Science:
Comparative Study of Three Different Fecal Calprotectin Immunoassays: TriCAL Study.

Summary:
CALiaGold performance was evaluated in comparison with two other calprotectin immunoassays (fCAL turbo and Quantum Blue fCAL). The correlation and the agreement to discriminate calprotectin positive samples between both immunoturbidimetric assays (CaliaGold and fCAL turbo) was higher than in comparison with the immunochromatographic assay.

HUIJGEN J.R. ET AL. (2020) NVKC Papendal Poster Presentation:
Analytical performance of the CALiaGold ® Quantitative latex immunoassay for Calprotectin measurement on the SENTiFIT®270 analyzer.

Summary:
Based on a method comparison on 100 stool samples between CALiaGold and EliA Calprotectin 2 it was judged that the performance of CALiaGold on the SENTiFIT 270 meets the requirements for quantitative determination of calprotectin.

SILVA B. ET AL. (2019) Euromedlab Barcelona Poster Presentation:
Method comparison of CALiaGold® (a new assay for quantitative determination of fecal calprotectin) and BÜHLMANN fCAL™ turbo.

Summary:
As a result of the method comparison a very strong relationship between CALiaGold on SENTiFIT 270 and fCAL™ turbo on Cobas 8000 was observed on 315 stool samples.

RASMUSSEN H.Y. ET AL. (2019) IBD Nordic conference Malmö Poster Presentation:
Comparison of two automated assays and extraction techniques for analyzing fecal calprotectin.

Summary:
The comparison of two different methods for fecal calprotectin measurement CALiaGold and EliA Calprotectin 2 (each method having its own unique extraction method) showed an overall acceptable correlation, particularly in the calprotectin <500 μg/g range.

PAPARELLA C. ET AL. (2018) UEG week Poster Presentation:
Evaluation of a new assay for the quantitative determination of calprotectin in human feces (CALiaGold).

Summary:
It was concluded that analytical and clinical performances of the CALiaGold assay on the SENTiFIT 270 meet the requirements for its use as quantitative determination of calprotectin in human feces. A method comparison versus Bühlmann fCAL turbo on Architect c16000 showed a high correlation in 114 samples.

FINAZZI S. ET AL. (2018) ELAS:
Comparison between two automated assays for the quantitative determination of fecal calprotectin.

Summary:
Goal of this study was to compare the new CALiaGold assay on SENTiFIT 270 with EliA Calprotectin 2 on Phadia 250 analyzer. The method comparison on 118 stool samples revealed a high concordance rate of 87.3% although both assays are based on different methods (immunoturbidimetry vs fluorescence enzyme immunoassay).

Colorectal cancer - Lymph node analysis by OSNA

ARCHILLA I et al. (2021) Clinical and Translational Gastroenterology:
Lymph Node Tumor Burden Correlates With Tumor Budding and Poorly Differentiated Clusters: A New Prognostic Factor in Colorectal Carcinoma?

Summary:
The amount of tumour burden in the lymph nodes determined by OSNA correlates with tumour budding and poorly differentiated clusters and could be used as a new prognostic factor in CRC. Molecular nodal status assessment in combination with other pathological risk factors, could help to improve risk stratification and management of patients with early-stage disease CRC.

ITABASHI M (2020) Annals of Surgical Oncology:
Lymph Node Positivity in One-Step Nucleic Acid Amplification is a Prognostic Factor for Postoperative Cancer Recurrence in Patients with Stage II Colorectal Cancer: A Prospective, Multicenter Study

Summary:
Among all clinical and pathological parameters assessed in this study, only the OSNA outcome significantly affected survival of pStage II colorectal cancer patients, showing that OSNA positivity can be considered a risk-factor for recurrence in these patients.

HIYOSHI Y et al. (2020) Annals of Gastroenterological Surgery:
The advantage of one-step nucleic acid amplification for the diagnosis of lymph node metastasis in colorectal cancer patients

Summary:
Comprehensive evaluation of published results on OSNA diagnostic performance revealed high specificity (96.8%), high concordance rate (96.0%) and negative predictive value (98.6%) in a pooled assessment.

DIAZ-MERCEDES S (2019) Applied Health Economics and Health Policy:
Budget Impact Analysis of Molecular Lymph Node Staging Versus Conventional Histopathology Staging in Colorectal Carcinoma

Summary:
Assessment of the budget impact in Spain by introduction of OSNA for lymph node analysis shows substantial savings when compared to standard node analysis. In addition, OSNA could lead a clinical benefit for colorectal cancer patients since a more accurate staging could be performed, thus avoiding unnecessary treatments.

ESPOSITO F (2019) Annals of Coloproctology:
Sentinel lymph node analysis in colorectal cancer patients using one-step nucleic acid amplification in combination with fluorescence and indocyanine green

Summary:
In colorectal cancer patients, combination of ICG-NIR lymphangiography mapping and SLN analysis by OSNA can detect lymph node involvement, allowing more accurate staging and reducing the delay between surgery and adjuvant chemotherapy

Marhic A. et al. (2017) Digestive and Liver Disease:
Molecular analysis of sentinel lymph node in colon carcinomas by one-step nucleic acid amplification (OSNA) reduces time to adjuvant chemotherapy interval

Summary:
Intraoperative analysis of SLNs by OSNA significantly reduces the time to adjuvant chemotherapy after surgery.

Yeung T.M. et al. (2017) Surgical Endoscopy:
Intraoperative identification and analysis of lymph nodes at laparoscopic colorectal cancer surgery using fluorescence imaging combined with rapid OSNA pathological assessment

Summary:
“OSNA can be combined with NIR and ICG lymphatic mapping to provide intraoperative assessment of nodal tissue in patients with colorectal cancer.”

Rakislova N. et al. (2017) Journal of Translational Medicine:
Lymph node pooling: a feasible and efficient method of lymph node molecular staging in colorectal carcinoma

Summary:
“LN pooling makes it possible to analyze a high number of LNs from surgical colectomies with few molecular tests per patient. This approach enables a feasible means to integrate LN molecular analysis from CC specimens into pathology diagnosis and provides a more accurate LN pathological staging with potential prognostic implications.”

Aldecoa I. et al. (2016) Virchows Archiv:
Molecularly determined total tumour load in lymph nodes of stage I-II colon cancer patients correlates with high-risk factors. A multicentre prospective study

Summary:
OSNA allows the identification of tumour burden (undetected by hystology) in lymph nodes of early colon cancer patients. Moreover, the Total Tumour Load (TTL) determined by OSNA correlates with high-risk factors and may be used for a better selection of stage I–II patients at risk of recurrence.

Aldecoa I. et al. (2016) Surgical Endoscopy:
Endoscopic tattooing of early colon carcinoma enhances detection of lymph nodes most prone to harbor tumor burden

Summary:
Endoscopic tattooing clearly improves identification of lymph nodes. Moreover, this method allows the detection of those lymph nodes most prone to carry tumor burden as demonstrated by the Total Tumour Load (TTL) values.

Yamamoto H. et al. (2016) Annals of Surgical Oncology:
OSNA-Assisted Molecular Staging in Colorectal Cancer: A Prospective Multicenter Trial in Japan

Summary:
High concordance between OSNA and histology. Besides, the TTL values determined by OSNA show to increase as the number of metastatic lymph node increases showing a trend compatible to the current pathological diagnosis system.

Vogelaar FJ. et al. (2014) Annals of Surgical Oncology:
The diagnostic value of one-step nucleic acid amplification (OSNA) for sentinel lymph nodes in colon cancer patients

Summary:
The OSNA method shows a performance comparable to multilevel fine pathological examination. Since it enables whole lymph node analysis, sampling bias can be avoided leading to a more accurate tumour staging.

Croner RS. et al. (2014) British Journal of Cancer:
Molecular staging of lymph node-negative colon carcinomas by one-step nucleic acid amplification (OSNA) results in upstaging of a quarter of patients in a prospective, European, multicentre study

Summary:
More than 25% of initially pN0 patients were upstaged by OSNA suggesting that this standardized and accurate method may improve staging.

Yamamoto N. et al. (2013) Japanese Journal of Clinical Oncology:
An optimal mRNA marker for OSNA (One-step nucleic acid amplification) based lymph node metastasis detection in colorectal cancer patients

Summary:
A CK19 mRNA copy number cut-off of 75-500 copies/µl leads to a high sensitivity and specificity of the OSNA method.

Güller U. et al. (2012) Cancer:
Molecular investigation of lymph nodes in colon cancer patients using one-step nucleic acid amplification (OSNA): a new road to better staging?

Summary:
The OSNA method shows comparable performance such as intensive histopathological evaluation and may lead to upstaging of more than 15% of colon cancer patients.

Yamamoto H. et al. (2011) Annals of Surgical Oncology:
OSNA-based novel molecular testing for lymph node metastases in colorectal cancer patients: results from a multicenter clinical performance study in Japan

Summary:
OSNA can be considered a novel molecular examination tool for the staging of colon cancer patients.

Croner RS. et al. (2010) Journal of Translational Medicine:
One step nucleic acid amplification (OSNA) - a new method for lymph node staging in colorectal carcinomas

Summary:
The OSNA method allows the rapid analysis of the whole node and can applied as tool to determine nodal status in colon cancer patients.

Faecal immunochemical test for colorectal cancer screening

SARKEALA T. ET AL. (2021) BMJ Open:
Piloting gender-oriented colorectal cancer screening with a faecal immunochemical test: population-based registry study from Finland.

Summary:
The Pilot study was designed to establish the best possible FIT cut-offs for both genders before the implementation of the national programme in Finland using FOB Gold. It represents the first approach with FOB Gold to report the performance of FIT screening with different screening schemes for men and women.

NIEDERMAIER T. ET AL. (2020) Clinical Gastroenterology and Hepatology:
Sensitivity of fecal immunochemical test for colorectal cancer detection differs according to stage and location.

Summary:
FOB Gold identified patients with newly diagnosed CRC with overall high sensitivity (84.6 % at a cut-off of 17 μg Hb/g) and showed a stage-specific gradient in sensitivity according to T and UICC stage, which is plausible because larger and deeper penetrating tumours are expected to be more likely to cause sufficiently strong bleeding to result in a positive FIT value.

PENG L. ET AL. (2020) The American Journal of Gastroenterology:
Risk-Adapted Cutoffs in Colorectal Cancer Screening by Fecal Immunochemical Tests.

Summary:
Variations of numbers needed to scope (NNS) and positive predictive values (PPV) were present across various CRC risk groups when uniform FOB Gold cut-offs were used in screening, which leads to the conclusion that using risk-adapted cut-offs might represent an option for personalised CRC screening.

NAVARRO M. ET AL. (2020) Frontiers in Medicine:
Reducing the Cut-Off Value of the Faecal Immunochemical Test for Symptomatic Patients does not Improve Diagnostic Performance.

Summary:
FOB Gold was evaluated in 727 patients with ‘red flag’ symptoms showing a high NPV for cancer (99.4 %) at 20 μg/g cut-off which was similar to the NPV (99.6 %) reached at the NICE DG30 recommended cut-off at 10 μg/g, thus can be used to avoid or prioritize colonoscopy procedures in symptomatic.

LUÉ A. ET AL. (2020) Therapeutic Advances in Gastroenterology:
The combination of quantitative faecal occult blood test and faecal calprotectin is a cost-effective strategy to avoid colonoscopies in symptomatic patients without relevant pathology.

Summary:
FOB Gold applied in the population-based Aragon CRC screening programme (cut-off 20 μg Hb/g) was used with the same cut-off combined with a calprotectin assay to improve the overall diagnostic accuracy for the detection of significant colonic pathology in prospectively enrolled symptomatic patients referred to colonoscopy.

CONSTANTIN A. ET AL. (2020) Chirurgia:
Short Term Outcomes of Using Fecal Immunochemical Test for a Pilot Colorectal Cancer Screening Program. A Single Center Study on 3024 Consecutive Patients.

Summary:
The first opportunistic CRC screening pilot programme based on FOB Gold in Romania proved its efficiency compared to screening colonoscopies.

O’DRISCOLL S. ET AL. (2020) Clinical Chemistry and Laboratory Medicine:
An evaluation of ten external quality assurance scheme (EQAS) materials for the faecal immunochemical test (FIT) for haemoglobin.

Summary:
Ten EQAS provided material for the study among them results from faecal-like matrices had a higher median CV when compared to those from schemes providing liquid ones. Faecal-like matrices were more aligned to a real stool sample, are prone to pre-examination variation so do not assess the analytical accuracy of a FIT whereas liquid ones are better able to assess the accuracy of a FIT system.

PIGGOTT C. ET AL. (2020) Clinical Chemistry and Laboratory Medicine:
Analytical evaluation of four faecal immunochemistry tests for haemoglobin.

Summary:
An assessment of the analytical performance of the FIT systems (HM-JACKarc, NS-Prime, OC-Sensor PLEDIA and SENTiFIT 270) was undertaken using Hb lysates, real patient samples and EQA samples. It was concluded that all four FIT systems perform acceptably when compared with manufacturers data and from an analytical point of view all are suitable for use.

PIGGOTT C. ET AL. (2020) Clinical Chemistry and Laboratory Medicine:
Independent internal quality control (IQC) for faecal immunochemical tests (FIT) for haemoglobin: use of FIT manufacturers’ IQC for other FIT systems.

Summary:
The goal was to assess whether IQC materials from each of the four manufacturers were compatible on the other three quantitative FIT systems (NS-Prime, OC-SENSOR PLEDIA, HM-JACKarc, SENTiFIT 270). All of the IQC materials showed results without any errors on all systems, suggesting commutability of the materials between systems whilst f-Hb values by each IQC were different to those originally assigned by each manufacturer for their own system due to lacking international standardisation or harmonisation for FIT.

TOES-ZOUTENDIJK E. ET AL. (2020) Journal of Medical Screening:
Participation in faecal immunochemical testing-based colorectal cancer screening programmes in the northwest of Europe.

Summary:
A large variability in the design of different screening programmes (Flanders, France, Basque country and the Netherlands) e.g. mailed-out FIT, pre-invitation and reminder letters showed significantly higher screening participation than in those countries without these performance indicators (highest participation rate in the Netherlands using FOB Gold).

KOOYKER A.I. ET AL. (2020) International Journal of Cancer:
The second round of the Dutch colorectal cancer screening program: Impact of an increased fecal immunochemical test cut-off level on yield of screening.

Summary:
This study presents the results of the 2nd round of the Dutch CRC screening program using FOB Gold and evaluates the impact of increasing the cut-off in the 1st round on the yield of the 2nd round.

DE KLERK C.M. ET AL. (2019) The American Journal of Gastroenterology:
Participation and ease of use in colorectal cancer screening: a comparison of two fecal immunochemical tests.

Summary:
A significant percentage of participants in the Dutch national screening programme preferred FOB Gold (36 %) over OC Sensor (5 %) – most had no preference (59 %) – whereas the rate of returned FIT samples was comparable between FOB Gold and OC Sensor (48.7 % vs 48.9 %, respectively).

TOES-ZOUTENDIJK E. ET AL. (2019) Clinical Gastroenterology and Hepatology:
Incidence of Interval Colorectal Cancer After Negative Results From First-round Fecal Immunochemical Screening Tests, by Cutoff Value and Participant Sex and Age.

Summary:
In the first screening round of the Dutch CRC screening program with FOB Gold, a low incidence of interval CRC in the 2 years after a negative FIT result was observed, irrespective of cut-off. Older age was associated with a higher interval CRC incidence and FIT sensitivity was lower for women than for men.

NAVARRO M. ET AL. (2019) Frontiers in Medicine:
Fecal Hemoglobin Concentration, a Good Predictor of Risk of Advanced Colorectal Neoplasia in Symptomatic and Asymptomatic Patients.

Summary:
Male gender, age and Hb concentration (FIT) can be used as predictors of risk of advanced neoplasia and CRC to triage colonoscopy in symptomatic population based on the results of using FOB Gold at a cut-off of 20 μg/g in 1227 symptomatic patients.

DE KLERK C.M. ET AL. (2019) The Lancet Gastroenterology and Hepatology:
Performance of two faecal immunochemical tests for the detection of advanced neoplasia at different positivity thresholds: a cross-sectional study of the Dutch national colorectal cancer screening programme.

Summary:
The goal of this study was to compare the Hb concentration distributions and positivity rates of FOB Gold and OC Sensor at different positivity cut-offs. Despite the Hb concentrations and dedicated positivity rates per cut-off measured with both assays out of the same stool sample varied, their power to detect advanced neoplasia (confirmed by colonoscopy) was similar when compared at the same positivity rate. Both FOB Gold and OC Sensor demonstrate an equal accuracy if the cut-off for positivity is standardized to result in the same positivity rate.

BRENNER H. ET AL. (2019) Journal of the American Medical Association:
Effect of a Single Aspirin Dose Prior to Fecal Immunochemical Testing on Test Sensitivity for Detecting Advanced Colorectal Neoplasms: A Randomized Clinical Trial.

Summary:
In this randomized, placebo-controlled study administration of a single dose of oral aspirin prior to FIT did not significantly increase test sensitivity for detecting advanced colorectal neoplasms at 2 predefined cut-offs of FOB Gold.

GIES A. ET AL. (2019) Clinical Gastroenterology and Hepatology:
Effect of Imperfect Compliance With Instructions for Fecal Sample Collection on Diagnostic Performance of 9 Fecal Immunochemical Tests.

Summary:
This study provides information on the varying faecal sampling instructions of different FITs and aims to assess potential effects on diagnostic performance if these instructions are not followed correctly. In total stool samples from 76 patients with CRC and 100 participants without advanced neoplasia (AN) were investigated for filling the sample tubes of 9 different FITs according to each manufacturers’ instruction and with 3 violations of the recommended protocol. It was concluded that in case of the CRC stool samples the quantitative FIT values increased consistently when inserting higher stool masses into tubes (violation of protocol of once-only insertion of stool-filled stick) which produced as well higher AUC for detection of CRC (FOB Gold with highest AUC of 90.1%). Overall only limited adverse effects on diagnostic performance revealed robustness of FITs.

National Monitoring of the Colorectal Cancer Screening Programme | RIVM (2019) National Institute for Public Health and the Environment (RIVM): Erasmus MC Rotterdam, NKI/Antoni van Leeuwenhoek COLORECTAL CANCER SCREENING PROGRAMME:
Monitor 2014-2019

Summary:
The Dutch national screening programme for CRC using FOB Gold started in 2014. This screening is for men and women in the age group 55 to 75 years. This CRC screening programme might prevent CRC by detecting and removing advanced adenomas (large polyps). In addition, CRC might be detected at an early stage, resulting in a better prognosis. In 2019, the participation rate in the CRC screening was 71.5%. In total, more than 1.5 million people participated, of these 4.3% had an unfavourable FIT result.

DE KLERK C.M. ET AL. (2018) United European Gastroenterology Journal:
A large proportion of fecal immunochemical test-positive participants in colorectal cancer screening is symptomatic.

Summary:
By using FOB Gold in the Dutch CRC screening programme a large proportion (47 %) of the FIT-positive participants reported CRC-related symptoms and showed an association between visible rectal blood loss and a change in bowel habits with the presence of CRC.

WIETEN E. ET AL. (2018) Gastroenterology:
Equivalent Accuracy of 2 Quantitative Fecal Immunochemical Tests in Detecting Advanced Neoplasia in an Organized Colorectal Cancer Screening Program.

Summary:
More than 21,000 randomly selected participants of the Dutch CRC screening programme completed the FOB Gold and OC Sensor FIT derived from the same stool sample. During this prospective study no significant differences in the power of the diagnostic performance of FOB Gold and OC Sensor were detected in regards to the detection of advanced neoplasia.

BRENNER H. ET AL. (2018) Clinical Epidemiology:
Variation of diagnostic performance of fecal immunochemical testing for hemoglobin by sex and age: results from a large screening cohort.

Summary:
In real screening settings (n=3211, age of 50 to 79) the diagnostic performance of FOB Gold was evaluated based on age and sex over a range of cut-offs. A higher sensitivity for the 65 to 79 age group compared to the 50 to 64 age group could be observed as well as a lower sensitivity and higher specificity for women versus men. PPVs and NPVs did not show significant differences between age groups, but higher NPVs were detected among women compared with men. These differences in diagnostic performance based on sex and age should be factored in for interpretation and comparison of FIT-based CRC screening studies.

GIES A. ET AL. (2018) Gastroenterology:
Direct Comparison of Diagnostic Performance of 9 Quantitative Fecal Immunochemical Tests for Colorectal Cancer Screening.

Summary:
This comparison study of diagnostic performance (sensitivity and specificity) of 9 different quantitative FITs (FOB Gold included) based on the same stool samples showed that setting the cut-offs to defined levels of specificity, levels of sensitivity could be ensured to be quite similar among all FITs.

NIEDERMAIER T. ET AL. (2018) Epidemiology:
Diagnostic Performance of One-off Flexible Sigmoidoscopy with Fecal Immunochemical Testing in a Large Screening Population.

Summary:
The goal of this study was to estimate the expected diagnostic performance of joint use of one-off flexible sigmoidoscopy (FS) and FOB Gold. Combining FS and FOB Gold might strongly enhance diagnostic performance of each single approach close to the diagnostic performance of screening colonoscopy while avoiding many unneeded endoscopic examinations (e.g. at 94% specificity and cut-off 17 µg/g, sensitivity of FOB Gold would increase from 39% to 78% for advanced neoplasm).

CARROLL M. ET AL. (2018) Annals of Clinical Biochemistry:
An assessment of the effect of haemoglobin variants on detection by faecal immunochemical tests.

Summary:
Of 20 common Hb variants studied, 17 did not affect detection of Hb by FOB Gold and three other quantitative FIT systems tested.

PIGGOTT C. ET AL. (2018) Annals of Clinical Biochemistry:
Does the mass of sample loaded affect faecal haemoglobin concentration using the faecal immunochemical test?

Summary:
Excess loading of faeces onto the FOB Gold probe did not impact the f-Hb significantly due to the presence of a probe collar as other tested devices did as well.

AUGÉ J.M. ET AL. (2018) Clinical Chemistry and Laboratory Medicine:
An Evaluation of the SENTiFIT 270 analyser for quantitation of faecal haemoglobin in the investigation of patients with suspected colorectal cancer.

Summary:
Performance of a technical and clinical evaluation on 487 symptomatic patients using SENTiFIT® 270. Outcome of the clinical evaluation: Hb levels from patients with advanced colorectal neoplasia (ACRN = CRC plus advanced adenoma) were significantly higher than from those with a normal colonoscopy examination. Sensitivity for ACRN at cut-offs from 10 to 60 μg Hb/g faeces ranged from 28.9% to 46.5%, specificity from 85.0% to 93.2%, PPV from 34.7% to 42.3% and NPV from 90.2% to 88.4%. Overall the performances of SENTiFIT® 270 makes it suitable for use in a clinical chemistry laboratory for the early detection of ACRN and as aid in diagnosis of symptomatic patients.

Brenner H. et al. (2017) International Journal of Cancer:
Strong subsite-specific variation in detecting advanced adenomas by fecal immunochemical testing for haemoglobin

Summary:
FOB Gold was applied prior to colonoscopy by 3.466 participants of the German screening colonoscopy program. The goal was to proof the subsite specific sensitivity for various types of colorectal neoplasms by comparing FIT results with findings at screening colonoscopy. The iFOBT FOB Gold showed a sensitivity of 95-100% and therefore an excellent performance in detecting CRC.

Toes-Zoutendijk E. et al. (2017) Gastroenterology:
Real-Time Monitoring of Results During First Year of Dutch Colorectal Cancer Screening Program and Optimization by Altering Fecal Immunochemical Test Cut-Off Levels

Summary:
Data were collected from the first year of the Dutch screening program (2014) with biennial FITs by real-time monitoring (529.056 people participating). Because of the higher than predicted positivity rate (10.6%) and the lower PPV (42.1%) after some months the FOB Gold test cut-off was increased (from 15 to 47 µg Hb/g feces), resulting finally in 6.7% positivity rate and 49.1% PPV. It has been concluded that for optimization of screening performance (test cut-off adjustments) a close monitoring of the implementation program is needed.

GIES A. ET AL. (2017) International Journal of Cancer:
Quantitative Fecal Immunochemical Tests for Colorectal Cancer Screening.

Summary:
A meta-analysis revealed 22 studies with 7 quantitative FITs (inclusive FOB Gold) that evaluated their diagnostic performance at several cut-off points. In these studies, colonoscopy was conducted independently from the FIT result. Heterogeneity in diagnostic performance (sensitivity, specificity) between the FITs can be completely overcome by appropriate cut-off adjustments. The authors recommended that screening programmes should adjust the FIT cut-off corresponding to a yielded positivity rate as a good indicator for the specificity and based on a feasible colonoscopy workload.

NICE Diagnostics Guidance (2017) National Institute for Health and Care Excellence:
Quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care (DG30).

Summary:
The FOB Gold quantitative FIT is recommended for adoption in primary care in order to guide referral for suspected CRC in people who have unexplained symptoms and no rectal bleeding, but do not meet the criteria for a suspected cancer pathway referral.

AUGÉ J.M. ET AL. (2017) Euromedlab Athens Poster Presentation:
FIT performance in surveillance and symptomatic patients. The same test but different interpretation.

Summary:
FOB Gold clinical performance was assessed on SENTiFIT 270 analyzer in symptomatic patients (520) in relation to colonoscopy findings showing a NPV of 88.9 % at a cut-off of 10 μg/g for advanced neoplasia (CRC + high risk adenoma).

BRENNER H. ET AL. (2017) Clinical and Translational Gastroenterology:
Selecting a Cut-off for Colorectal Cancer Screening With a Fecal Immunochemical Test

Summary:
The diagnostic performance of FOB Gold for detecting advanced neoplasms (AN) across a cut-off range of 5-50 µg Hb/g feces has been assessed in a true screening setting (50–79 years) in Germany. As example a cut-off defined as 17 µg Hb/g feces would yield to a 8.7% positivity rate, 35.7% sensitivity, 94.7% specificity and 46.5% PPV for detecting AN. Therefore selecting a cut-off according to the range of 5-50 µg Hb/g feces should reflect characteristics of the target population such as AN prevalence or available colonoscopy capacity (tailoring to the needs of the respective program).

SOLÉ LLOP M.E. ET AL. (2017) Gaceta Sanitaria:
Colorectal cancer screening programme in Aragon (Spain): preliminary results

Summary:
Data were collected from the 1st year of the Aragon screening program (2014) based on FIT in patients 60-69 years old (participation rate: 45.28%). FOB Gold is applied biannually with a cut-off of 20 µg/g feces (on SENTiFIT® 270). After the 1st year the positivity rate was 10.75% and the PPV for any adenoma/advanced adenoma/CRC 58.55%/14.36%/5.36%. The inadequate test rate has been judged as quite acceptable with 0.21%. The analysis of the ongoing program suggests the program is being correctly implemented.

Dancourt V. et al. (2016) European Journal of Cancer Prevention:
Influence of sample return time and ambient temperature on the performance of an immuno-chemical faecal occult blood test with a new buffer for colorectal cancer screening

Summary:
Investigation on the effects of sample return time and of season on the FOB-Gold performance with a new buffer (study included 20.371 participants from French SP). The positivity rates were 4.1, 4.1 and 4.6% for a sample return time of up to 3 days, 4-5 days and 6-7 days. At 20°C there was a decrease in Hb concentration of 5.1% after 7 days, at 30°C of 20.5%. As result at 20°C after 7 days 100% of the samples of participants with CRC (4/4) and 97% of samples of participants with advanced adenomas (38/39) remained positive. It was concluded that a delay in sample return and season did not affect the diagnostic yield of FOB-Gold.

Grobbee E.J. et al. (2016) Gut:
A randomised comparison of two faecal immuno-chemical tests in population-based colorectal cancer screening

Summary:
Comparison of two iFOBTs (FOB-Gold and OC-Sensor) on Dutch screening population (n=19.291; 60-74 years old). Both iFOBTs were equally acceptable to the participants. The test performance regarding detection of colorectal advanced neoplasia was comparable for both tests, as well as the positive predictive value. In conclusion, the OC-Sensor and FOB-Gold perform similar in population-based screening.

Chen H. et al. (2016) Clinical Gastroenterology and Hepatology:
Fresh vs Frozen Samples and Ambient temperature have Little Effect on Detection of Colorectal Cancer or Adenomas by a Fecal Immunochemical Test in a Colorectal Cancer Screening Cohort in Germany

Summary:
Comparison of detection of CRCs and colorectal neoplasms by FOB-Gold using fresh samples vs frozen samples and assessment of the influence of seasonal variations (temperatures) on test performance. 3.466 FIT sample results from the German colonoscopy screening program were assessed. 12.8% of frozen stool samples and 8.7% of fresh stool samples had positive results by FIT. After adjusting the test cut-off to achieve the same %age of positive results, both sample cohorts showed similar levels of sensitivity and specificity for colorectal neoplasms. In addition no differences in detection of neoplasms during different seasons (different outdoor temperatures) were observed. It has been concluded that the use of fresh vs frozen samples only slightly affected positivity rates at the recommended test cut-off.

Dvir R. et al. (2016) United European Gastroenterology Journal:
SENTIFIT 270 SYSTEM CLINICAL PERFORMANCE EVALUATION COMPARED WITH OC SENSOR DIANA, FOR THE DETECTION OF HUMAN HAEMOGLOBIN AS FAECAL OCCULT BLOOD (FOB)

Summary:
The study goal was to compare the clinical performances of SENTiFIT FOB-Gold (SENTiFIT270 system) with the OC-SENSOR DIANA system. A good concordance between the SENTiFIT and the DIANA assay was observed: SENTiFIT assay is a valid quantitative FIT.

Soliera A.R. et al. (2014) IFCC WorldLab Istanbul:
Automated Faecal Imunoassay Testing (FIT) for Hemoglobin on a new dedicated analyzer

Summary:
The SENTiFIT® 270 system with SENTiFIT® pierceTube for the quantitative determination of faecal occult blood was subjected to a performance evaluation based on CLSI standards. All of the manufacturer's data with respect to the analytical performance, linearity, prozone effect and reagent and calibration stability could be confirmed with a high accuracy.

Correale M. et al. (2014) IFCC WorldLab Istanbul:
SENTiFIT® - FOB Gold® latex Fecal Immunoassay Test (FIT) evaluation on SENTiFIT® 270 analyzer

Summary:
The SENTiFIT® 270 system with SENTiFIT® pierceTube for the immunochemical quantitative determination of faecal occult blood was subjected to a performance evaluation based on CLSI standards. All of the manufacturer's data with respect to the analytical performance, linearity, prozone effect and reagent and calibration stability could be confirmed with a high accuracy. The system is user friendly and easy to use. The new, pierceable sample tube improves the measurement accuracy, reduces the input and leads to a complete automation of the FIT.

Gnatta E. et al. (2014) Clin Chem Lab Med:
A new sampling device for faecal immuno-chemical testing: haemoglobin stability is still an open issue

Summary:
Evaluation of the Hb stability in faeces collected with FOB-Gold Tube Screen and Tube NG that contain different buffers (buffer H, BH). 15 true positive samples were collected with both buffers, portioned and incubated at 4, 21 and 32°C for 10 days. Endpoint was the percentage of cumulative faecal Hb decrease (HbCD%). The results showed that no significant difference was visible between BH and BN in HbCD% at 4°C. At 21 and 32°C the HbCD% was lower in BH than in BN samples whereas no difference was found between samples stored in BH at 4 and 21°C.

Anelli MC. et al. (2014) AACC ANNUAL MEETING & CLINICAL LAB EXPO (Chicago):
SENTiFIT®-FOB Gold® latex Fecal Immunoassay Test (FIT) evaluation on SENTiFIT® 270 analyzer in CoreLab at the AUSL Modena Nuovo S.Agostino Estense hospital in Emilia Romagna Region

Summary:
The aim of this study was to compare two quantitative FITs: SENTiFIT270 and OC-Sensor Diana. Both systems showed a high concordance (95.8%), sensitivity (100%) and specificity (95.2%).

Hamza S. et al (2013) European Journal of Cancer:
Diagnostic yield of a one sample immunochemical test at different cut-off values in an organised screening programme for colorectal cancer

Summary:
The objective target of this evaluation was to check the performance of the quantitative immunochemical test FOB-Gold and to propose a possible strategy for an organized screening programme. Result of this study: a one-sample strategy is preferred and with a recommended cut-off, the overall positivity rate would be manageable in EU countries.

Faivre J. et al. (2012) European Journal of Cancer:
Comparison between a guaiac and three immunochemical faecal occult blood tests in screening for colorectal cancer

Summary:
The objective of this study was to evaluate a guaiac-based (G-) FOBT (Hemoccult-II) versus 3 immunochemical (I-)FOBTs (FOB-Gold, OC-Sensor, Magstream) within the French population-based organized screening programme. The study outcome reveals additional proof that I-FOBTs are superior to the selected G-FOBT whereas none of the 3 applied I-FOBTs pointed out any significant performance advantages towards the others.

Faivre J. et al. (2012) Digestive and Liver Disease:
Positivity rates and performances of immunochemical faecal occult blood tests at different cut-off levels within a colorectal cancer screening programme

Summary:
The goal of this study was to investigate the following approaches: on the one hand a 2-sample strategy with at least one positive test and on the other hand a 1-sample strategy implying various cut-off values for one of the two I-FOBTs (FOB-Gold or OC-Sensor) performed in combination with a G-FOBT (Hemoccult-II). It turned out that using I-FOBTs, an acceptable strategy (for the French CRC screening programme) would be 2-day sampling with at least one positive test at a cut-off between 150-200 ng/mL (OC-Sensor) and 176-234 ng/mL (FOB-Gold).

KRIVEC S. ET AL. (2011) Euromedlab Berlin Poster Presentation:
Assessment of the diagnostic applicability of quantitative immunochemical faecal occult blood (iFOB) test.

Summary:
FOB Gold revealed a sensitivity of 45.2 % and specificity of 92.3 % for significant bowel disease (cancer, polyps or bleeding) using a threshold of 9.35 micrograms Hb/g faeces (55 ng/mL) in a symptomatic patient cohort.

Gastric cancer - Sentinel lymph node analysis by OSNA

SHIMADA A et al. (2020) Gastric Cancer:
Utility of the one-step nucleic acid amplification assay in sentinel node mapping for early gastric cancer patients

Summary:
To perform minimized gastrectomies based on sentinel lymph node concept in early-stage gastric cancer patients, an accurate intraoperative diagnostic method such OSNA is essential. The outcome of this study shows OSNA’s utility in this setting.

YAGUCHI Y et al. (2011) Annals of Surgical Oncology:
One-step nucleic acid amplification (OSNA) for the application of sentinel node concept in gastric cancer

Summary:
First performance evaluation study in gastric cancer in which lymph nodes were analysed by both H&E and OSNA. Results showed that OSNA is a highly sensitive and specific method in detecting nodal metastases and could be applied for the intraoperative diagnosis of sentinel lymph nodes in this cancer entity.

Gynaecological cancer - Sentinel lymph node analysis by OSNA

NOVELLI AA et al. (2021) Facts, Views & Visions in Obgyn:
Diagnostic accuracy and economic impact of three work-up strategies identifying risk groups in endometrial cancer, fully incorporating sentinel lymph node algorithm

Summary:
Accurate determination of pre-operative risk groups in endometrial cancer is crucial as well as agreement on a gold standard work-up strategy to be offered in every oncological center, including the role of sentinel lymph node and its most appropriate examination technique.

FANFANI F et al. (2020) International Journal of Gynecological Cancer:
Standard ultra-staging compared to one-step nucleic acid amplification for the detection of sentinel lymph node metastasis in endometrial cancer patients: a retrospective cohort comparison

Summary:
Higher detection rate of micrometastasis by OSNA when compared to ultra-staging, though both methods showed similar overall rate of sentinel lymph node positivity in endometrial cancer patients.

BIZZARRI N et al. (2020) International Journal of Gynecological Cancer:
Role of one-step nucleic acid amplification (OSNA) to detect sentinel lymph node low-volume metastasis in early-stage cervical cancer

Summary:
Detection rate of micrometastasis with OSNA seems to be slightly higher than with ultra-staging/immunohistochemistry and may indicate a superior accuracy of molecular methods.

RAFFONE A et al. (2019) Pathology & Oncology Research::
Accuracy of One-Step Nucleic Acid Amplification in detecting lymph Node metastases in endometrial cancer

Summary:
OSNA appears to be a highly accurate tool for intraoperative assessment of sentinel lymph node in endometrial cancer.

MONTEROSSI G et al. (2019) International Journal of Gynecological Cancer:
Intra-operative assessment of sentinel lymph node status by one-step nucleic acid amplification assay (OSNA) in early endometrial cancer: a prospective study

Summary:
Data shows correlation between the size of metastasis in the sentinel lymph node (SLN) and non-SLN positivity suggesting that the OSNA results could support surgical tailoring of early-stage EC patients for better risk stratification and individualisation of adjuvant therapy.

KOSTUN J et al. (2019) Journal Surgical Oncology:
One-step nucleic acid amplification vs ultrastaging in the detection of sentinel lymph node metastasis in endometrial cancer patients

Summary:
A combination of OSNA and SLNM approaches in endometrial cancer patients has great potential for the highly sensitive detection of metastatic lymph nodes as well as application of adjuvant therapy.

FANFANI F et al. (2018) PLoS One:
One-Step Nucleic Acid Amplification (OSNA): A fast molecular test based on CK19 mRNA concentration for assessment of lymph-nodes metastases in early stage endometrial cancer

Summary:
OSNA, together with SLNM could represent an efficient intraoperative tool for the selection of early stage endometrial cancer patients to be submitted for systematic lymphadenectomy.

LÓPEZ-RUIZ ME et al. (2016) Gynecological Oncology:
One-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node metastasis in endometrial cancer

Summary:
OSNA allows the analysis of the entire lymph node, thus it avoids missing metastases due to partial tissue analysis by standard H&E examination.

NAGAI T et al. (2015) Gynecological Oncology:
A new diagnostic method for rapid detection of lymph node metastases using a one-step nucleic acid amplification (OSNA) assay in endometrial cancer

Summary:
The OSNA assay using CK19 mRNA is useful for the detection of lymph node metastases in endometrial cancer patients and in combination with SLN may facilitate individualised treatments.

OKAMOTO S et al. (2013) Gynecological Oncology:
Detection of sentinel lymph node metastases in cervical cancer: assessment of KRT19 mRNA in the one-step nucleic acid amplification (OSNA) method

Summary:
OSNA can detect lymph node metastasis as accurately as conventional histopathology and may be an effective method for rapid intraoperative examination of sentinel lymph node in cervical cancer patients.

Liquid biopsy in colorectal cancer

Garcia-Foncillas J. et al. (2018) British Journal of Cancer:
Prospective multicenter real-world RAS mutation comparison between OncoBEAM-based liquid biopsy and tissue analysis in metastatic colorectal cancer

Summary:
This study represents the first prospective RAS mutation performance comparison providing a final concordance of 92% between plasma and tissue samples using the OncoBEAM™ RAS CRC assay (236 mCRC patients). This outcome reveals that the plasma-based OncoBEAM™ RAS CRC assay is a reliable opportunity to detect RAS mutations in order to decide about the rationale of applying anti-EGFR therapy.

Garcia J. et al. (2018) Oncotarget:
Cross-platform comparison for the detection of RAS mutations in cfDNA (ddPCR Biorad detection assay, BEAMing assay, and NGS strategy)

Summary:
This study compared the performance of the OncoBEAM™ RAS CRC IVD assay to ddPCR and NGS for the detection of KRAS/NRAS mutations in plasma from mCRC and NSCLC patients based of the analysis of paired blood and tissue samples. The OncoBEAM™ RAS CRC test revealed higher sensitivity than the two other technologies by testing cfDNA vs tissue analysis in mCRC and NSCLC samples (extended RAS panel) and enabled monitoring of somatic alterations in plasma-derived cfDNA.

Klein-Scory S. et al. (2018) Translational Oncology:
Significance of Liquid Biopsy for Monitoring and Therapy Decision of Colorectal Cancer

Summary:
This study monitored three mCRC patients who initially were RAS WT and demonstrate that follow-up using OncoBEAM RAS testing in plasma provides information about the clonal redistribution after discontinuation of anti-EGFR as well as emerging RAS mutations leading to resistance during anti-EGFR administration. On top of this it has been observed that RAS mutations can even develop in the absence of anti-EGFR therapy pressure.

Garcia-Foncillas J. et al. (2017) Annals of Oncology:
Incorporating BEAMing technology as a liquid biopsy into clinical practice for the management of colorectal cancer patients: an expert taskforce review

Summary:
BEAMing technology for the detection of mutated ctDNA in plasma based on international guideline-recommended expanded RAS testing offers the opportunity of rapid turnaround times, high sensitivity and standardization compared to conventional testing of tissue samples. The high degree of concordance between plasma OncoBEAM RAS testing versus standard tissue testing methods has been shown in several studies. BEAMing posseses the potential to replace tissue biopsy for the detection and monitoring of RAS mutations and enables precision and cost-effective CRC patient management by individualizing treatment plans.

Grasselli J. et al. (2017) Annals of Oncology:
Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in mCRC

Summary:
“Tumor tissue from 146 mCRC patients was tested for RAS status with standard of care (SoC) PCR techniques, and Digital PCR (BEAMing) was used both in plasma and tumor tissue. Plasma RAS determination showed high overall agreement and captured a mCRC population responsive to anti-EGFR therapy with the same predictive level as SoC tissue testing. The feasibility and practicality of ctDNA analysis may translate into an alternative tool for anti-EGFR treatment selection.”

Vidal J. et al. (2017) Annals of Oncology:
Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients

Summary:
RAS in tissue and plasma samples from 115 mCRC patients showed a 93% overall agreement using the OncoBEAM™ RAS CRC assay. Monitoring of RAS ctDNA in patients RAS wt showed that OncoBEAM was useful to detect RAS mutations during anti-EGFR treatment. It was finally concluded that the high overall agreement in RAS mutational assessment between plasma and tissue supports blood-based testing with OncoBEAM™ as a viable alternative for genotyping RAS of mCRC patients and that it is useful to monitor RAS in patients undergoing systemic therapy to detect potential treatment resistances.

Toledo R.A. et al. (2017) Oncotarget:
Clinical validation of prospective liquid biopsy monitoring in patients with wild-type RAS metastatic colorectal cancer treated with FOLFIRI-cetuximab

Summary:
”The current study provides evidences, obtained for the first time in an unbiased and prospective manner, that reinforces the utility of LqB for monitoring mCRC patients.”

Jones F.S. et al. (2016) ASCO:
Performance of Standardized BEAMing Platform for Detecting RAS Mutations in the Blood of Metastatic Colorectal Cancer (mCRC) Patients

Summary:
“The high overall agreement of plasma and tissue RAS testing results (93.3%) demonstrates that blood-based OncoBEAMTM RAS CRC testing is a viable alternative to tissue-based RAS testing. Plasma RAS testing also provides an opportunity to monitor tumor RAS mutation dynamics during therapy in patients with systemic disease.”

Saunders M.P. et al. (2016) ESMO:
Performance assessment of blood based RAS mutation testing: concordance of results obtained from prospectively collected samples

Summary:
“The high overall agreement of plasma and tissue RAS testing results (92.2%) shows that OncoBEAMTM RAS CRC testing is a viable alternative to tissue-based testing in this prospective study. Analysis of discordants shows that differences between plasma and tissue RAS results may arise from tumour heterogeneity, disease evolution, low ctDNA shedding, or low tumour burden.”

Schmiegel W. et al. (2016) Molecular Oncology:
Blood-based detection of RAS mutations to guide anti-EGFR therapy in colorectal cancer patients: Concordance of results from circulating tumor DNA and tissue-based RAS testing

Summary:
”The high concordance of plasma and tissue results demonstrates that blood-based RAS mutation testing is a viable alternative to tissue-based RAS testing.”

Siravegna G. et al. (2015) Nature Medicine:
Clonal Evolution and Resistance to EGFR Blockade in the Blood of Colorectal Cancer Patients

Summary:
Liquid instead of tissue biopsy can be used to closely monitor the dynamic molecular evolution of metastatic colorectal tumors during anti-EGFR therapy in order to identify those patients that benefit from anti-EGFR.

Morelli M.P. et al. (2015) Annals of Oncology:
Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment

Summary:
”Monitoring treatment-induced genetic alterations by sequencing ctDNA could identify biomarkers for treatment screening in anti-EGFR-refractory patients.”

Tabernero J. et al. (2015) The Lancet Oncology:
Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial

Summary:
BEAMing of circulating tumour DNA allowed the non-invasive analysis of tumour genotype in real time and the detection of tumour-associated mutations.

Misale S. et al. (2014) Science Translational Medicine:
Blockade of EGFR and MEK Intercepts Heterogeneous Mechanisms of Acquired Resistance to Anti-EGFR Therapies in Colorectal Cancer

Summary:
Liquid biopsies used for monitoring RAS mutations of mCRC patients on anti-EGFR therapy enable early initiation of combination therapies with MEK inhibitors in order to optimize the therapy success and delay disease progression.

Misale S. et al. (2012) Nature:
Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer

Summary:
“…our results suggest that blood-based non-invasive monitoring of patients undergoing treatment with anti-EGFR therapies for the emergence of KRAS mutant clones could allow for the early initiation of combination therapies that may delay or prevent disease progression.”

Diehl F. et al. (2008) Nature Medicine:
Circulating mutant DNA to assess tumor dynamics

Summary:
“We found that ctDNA measurements could be used to reliably monitor tumor dynamics in subjects with cancer who were undergoing surgery or chemotherapy. We suggest that this personalized genetic approach could be generally applied to individuals with other types of cancer.”

Lung cancer - Lymph node analysis by OSNA

VODICKA J ET AL. (2020) Cells:
Prognostic Significance of Lymph Node Examination by the OSNA Method in Lung Cancer Patients-Comparison with the Standard Histopathological Procedure

Summary:
Lymph nodes are pooled in to 3-5 groups within a framework of a nodal zone and analysed by OSNA. In this setting, the authors proposed a higher nodal zone cut-off for OSNA of 615 copies.

Pérez M et al. (2019) Journal of Translational Medicine:
Detection of lymph node metastasis in lung cancer patients using a one-step nucleic acid amplification assay: a single-centre prospective study.

Summary:
The high sensitivity of OSNA enables detection of tumour cells missed by pathological examinations. These occult metastases may be the key to explaining why some patients classified as pN0 or pN1 after surgery are progressing with worse prognosis

Lymph node localisation in colorectal cancer

Pouw et al. (2016) Colorectal Disease:
Ex vivo sentinel lymph node mapping in colorectal cancer using a magnetic nanoparticle tracer to improve staging accuracy: a pilot study

Summary:
Based on 28 ex-vivo specimens of colorectal cancer, the authors concluded that ex vivo magnetic sentinel lymph node mapping with the Sentimag®/Sienna+® System is a feasible technique, which improves nodal staging accuracy.

https://link.springer.com/chapter/10.1007/978-3-642-12197-5_107 (2010) IFMBE Proceedings:
ten Haken et al. Magnetic Detection of the Sentinel Lymph Node in Ex Vivo Tissue with Colorectal Cancer

Summary:
The experimental approach on ex-vivo specimen indicated that SLN detection with Sentimag® is possible in colon cancer.

Magnetic impalpable lesion localisation

Harvey et al. (2017) ABS Conference:
Magseed – Safety and feasibility study of the use of magnetic marker seeds to localise breast cancers

Summary:
Based on an initial experience in 29 breast cancer patients. All seed were detected and recovered without challenges. The author concluded, that Magseed is a safe and feasible device that offers accurate localisation and logistic enhancements.

Prostate cancer - Lymph node analysis by OSNA

ENGELS S et al. (2021) Cancers:
Evaluation of Fast Molecular Detection of Lymph Node Metastases in Prostate Cancer Patients Using One-Step Nucleic Acid Amplification (OSNA)

Summary:
OSNA identifies nodal metastases at an equivalent or, in cases of micrometastases, better rate than enhanced histological examination in prostate cancer patients and enables reliable intra-operative diagnostics that support personalised lymph node surgery. Molecular nodal analysis may improve nodal staging in prostate cancer while reducing pathologists’ workload, as most processes are automated and can be performed with minimal effort by a skilled technician.

WINTER A et al. (2018) Journal of Cancer:
Detection of CK19 mRNA Using One-step Nucleic Acid Amplification (OSNA) in Prostate Cancer: Preliminary Results

Summary:
Pioneer study in prostate cancer showing that OSNA reliably detected CK-19 mRNA in tumor specimens. Results indicated the promising usage of the OSNA diagnostic test for the detection of lymph node metastases also in this cancer entity.

SafeSEQ NGS liquid biopsy in various cancers

SATHYANARAYAN P. ET AL. (2021) (2021) ELCC Poster Presentation:
Rapid liquid biopsy genotyping in NSCLC patients.

Summary:
SafeSEQ showed equivalent sensitivity to OncoBEAM (overall percent agreement of 99.6%) on 176 stage IV NSCLC patient samples collected prior to/during treatment or at disease progression and assessed with both OncoBEAM (EGFR, KRAS and BRAF V600E) and SafeSEQ (BRAF, EGFR, ERBB2, KRAS, MET, NRAS, PIK3CA and TP53) panel.

SLOANE H. ET AL. (2021) AACR Poster Presentation:
Clinical evaluation of SafeSEQ NGS liquid biopsy testing in non-small cell lung cancer (NSCLC) patients.

Summary:
SafeSEQ demonstrates clinical sensitivity comparable to OncoBEAM, with a strong positive correlation between MAF values and also provides expanded coverage across broader genomic regions, which should better inform treatment selection, improve high resolution monitoring of therapeutic efficacy and enable MRD detection and surveillance for NSCLC patients.

SLOANE H. ET AL. (2021) ASCO Poster Presentation:
Ultra-sensitive detection and quantification of HPV DNA in the plasma of patients with oropharyngeal squamous cell carcinoma (OPSCC) enrolled in the OPTIMA 2 treatment de-escalation trial.

Summary:
SafeSEQ NGS technology for highly sensitive and specific cfHPV-DNA detection was successfully applied to monitor therapeutic response in HPV+ OPSCC patients.

SLOANE H. ET AL. (2021) ASCO Abstract (not selected for Poster):
Tumor-informed SafeSEQ ctDNA monitoring for treatment response evaluation and detection of minimal residual disease in advanced CRC and NSCLC.

Summary:
Personalized SafeSEQ testing was applied for longitudinal ctDNA monitoring as compared to serial multidimensional measures of tumor burden and demonstrated concordant and potentially more rapid identification of therapeutic responses than by radiographic imaging.

ROTH M.T. ET AL. (2021) ASCO Poster Presentation:
A randomized phase III study of immune checkpoint inhibition with chemotherapy in treatment-naïve metastatic anal cancer patients.

Summary:
SafeSEQ NGS technology is utilized to quantify ct-derived HPV16- and HPV18-DNA during treatment meaning to evaluate the role of HPV ctDNA in monitoring treatment response in metastatic SCCA.

HUNTER N. ET AL. (2020) SABCS Abstract:
Pathologic Response Evaluation and Detection in Circulating Tumor DNA (PREDICT DNA): Initial Results Piloting a Tissue-Biopsy Independent Method of Identifying and Monitoring Tumor-Specific Mutations in Early Stage Breast Cancer.

Summary:
The goal was to validate ctDNA as a biomarker for treatment response and recurrence in early stage, triple-neg or HER2-pos (any HR status) BC and to determine NPV of the absence of ctDNA after NAT for achievement of pathologic complete response. SafeSEQ was proven to enable the identification of tumor specific mutations in the plasma in early-stage BC without the need for biopsy tissue.

DUCHSTEIN L. ET AL. (2020) ASH Annual Meeting Presentation::
Ultrasensitive Measurable Residual Disease (MRD) Detection in Acute Myeloid Leukemia (AML) Using a Targeted Next Generation Sequencing (NGS) Panel.

Summary:
The SafeSEQ AML MRD assay demonstrates ultra-sensitive detection of low frequency mutations, with a calling threshold of 5 MM (0.025% MAF) while specificity remains very high. SafeSEQ versus BEAMing dPCR technology concordance was shown to have 100% overall agreement in 50 patient samples.

CIRIACO N. ET AL. (2020) AACR Poster Presentation:
Clearance of ctDNA in triple-negative and Her2-positive breast cancer patients during neoadjuvant treatment is correlated with pathologic complete response.

Summary:
SafeSEQ was used to assess ctDNA clearance during NAT as a correlate to effective response to treatment as benchmarked by clinical complete response (cCR) and pathological complete response. Absence of ctDNA following NAT was observed in 100% of cCR patients, indicating a favorable correlation with effective NAT response.

WANG Y. ET AL. (2019) JAMA Oncology:
Prognostic Potential of Circulating Tumor DNA Measurement in Postoperative Surveillance of Nonmetastatic Colorectal Cancer.

Summary:
Serial ctDNA monitoring using SafeSEQ technology detected disease recurrence in resectable CRC earlier compared with conventional postoperative surveillance strategies and could serve as a triage test to stratify those patients on the basis of risk of disease recurrence.

TIE J. ET AL. (2019) JAMA Oncology:
Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer.

Summary:
It was concluded that applying SafeSEQ for ctDNA analysis after surgery is a promising prognostic marker in stage III colon cancer whereas ctDNA analysis after chemotherapy could characterize a patient group remaining at high risk of recurrence although having received adjuvant treatment.

RUGO H. ET AL. (2019) AACR Abstract:
Palbociclib in Combination with Fulvestrant or Tamoxifen as Treatment for Hormone Receptor Positive (HR+) Metastatic Breast Cancer (MBC) with Prior Chemotherapy for Advanced Disease (TBCRC 035) A Phase II Study with Pharmacodynamics Markers.

Summary:
The SafeSEQ BC panel was compared to BEAMing dPCR applied on a subset of 69 breast cancer patient samples (52 with detected mutations and 17 without mutations in cfDNA) showing excellent correlation in plasma samples obtained prior to therapy.

RODRIGUEZ B. ET AL. (2019) Journal of Clinical Medicine:
Detection of TP53 and PIK3CA Mutations in Circulating Tumor DNA Using Next-Generation Sequencing in the Screening Process for Early Breast Cancer Diagnosis.

Summary:
ctDNA analysis with SafeSEQ could be used in early BC diagnosis before any invasive diagnostic procedure or treatment, providing critical clinical information to improve diagnosis and may reflect PIK3CA/ TP53 tumor-derived mutations present in very early BC patients.

FOSTIRA F. ET AL. (2019) ESMO Poster Presentation:
Blood-Based Testing of Mutations in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC) Using Highly Sensitive SafeSEQ Technology.

Summary:
Plasma mutation detection with SafeSEQ was done in locally advanced and metastatic HNSCC patient samples, compared to tissue mutation status and judged to be useful in HNSCC for molecular profiling and real-time disease monitoring.

LEE B. ET AL. (2019) Annals of Oncology:
Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer.

Summary:
SafeSEQ ctDNA analysis in localized pancreatic cancer (pre- and post-operatively) for mutations at codon 12, 13 and 61 of KRAS was shown to have prognostic value. Patients with detectable ctDNA post-operatively appear to have a very high risk of recurrence despite adjuvant therapy.

RODRIGUEZ B. ET AL. (2018) ASCO Poster Presentation:
Plasma sequencing of ctDNA in early stage breast cancer as part of the screening process.

Summary:
SafeSEQ was applied to detect ctDNA in early-stage BC patients compared to tissue analysis and revealed a trend for higher plasma mutant allele burden in patients with clinical characteristics associated with more aggressive disease (tumor grade, Ki67%, luminal B vs luminal A).

WANG Y. ET AL. (2018) Science Translational Medicine:
Evaluation of Liquid from the Papanicolaou Test and Other Liquid Biopsies for the Detection of Endometrial and Ovarian Cancers.

Summary:
SafeSEQ technology was used for all sequencing analyses (18 genes of interest) on Pap brush samples leading to results which demonstrate the potential of mutation-based diagnostics to detect gynecologic cancers at a stage when they are more likely to be curable.

COHEN J.D. ET AL. (2018) Science:
Detection and Localization of Surgically Resectable Cancers with a Multi-Analyte Blood Test.

Summary:
Patented SafeSEQ technology (designed 61-amplicon panel with 16 genes) represents the basis of the CancerSEEK approach for the detection of gene mutations via a new multi-analyte blood test that can detect the presence of eight common solid tumor types.

COHEN J.D. ET AL. (2017) Proceedings of the National Academy of Sciences:
Combined Circulating Tumor DNA and Protein Biomarker-Based Liquid Biopsy for the Earlier Detection of Pancreatic Cancers.

Summary:
KRAS gene (codons 12 and 61) which is most frequently mutated in PDAC and TP53 were chosen for the specific design of the SafeSEQ panel to be applied for the early detection of pancreatic cancer.

ANGLESIO M.S. ET AL. (2017) New England Journal of Medicine:
Cancer-Associated Mutations in Endometriosis without Cancer.

Summary:
SafeSEQ was used as an error reduction technology for fixed tissues and low frequency mutations to validate the driver mutations detected by exome sequencing in patients with endometriosis without cancer.

TIE J. ET AL. (2016) Science Translational Medicine::
Circulating Tumor DNA Analysis Detects Minimal Residual Disease and Predicts Recurrence in Patients with Stage II Colon Cancer.

Summary:
For designed personalized ctDNA analysis (tumour-informed) SafeSEQ technology was chosen to achieve error reduction for detection of low-frequency mutations. In 230 stage II colon cancer patients ctDNA detection using SafeSEQ after resection provides information on residual disease and high risk of recurrence.

FREDEBOHM J. ET AL. (2016) AACR Poster Presentation:
Performance Assessment of Highly Sensitive NGS Assay for TP53.

Summary:
SafeSEQ was designed to detect de novo mutations in the TP53 gene using wild-type DNA spiked with synthetic mutant DNA.

FREDEBOHM J. ET AL. (2016) Circulating Nucleic Acids in Serum and Plasma – CNAPS IX:
Detection and Quantification of KIT Mutations in ctDNA by Plasma Safe-SeqS.

Summary:
The performance of the SafeSEQ technology, designed to detect de novo mutations in the KIT gene, was assessed by testing plasma samples of GIST patients before and after treatment with regorafenib.

COWAN M. ET AL. (2016) Modern Pathology:
High Prevalence of TERT Promoter Mutations in Primary Squamous Cell Carcinoma of the Urinary Bladder.

Summary:
Tissue samples deriving from bladder cancer patients were analyzed by SafeSEQ which better discriminates genuine TERT-mutations from artefactual sequencing variants introduced during the sequencing process.

COWAN M. ET AL. (2016) Human Pathology:
Detection of TERT Promoter Mutations in Primary Adenocarcinoma of the Urinary Bladder.

Summary:
TERT-mutation sequencing analysis was performed using SafeSEQ technology out of tissue samples from bladder cancer patients.

TIE J. ET AL. (2015) Annals of Oncology:
Circulating Tumor DNA as an Early Marker of Therapeutic Response in Patients with Metastatic Colorectal Cancer.

Summary:
One of the mutations identified in tumour tissue (15 gene panel) deriving from mCRC patients was then assessed in plasma by SafeSEQ, a massively parallel sequencing-based technology that enables the detection of low-frequency mutations (tissue-plasma concordance of 92.3%). SafeSEQ can be used to monitor early changes in ctDNA during 1st-line chemotherapy which can predict the later radiologic response.

JEFFERS M. ET AL. (2015) European Cancer Congress Poster Presentation:
Tumor genotyping and clonal evolution in KIT during regorafenib treatment in the phase 3 GRID study of regorafenib vs placebo in tyrosine kinase inhibitor (TKI)-refractory GIST.

Summary:
Mutation detection with SafeSEQ covered KIT exons 8–18 and was applied in a subset of plasma samples examined as well via BEAMing (concordance of 85% in 15 patients). It was concluded that SafeSEQ is at least as sensitive as BEAMing in detecting KIT mutations from plasma samples and on top allows the detection of primary KIT mutations that had not been evaluated by BEAMing and additional novel KIT mutations for a more thorough correlative analysis.

KINDE I. ET AL. (2013) Science Translational Medicine:
Evaluation of DNA from the Papanicolaou Test to Detect Ovarian and Endometrial Cancers.

Summary:
To define the percentage of mutant alleles in liquid Pap smear specimens, SafeSEQ was designed to assess a 12 gene panel and could be used in a screening setting without previous knowledge of the tumor’s genotype (early detection of gynecologic malignancies).

KINDE I. ET AL. (2011) Proceedings of the National Academy of Sciences:
Detection and Quantification of Rare Mutations with Massively Parallel Sequencing.

Summary:
This background technology paper illustrates the utility of SafeSEQ which consists of the assignment of a unique identifier (UID) to each template molecule, the amplification of each uniquely tagged template molecule to create UID families and redundant sequencing of the amplification products. PCR fragments with the same UID are considered as “supermutants” only if ≥ 95% of them contain the identical mutation.

Sentinel lymph node localisation in prostate cancer

Winter et al. (accepted) European Urology:
Magnetic Resonance Imaging of Sentinel Lymph Nodes Using Intraprostatic Injection of Superparamagnetic Iron Oxide Nanoparticles in Prostate Cancer Patients: First-in-human Results.

Summary:
The study in 50 patients with prostate cancer provided high sensitivity results in sentinel lypmph node biopsy with the Sentimag®/Sienna+® System and can be performed by an urologist alone.

WINTER A et al. (2018) Journal of Cancer:
Detection of CK19 mRNA Using One-step Nucleic Acid Amplification (OSNA) in Prostate Cancer: Preliminary Results

Summary:
Pioneer study in prostate cancer showing that OSNA reliably detected CK-19 mRNA in tumor specimens. Results indicated that the promising usage of OSNA assay for the detection of lymph node metastases also in this cancer entity.

Winter et al. (2017) Current Opinion in Urology:
Sentinel lymph node surgery in prostate cancer using magnetic particles

Summary:
In this review it was concluded that SPION-MRI, combined with a hand-held magnetometer (Sentimag), provides a nonradioactive technique for preoperative and intraoperative SLN localization. Compared with ePLND, sPLND provides increased diagnostic value and supports the individualized extension of PLND using sPLND in prostate cancer.

Winter et al. (2017) Molecules:
Magnetic Marking and Intraoperative Detection of Primary Draining Lymph Nodes in High-Risk Prostate Cancer Using Superparamagnetic Iron Oxide Nanoparticles: Additional Diagnostic Value?

Summary:
By using the Sentimag®/Sienna+® System in 104 patients with prostate cancer, the authors demonstrate the high sensitivity and additional diagnostic value of magnetometer-guided sentinel lymph node biopsy, exceeding that of ePLND.

Stanik et al. (2017) European Urology Supplements:
Sentinel lymph node dissection in prostate cancer using superparamagnetic particles of iron oxide: Early clinical experience.

Summary:
Based on 20 patients with prostate cancer, the authors state, that the Sentimag®/Sienna+® method provides results comparable to radiotracer with the avoidance of radioactivity and preoperative imaging.

Winter et al. (2014) Annals of Surgical Oncology:
A novel method for intraoperative sentinel lymph node detection in prostate cancer patients using superparamagnetic iron oxide nanoparticles and a handheld magnetometer: the initial clinical experience.

Summary:
First data of 20 patients with prostate cancer indicate that the sentinel lymph node biopsy with Sentimag®/Sienna+® is a simple, radiation-free, safe, feasible, and reliable method.

sentinel lymph node localisation in breast cancer

Karakatsanis et al. (2017) British Journal of Surgery:
Superparamagnetic iron oxide nanoparticles as the sole method for sentinel node biopsy detection in patients with breast cancer

Summary:
This study in 338 breast cancer patients showed that the use of SPIO is easy and can be performed by the surgeon alone. Detection rates in Sentinel Lymph Node Biopsy are comparable to the dual technique.

Karakatsanis A. et al. (2016) Breast Cancer Research and Treatment:
The Nordic SentiMag trial: a comparison of super paramagnetic iron oxide (SPIO) nanoparticles versus Tc99 and patent blue in the detection of sentinel node (SN) in patients with breast cancer and a meta-analysis of earlier studies

Summary:
“SPIO is an effective method for the detection of SN in patients with breast cancer. It is comparable to the standard technique and seems to simplify logistics.”

Teshome M. et al. (2016) Annals of Surgical Oncology:
Use of a Magnetic Tracer for Sentinel Lymph Node Detection in Early-Stage Breast Cancer Patients: A Meta-analysis

Summary:
Sentinel Lymph node detection with Sienna+® revealed non-inferior performance to the standard method in breast cancer patients with clinically node-negative status.

Houpeau J.L. et al. (2015) Journal of Surgical Oncology:
Sentinel lymph node identification using superparamagnetic iron oxide particles versus radioisotope: The French Sentimag feasibility trial

Summary:
Sentinel lymph node detection with Sienna+ is seen as a feasible method and a promising alternative to radiotracer. A beneficial potential was identified for ambulatory surgery or sites without nuclear medicine departments.

Ghilli M. et al. (2015) European Journal of Cancer Care:
The superparamagnetic iron oxide tracer: a valid alternative in sentinel node biopsy for breast cancer treatment

Summary:
Sentimag® was identified as safe with non-inferior performance compared to the radiotracer. The Sentimag® technique can be applied after a minimum learning curve. Especially when nuclear medicine units are not available, the magnetic detection provides an effective treatment of breast cancer patients.

Piñero-Madrona et al. (2015) European Journal of Surgical Oncology:
The superparamagnetic iron oxide as a tracer for sentinel node biopsy in breast cancer: A comparative non-inferiority study

Summary:
This study showed non-inferiority of the Sentimag technique compared to radiotracer. Ex-vivo and intraoperative detection rates at the node level were found to be slightly higher with Sentimag.

Rubio I.T. et al. (2014) European Journal of Surgical Oncology:
The superparamagnetic iron oxide is equivalent to the Tc99 radiotracer method for identifying the sentinel lymph node in breast cancer

Summary:
Detection of SLNs with SPIO was not inferior to radiotracer. Procedure is safe, reliable and facilitates patients and OR management.

Thill M. et al. (2014) The Breast:
The Central-European SentiMag study Sentinel lymph node biopsy with superparamagnetic iron oxide (SPIO) vs. radioisotope

Summary:
“We obtained convincing results that magnetic SLNB can be performed easily, safely and equivalently well in comparison to the radiotracer method.”

Douek M. et al. (2013) Annals of Surgical Oncology:
Sentinel Node Biopsy Using a Magnetic Tracer Versus Standard Technique: The SentiMAG Multicentre Trial

Summary:
Sentimag/Sienna+ is a feasible technique for SLNB. The identification rate is not inferior to the standard.

Platelets

Fluorescence platelets (PLT-F)

Tantanate C et al. (2019) Scand J Clin Lab Invest; 79(3):160:
Analytical performance of automated platelet counts and impact on platelet transfusion guidance in patients with acute leukemia.

Summary:
In this study the performance of impedance platelet counting using PLT-I, LH-750 (PLT-LH), as well as PLT-F was analysed in patients with acute leukaemia. PLT-F demonstrated an excellent performance for the identification of thrombocytopenia and had the lowest rate of under transfusion. Additionally, the authors found that a high blast count is associated with inaccurate PLT-LH and PLT-I counts.

Tantanate C et al. (2017) Arch Pathol Lab Med; 141(6): 830:
Performance Evaluation of Automated Impedance and Optical Fluorescence Platelet Counts Compared With International Reference Method in Patients With Thalassemia.

Summary:
PLT-I, PLT-O and PLT-F were compared with CD41/CD61 immune flow cytometry in thalassaemia patients. PLT-O and PLT-F had better correlations with flow cytometry than PLT-I and PLT-F had a better specificity for detection of PLT counts below 100,000/μL in this study.

Wada A et al. (2015) PLoS One; 10(10):
Accuracy of a New Platelet Count System (PLT-F) Depends on the Staining Property of Its Reagents.

Summary:
The study showed that the PLT-F reagent labels intracellular structures within platelets and confirms previous findings that it strongly marks CD41/CD61-positive platelets.

Park SH et al. (2015) Ann Lab Med; 34(6): 471:
The Sysmex XN-2000 Hematology Autoanalyzer Provides a Highly Accurate Platelet Count than the Former Sysmex XE-2100 System Based on Comparison with the CD41/CD61 Immunoplatelet Reference Method of Flow Cytometry.

Summary:
PLT-F counts from the XN-Series were more accurate than PLT-O counts from the XE-series when compared with the CD41/CD61 immunoplatelet reference method in this study.

Tailor H et al. (2014) Hospital Health Care Europe (HHE); 2:181:
Evaluating platelet counting on a new automated analyser.

Summary:
The PLT-F channel of the XN-Series shows excellent precision and accuracy even in abnormal samples or samples with fragmented red cells, large platelets and low PLT counts when compared to the reference flow cytometric method in this evaluation study.

Tanaka Y et al. (2014) J Clin Lab Anal; 28(5): 341:
Performance Evaluation of Platelet Counting by Novel Fluorescent Dye Staining in the XN-Series Automated Hematology Analyzers.

Summary:
Compared to PLT-I and PLT-O counts, PLT-F had the best correlation with CD61-immunoplatelet counts. PLT-F counts were not affected by WBC fragments in two acute leukaemia patients or by RBC fragments and microcytes in a burn injury patient.

Schoorl M et al. (2013) Am J Clin Pathol;140: 495:
New fluorescent method (PLT-F) on Sysmex XN2000 hematology analyzer achieved higher accuracy
in low platelet counting.

Summary:
The PLT-F method of the XN-2000 demonstrated excellent reproducibility in samples with low platelet counts. Therefore, the authors recommended it for making decisions about platelet transfusions.

General

Tabata M et al. (2024) Clin Chem Lab Med; online ahead of print:
Performance evaluation and user experience of BT-50 transportation unit with automated and scheduled quality control measurements.

Summary:
The authors evaluated the performance of the BT-50 and the manual method using XN Check Levels 1, 2 and 3 and the results were equivalent. For PLT, BT-50 showed lower variability compared to the manual method. The BT-50 streamlined the workflow, reduced operator workload and provided standardised control measurements.

Lunde HE et al. (2022) Int J Lab Hematol; 44(5): 854:
The diagnostic accuracy of Sysmex XN for identification of pseudothrombocytopenia using various thresholds for definition of platelet aggregation.

Summary:
The diagnostic accuracy of the flag PLT Clumps from PLT-F channel for identification of pseudothrombocytopenia was very high (AUC = 0.97) and superior to the WNR/WDF channel (AUC = 0.57) in samples with platelet count <150 x 10^9/L and a moderate to high number of aggregates in the smear.

Shaikh MS et al. (2021) Int J Lab Hematol; 43(3): e141:
Ensuing adequate mixing of blood samples before analysis—A proposed method for verification of satisfactory sample mixing by automated red blood cell count analyzers.

Summary:
The authors report an excellent correlation (r value of 0.99) between manual and automated blood sample mixing with a minimal bias (0.009), proving an exceptional pre-analysis mixing of samples on the XN-1000 analyser.

Ortiz A et al. (2020) Sysmex J Int; 30(1): 9:
Performance Comparison of Sysmex Hematology Analyzers XN-550 and XN-10.

Summary:
According to the authors XN-550 is highly reliable with functionality comparable to the XN-10. It has shown high correlation coefficients and excellent comparative performance in all CBC, DIFF and RET parameters (except BASO%). In this study the overall flagging comparison was excellent among the XN-10, the XN-550 and the manual differential.

Cao J et al. (2017) Lab Med; 48(2): 188:
Establishing a Stand-Alone Laboratory Dedicated to the Care of Patients With Ebola Virus Disease.

Summary:
The pocH-100i was used in a laboratory dedicated to detection of Ebola virus disease. Its accuracy was verified by comparison with the XE-2100 in the main laboratory, and precision and reportable range were also consistent with specifications by the manufacturer.

Cornet E et al. (2016) Scand J Clin Lab Invest; 76(6): 465:
Evaluation and optimization of the extended information process unit (E-IPU) validation module integrating the sysmex flag systems and the recommendations of the French-speaking cellular hematology group (GFHC).

Summary:
Using the biomedical validation criteria, 21.3 % of samples triggered a smear review in this study. Modification of four criteria reduced the number of smears from 21.3 % to 15.0 % without losing clinical value.

Van Dievoet MA et al. (2016) Int J Lab Hematol; 38(5): 490:
Performance evaluation of the Sysmex® XP-300 in an oncology setting: evaluation and comparison of hematological parameters with the Sysmex® XN-3000.

Summary:
The XP-300 showed very good precision and linearity results in this study, comparable with the XN-3000 analyser.

SEO JY et al. (2015) Int J Lab Hematol; 37(2): 155:
Performance evaluation of the new hematology analyzer Sysmex XN-series.

Summary:
In this study, a good correlation was found between the XN-Series and XE-series for all parameters. The XN-Series dramatically reduced the smear rate (by 58 %). Even at counts below 500/μL the XN provided an accurate WBC count using the Low WBC mode.

Arneth B et al. (2015) J Clin Lab Anal; 29(3): 175:
Technology and New Fluorescence Flow Cytometry Parameters in Hematological Analyzers.

Summary:
This paper gives a good overview of the technology behind the XE-series and the benefits of flow cytometry and automatic cell counting. It shows that the XE-5000 delivers faster accurate results than older analysers.

Genevieve F et al. (2014) feuillets de Biologie; VOL LVI N° 317:
Smear microscopy revision: propositions by the GFHC.

Summary:
The GFHC reviewed in detail the criteria used within the CBC to generate blood smears and has decided on a number of minimum recommendations, defining threshold values and various situations in which the blood smear review is desirable.

Briggs C et al. (2012) J Clin Pathol; 65:1024:
Performance evaluation of the Sysmex haematology XN modular system.

Summary:
The XN showed reduced sample turnaround time and reduced number of blood film reviews compared to the XE-2100 without loss of sensitivity and with more precise and accurate results for both platelets and low WBC counts.

Immature platelet fraction (IPF)

Kouno H et al. (2023) Int J Lab Hematol; 45(5): 700:
Measurement of immature platelet fraction is useful in the differential diagnosis of MYH9 disorders.

Summary:
The study found that a median IPF of 48.7% in MYH9 disorders was significantly higher than in all other groups (ITP: 13.4%, MDS: 9.4%, control group: 2.6%). The authors concluded that IPF could be a useful supportive parameter in the differential diagnosis between MYH9 disorders and other types of thrombocytopenia.

Anetsberger A et al. (2023) Platelets; 34(1): 2185462:
Association of immature platelets with perioperative complications in neurosurgery.

Summary:
The study on 301 subjects revealed that increased levels of highly fluorescent immature platelets measured postoperatively (H-IPF ≥ 0.95%) are independently associated with an increased risk for serious complications after neurosurgical procedures (odds ratio: OR = 1.97).

Bongiovanni D et al. (2023) Arterioscler Thromb Vasc Biol; 43(2): e83:
Immature Platelet Fraction Predicts Adverse Events in Patients With Acute Coronary Syndrome: the ISAR-REACT 5 Reticulated Platelet Substudy.

Summary:
In acute coronary syndrome treated patients the incidence of the primary end point consisting of death, myocardial infarction or stroke was significantly higher in the IPF-high (IPF>3.6%) group compared to the IPF-low (IPF≤3.6%) group: 13.0% versus 7.2% regardless of the antiplatelet treatment used (prasugrel or ticagrelor).

Bongiovanni D et al. (2022) Arterioscler Thromb Vasc Biol; 42(5): 527:
Role of Reticulated Platelets in Cardiovascular Disease.

Summary:
The authors present a structured overview of preclinical and clinical findings concerning the role of reticulated platelets in cardiovascular disease. They conclude that reticulated platelets with their prothrombic features are a new biomarker that helps to identify patients at high risk for adverse ischemic events.

Jones N et al. (2021) Platelets; 7: 32(7): 941:
Immature platelet indices alongside procalcitonin for sensitive and specific identification of bacteremia in the intensive care unit.

Summary:
The study results demonstrate the predictive power of IPF and IPF# for identification of bacteremia in ICU patients as individual parameters and even more by calculating the change in these parameters between day 1 and 2 of ICU stay (ΔIPF, ΔIPF#). The use of a combination of ΔIPF (cut-off > 1.95%) and day 2 PCT (cut-off > 0.57 ng/ml) has a PPV of 100% and a NPV of 96.1% and thereby accurately ruling out patients from a diagnosis of bacteremia.

Looi K et al. (2021) Int J Inf Dis; 110: 187:
Evaluation of immature platelet fraction as a marker of dengue fever progression.

Summary:
This study evaluated the trend of immature platelet fraction (IPF) as an early recovery indicator of platelets in dengue patients. Patients with severe dengue had higher IPF and stronger thrombocytopenia compared to non-severe dengue. The increase in IPF preceded platelet recovery by at least 3 days.

Zhao Y et al. (2020) Front Cardiovasc Med; 7: 578041:
The Prognostic Value of Reticulated Platelets in Patients With Coronary Artery Disease: A Systematic Review and Meta-Analysis.

Summary:
This comprehensive meta-analysis presents immature platelets as a potentially useful prognostic biomarker for adverse cardiovascular events in patients with coronary artery disease, even after adjustment for other prognostic factors.

Benlachgar N et al. (2020) Thromb Res; 195: 43:
Immature platelets: a review of the available evidence.

Summary:
The authors summarized literature evidence about IPF%, # focussing on reference values, stability, correlation of IPF and MPV, and contribution of IPF to haematological and non-haematological disorders such as ITP, TTP, disseminated intravascular disorder, aplastic anaemia, MDS and cardiovascular disease, and on IPF in chemotherapy and stem cell transplantation.

Buttarello M et al. (2020) Int J Lab Hematol; 42(4): 363 (IPF):
Reticulated platelets and immature platelet fraction: Clinical applications and method limitations

Summary:
Thorough review about reticulated platelets and immature platelet fraction including overview of preanalytical and analytical limitations of methods and clinical applications.

Jeon MJ et al. (2020) Korean J Intern Med; 35(4): 970:
Immature platelet fraction based diagnostic predictive scoring model for immune thrombocytopenia.

Summary:
The authors concluded that immature platelet fraction (IPF) could be a useful parameter to distinguish immune thrombocytopenia (ITP) from other causes of thrombocytopenia. They developed the predictive scoring model that could predict ITP with high probability.

Jeon K et al. (2020) Medicine (Baltimore); 99(7): e19096:
Immature platelet fraction: A useful marker for identifying the cause of thrombocytopenia and predicting platelet recovery.

Summary:
The authors demonstrated that the IPF is an excellent marker for distinguishing hyperdestructive/consumptive from hypoproductive thrombocytopenia. Moreover, IPF is presented as a robust and reliable predictor of platelet recovery in patients with immune thrombocytopenia (ITP) and with malignancies undergoing chemotherapy.

El-Gamal RA et al. (2020) Indian J Hematol Blood Transfus; 36(2): 316:
Combined Immature Platelet Fraction and Schistocyte Count to Differentiate Pregnancy-Associated Thrombotic Thrombocytopenic Purpura from Severe Preeclampsia/Haemolysis, Elevated Liver Enzymes, and Low Platelet Syndrome (SPE/HELLP).

Summary:
This study concluded that IPF and manual schistocyte counts can assist in differentiating pregnancy-associated severe pre-eclampsia/haemolysis, elevated liver enzymes and low platelet syndrome (SPE/HELLP) from thrombotic thrombocytopenic purpura (TTP). The model based on combination of parameters had a good predictive value to discriminate TTP from SPE/HELLP - sensitivity of 92.3%, specificity of 62.5% and AUC 0.827.

Perl L et al. (2019) Platelets; 17:1:
Prognostic significance of reticulated platelet levels in diabetic patients with stable coronary artery disease.

Summary:
In stable coronary artery disease patients with diabetes the increased level of immature platelets (IPF) show an association with a higher risk of major adverse cardiovascular events and inversely correlated with the risk of bleeding.

Thorup C et al. (2019) Semin Thromb Hemost; 46(3): 320:
Immature Platelets As a Predictor of Disease Severity and Mortality in Sepsis and Septic Shock - A Systematic Review.

Summary:
Based on nine studies the review highlighted that an increased number of immature platelets is associated with increase disease severity and mortality in patients with sepsis and septic shock.

Bernstein U et al. (2019) Arch Gynecol Obstet; 299(6): 1537:
The immature platelet fraction in hypertensive disease during pregnancy

Summary:
This study shows that IPF% can be used to identify hypertensive diseases in pregnancy. Moreover, the absolute number of IPF and platelets could help to differentiate preeclampsia and HELLP syndrome.

van De Wyngaert Z et al. (2019) Curr Res Transl Med; 68(1):37:
Immature platelet fraction (IPF): A reliable tool to predict peripheral thrombocytopenia.

Summary:
This retrospective study found that IPF higher than 13 % is predictive of peripheral thrombocytopenia. In isolated thrombocytopenia bone marrow aspiration could have been avoided in 66 % of patients in this study cohort.

Johnson S et al. (2019) Int J Lab Hematol; 41(2): 271:
A CBC algorithm combined with immature platelet fraction is able to identify JAK2 V617F mutation-positive polycythaemia vera patients.

Summary:
The study proposes an algorithm based on CBC and IPF# parameters that allows to identify a cohort of high-likelihood polycythaemia vera (PV) patients and refer them for haematological review. IPF# > 20 ×109/L in combination with positive CBC criteria can identify JAK2 V617F mutation-positive PV patients.

Ali I et al. (2019) Exp Haematol; 78: 56:
Immature platelet fraction as a useful marker in the etiological determination of thrombocytopenia.

Summary:
In this study, the IPF was assessed to determine the aetiology of thrombocytopenia, in a relatively large cohort (n=637). The IPF was significantly higher in cases of increased platelet consumption or pseudothrombocytopenia compared with the control, and was able to discriminate idiopathic thrombocytopenic purpura (ITP) (p<0.05) from other causes of increased platelet consumptive disorders (infection, haemorrhage).

Buoro S et al. (2018) J Clin Pathol.; 71(4): 330:
Innovative haematological parameters for early diagnosis of sepsis in adult patients admitted in intensive care unit.

Summary:
The authors concluded that a combination of an increased IPF# value and a decreased RET% value 24 hours before the onset of sepsis in ICU patients can be considered an early, rapid, cost-effective and widely available measure for sepsis prediction.

Sakuragi M et al. (2018) Int J Hematol; 107(3): 320:
Immature platelet fraction (IPF) as a predictive value for thrombopoietic recovery after allogeneic stem cell transplantation.

Summary:
In this study IPF was able to predict platelet recovery in patients after allogeneic haematopoietic stem cell transplantation in 5 out of 11 patients, while IPF# predicted recovery in 7 out of 11 patients, at cut-offs of 5.8 % and 200/μL, respectively.

Hannawi B et al. (2018) Thromb Haemost; 118(9): 1517:
Reticulated Platelets - Changing Focus from Basics to Outcomes.

Summary:
The authors discussed the role of reticulated platelets in coronary artery disease and in hypo responsiveness to the commonly used anti-platelet drugs. They concluded that reticulated platelets may be a useful marker for predicting worse cardiovascular outcome.

Pedersen OH et al. (2017) Am J Case Rep; 18: 945:
Recurrent Cardiovascular Events Despite Antiplatelet Therapy in a Patient with Polycythemia Vera and Accelerated Platelet Turnover.

Summary:
The case report illustrates that insufficient platelet inhibition with clopidogrel monotherapy in a patient with thrombocytosis may be associated with recurrent arterial thrombosis. A plausible explanation may be an accelerated platelet turnover reflected by an increased number of immature platelets.

Anetsberger A et al. (2017) Thromb Haemost; 117(10): 1887:
Immature platelets as a novel biomarker for adverse cardiovascular events in patients after non-cardiac surgery.

Summary:
In this study, IPF presented as an independent predictor of serious adverse cardiovascular events, deep vein thrombosis or pulmonary embolism (modMACE) after non-cardiac surgery using the optimal cut-off value of > 5.4 % and improves risk stratification of surgical patients.

Ferreira FLB et al. (2017) Sci Rep; 7(1): 3355:
Evaluation of the immature platelet fraction contribute to the differential diagnosis of hereditary, immune and other acquired thrombocytopenias.

Summary:
The authors evaluated the use of IPF in the differential diagnosis between ITP and hereditary macrothrombocytopenia (HM). The IPF values were higher in HM than in ITP as already demonstrated by other studies.

Freynhofer MK et al. (2017) Thromb Haemost; 117(5): 923:
Platelet turnover predicts outcome after coronary intervention.

Summary:
In this study an elevated platelet turnover independently predicted major adverse cardiovascular events after percutaneous coronary intervention. The optimal cut-off value was at IPF = 3.35 %.

Buoro S et al. (2017) Scand J Clin Lab Invest; 77(1): 73:
Abnormal leukocyte scattergrams and immature platelet fraction on Sysmex XN-9000 analyzer: a new diagnostic tool for altered megakaryopoiesis?

Summary:
This case report shows how a high IPF, combined with abnormal WNR, WDF and WPC scattergrams could be used as a marker of dysmegakaryopoiesis, and led to the diagnosis of MDS type 2-refractory anaemia with excess blasts (REAB-2) in a nine year-old girl.

Jaing TH et al. (2016) Cell Transplant; 25: 1259:
Assessment of platelet activation and immature platelet fraction as predictors of platelet engraftment after hematopoietic stem cell transplantation.

Summary:
In this study IPF (XE-2100) was used to assess thrombopoietic recovery after stem cell transplantation. Patients in the cord blood group had a higher IPF than the peripheral blood group on day 56 and day 97 post-transplantation.

Cremer M et al. (2016) Seminars in Fetal & Neonatal Medicine; 21(1): 10:
Thrombocytopenia and platelet transfusion in the neonate.

Summary:
The review summarises the pathophysiology and current management (including platelet transfusion thresholds) of neonatal thrombocytopenia. A novel index score for bleeding risk in thrombocytopenic neonates was proposed (including IPF#).

Moraes D et al. (2016) Platelets; 27(4): 333:
Immature platelet fraction in hypertensive pregnancy.

Summary:
In this study IPF% measured on the XE-5000 exhibited higher values in pregnant women suffering hypertensive disorders than the control group.

Hong H et al. (2015) Transfusion; 55(4): 756:
Absolute immature platelet count dynamics in diagnosing and monitoring the clinical course of thrombotic thrombocytopenic purpura.

Summary:
In this study absolute IPF count (from XE-5000) was shown to be useful to diagnose and to monitor the clinical course of therapeutic plasma exchange in TTP patients. Routine analysis of absolute IPF count was recommended for diagnosis and to better assess the need for adjustment of treatment.

Sakuragi M et al. (2015) Int J Hematol; 101(4): 369:
Clinical significance of IPF% or RP% measurement in distinguishing primary immune thrombocytopenia from aplastic thrombocytopenic disorders.

Summary:
IPF% (XN-1000) and RP% (flow cytometry) exhibited comparable diagnostic accuracy in differentiating control patients, immune thrombocytopenia, and aplastic thrombocytopenia in this study.

Mao W et al. (2015) Clin Res Hepatol Gastroenterol; 39(4): 469:
Immature platelet fraction values predict recovery of platelet counts following liver transplantation.

Summary:
In this study, the IPF percentage was shown to predict recovery of PLT numbers after liver transplantation. PLT counts reached the pre-transplant levels at 3-4 days after the IPF% peak value.

Miyazaki K et al. (2015) Hematology; 20(10): 587:
Immature platelet fraction measurement is influenced by platelet size and is a useful parameter for discrimination of macrothrombocytopenia.

Summary:
The IPF% values were about five times higher in May-Hegglin disorders (IPF 48.6 ± 1.9 %) and about twice as high in other macrothrombocytopenias (IPF 18.4 ± 2.1 %) than in ITP patients with similar platelet counts (IPF 9.2 ± 0.3 %).

Adly AA et al. (2015) Platelets; 26(7): 645:
Evaluation of the immature platelet fraction in the diagnosis and prognosis of childhood immune thrombocytopenia.

Summary:
IPF% obtained from the XE-2100 was increased in immune thrombo-cytopenia patients but not in patients with haematological malignancies in this study. The authors therefore suggest using IPF% to evaluate the thrombopoietic state of the bone marrow.

Morkis IVC et al. (2015) Int J Lab Hematol; 37(2): 259:
Assessment of immature platelet fraction and immature reticulocyte fraction as predictors of engraftment after hematopoietic stem cell transplantation.

Summary:
In this study, both IRF% and IPF% measured on an XE-5000 predicted neutrophil and platelet recovery, respectively.

Greene LA et al. (2015) Br J Haematol; 166(4): 592:
Beyond the platelet count: immature platelet fraction and thromboelastometry correlate with bleeding in patients with immune thrombocytopenia.

Summary:
In this study IPF# demonstrated stronger correlation with acute bleeding score than platelet counts. The strongest correlation was seen for paediatric patients with platelet counts <30 x109/L. High IPF# was associated with low bleeding score.

Ibrahim H et al. (2014) J Am Coll Cardiol; 64: 2122:
Association of Immature Platelets With Adverse Cardiovascular Outcomes.

Summary:
According to this study IPF# (XE-2100) allows for stratification of patients with coronary artery disease in terms of risk for future adverse events. Patients with an IPF# level ≥ 7,632 /μL were more likely to experience an adverse event (hazard odds ratio: 4.65; p < 0.002).

Dadu T et al. (2014) Int J Lab Hematol; 36(5): 499:
Evaluation of the IPF as an indicator of PLT recovery in dengue patients.

Summary:
This study presents IPF as a useful parameter to monitor the thrombocytopenia in patients with dengue fever. Furthermore, it can predict the recovery of PLT and so avoid unnecessary blood transfusions.

Everett TR et al. (2014) Thromb Haemost; 111(6): 1177:
Immature platelet fraction analysis demonstrates a difference in thrombopoiesis between normotensive and preeclamptic pregnancies.

Summary:
The study illustrates the potential utility of IPF as a parameter to distinguish between normotensive and preeclamptic pregnant women. The authors suggest that IPF is a far better parameter than MPV, which has previously been suggested for this purpose, and can distinguish between the two groups even at normal platelet counts.

Van der Linden N et al. (2014) Eur J Haematol; 93(2): 150:
Immature platelet fraction (IPF) measured on the Sysmex XN haemocytometer predicts thrombopoietic recovery after autologous stem cell transplantation.

Summary:
Quote: 'IPF is a promising predictor of platelet recovery in patients after autologous SCT.' 'The proposed cut-off value of 5.3% can theoretically be used to decide whether or not to give a platelet transfusion.'

Cesari F et al. (2013) Thrombosis and Haemostasis; 109: 846:
Reticulated platelets predict cardiovascular death in acute coronary syndrome patients. Insights from the AMI-Florence 2 Study.

Summary:
In this study, reticulated (immature) platelets predicted cardiovascular death independently and improved risk stratification for acute coronary syndrome patients.

Bat T et al. (2013) Transfusion; 53(6): 1201:
Measurement of the absolute immature platelet number reflects marrow production and is not impacted by platelet transfusion.

Summary:
In this study, the IPF count was presented as a suitable parameter for assessing bone marrow activity in transfusion-dependent thrombocytopenic patients.

Cremer M et al. (2013) J Perinatol; 33(8): 622:
Low immature platelet fraction suggests decreased megakaryopoiesis in neonates with sepsis or necrotizing enterocolitis.

Summary:
Low absolute IPF values during the course of neonatal sepsis/necrotising enterocolitis suggest suppression of megakaryopoietic activity according to the study conclusions.

Funck-Jensen K et al. (2013) Platelets; 24(7): 528:
Increased platelet aggregation and turnover in the acute phase of ST-elevation myocardial infarction.

Summary:
Increased platelet turnover, indicated by IPF and MPV, was observed in the acute phase of ST-elevated myocardial infarction in this study and may partly explain reduced efficacy of oral antiplatelet drugs.

Sinclair L (2012) Aust J Med Sci; 33(1): 10:
The immature platelet fraction: where is it now?

Summary:
A clear and concise review of 53 original publications concerning the clinical value of IPF. The diagnostic and prognostic potential of IPF in various conditions, and also advantages and limitations of IPF are described.

Sinclair L (2012) Aust J Med Sci; 33(2): 48:
The immature platelet fraction: an assessment of its application to a routine clinical laboratory.

Summary:
The purpose of the review is to assess the suitability of the IPF%
as a routine test. Productivity rather than clinical value is discussed. Reference ranges are given.

Psaila B et al. (2012) Blood; 119: 4066:
In vivo effects of eltrombopag on platelet function in immune thrombocytopenia: no evidence of platelet activation.

Summary:
IPF% was higher in patients with ITP than the controls, reflecting the increased platelet production. Treatment with eltrombopag led to increased platelet counts, platelet size, and absolute IPF, but no significant change in IPF%.

Parco S et al. (2012) OncoTargets and Therapy; 5: 1:
Application of reticulated platelets to transfusion management during autologous stem cell transplantation.

Summary:
The use of IPF-rich platelet transfusions reduced the number of transfusions and bleedings after stem cell transplantation in paediatric patients in this study.

Zucker ML et al. (2012) Int J Lab Hematol; 34: 525:
Mechanism of thrombocytopenia in chronic hepatitis C as evaluated by the immature platelet fraction.

Summary:
IPF% supported the differentiation between platelet destruction and bone marrow failure in hepatitis C patients in this study.

Goncalo A et al. (2011) Transplant Proc; 43: 241:
Predictive value of immature reticulocyte and platelet fractions in hematopoietic recovery of allograft patients.

Summary:
In this study, immature platelet (IPF) and immature reticulocyte fraction (IRF) were presented as early and readily available assessment methods for post-transplant bone marrow recovery.

Barsam SJ et al. (2011) Blood 117; 5723:
Platelet production and platelet destruction: assessing mechanisms of treatment effect in immune thrombocytopenia.

Summary:
In this study, absolute immature platelet count (IPF#) was shown to reflect the effect of different treatments of immune thrombocytopenia and was in such cases considered more useful than IPF%.

Strauss G et al. (2010) Pediatr Blood Cancer; 57(4): 641:
Immature Platelet Count: A Simple Parameter for Distinguishing Thrombocytopenia in pediatric acute lymphocytic leukemia from immune thrombocytopenia.

Summary:
Quote: 'Both IPF% and IPF# parameters should become a standard for evaluating the respective pathophysiology’s underlying both congenital and acquired thrombocytopenias.'

Cesari F et al. (2010) Thrombosis and Haemostasis; 104: 804:
High platelet turnover and reactivity in renal transplant recipients patients.

Summary:
Renal transplant recipients showed significantly higher values of reticulated platelets (IPF) than healthy control subjects, especially in those not on aspirin treatment. An elevated IPF% value was shown to be an additional indication of a mechanism involved in the increased cardiovascular risk profile of those patients in this study.

Yamaoka G et al. (2010) Int J Lab Hematol; 32: e208:
The immature platelet fraction is a useful marker for predicting the timing of platelet recovery in patients with cancer after chemotherapy and hematopoietic stem cell transplantation.

Summary:
In this study, IPF above 10% was a useful marker for predicting the timing of platelet recovery after chemotherapy and haematopoietic stem cell transplantation and could allow optimised platelet transfusion.

Cremer M et al. (2009) Br J Haematol 144: 619:
Immature platelet fraction as novel laboratory parameter predicting the course of neonatal thrombocytopenia.

Summary:
In this study, thrombocytopenic neonates were more likely to recover when IPF levels were high.

Hong KH et al. (2009) Blood Coag and Fibrinolysis; 20(6): 409:
Prognostic value of immature platelet fraction and plasma thrombopoietin in disseminated intravascular coagulation

Summary:
The authors demonstrated that the IPF is an excellent marker for distinguishing hyperdestructive/consumptive from hypoproductive thrombocytopenia. Moreover, IPF was a robust and reliable predictor of platelet recovery in patients with immune thrombocytopenia (ITP) and with malignancies undergoing chemotherapy.

Takami A et al. (2007) Bone Marrow Transplant; 39: 501:
Immature platelet fraction for prediction of platelet engraftment after allogeneic stem cell transplantation.

Summary:
In this study, IPF was presented as an easily available marker for the engraftment after stem cell transplantation, especially regarding thrombopoietic activity.

Abe Y et al. (2006) Thromb Res; 118: 463:
A simple technique to determine thrombopoiesis level using immature platelet fraction (IPF).

Summary:
The results of this study showed that the IPF reflects the pathology of thrombocytopenic disorders (i.e. consumptive versus productive). Measurement of IPF was concluded to be useful for the differential diagnosis and analysis of platelet kinetics and significantly more so than the mean platelet volume (MPV).

Briggs C et al. (2006) Transfus Med; 16: 101:
Immature platelet fraction measurement: a future guide to platelet transfusion requirement after haematopoietic stem cell transplantation.

Summary:
Automated IPF was presented as a useful parameter in the clinical evaluation of thrombocytopenic patients and the authors saw a potential to optimise transfusion management.

Kickler T et al. (2006) Am J Clin Pathol; 125: 282:
A Clinical Evaluation of High Fluorescent Platelet Fraction Percentage in Thrombocytopenia

Summary:
In this study, IPF (here named HFPF for ‘high fluorescence platelet fraction’) was predictive in the evaluation of thrombocytopenia. Elevated IPF values were found in case of increased platelet production, associated with peripheral platelet destruction. In disorders associated with decreased platelet production IPF was found normal.

Briggs C et al. (2004) Br J Haematol; 126: 93:
Assessment of an immature platelet fraction (IPF) in peripheral thrombocytopenia.

Summary:
The authors recommend automated IPF% as a standard parameter in evaluating the thrombocytopenic patient.

Optical platelets (PLT-O)

Briggs C et al. (2004) Clin Lab Haematol; 26:157:
The most accurate platelet count on the Sysmex XE-2100. Optical or impedance?

Summary:
In this study different options for counting platelets on XE-2100 were compared using chemotherapy samples. The accuracy of XE-2100 platelet counting was excellent on low-count samples when the switching algorithm was applied.

Reference intervals

Bildirici A et al. (2023) Turk J Biochem; 48(4): 388:
Determination of reference intervals of hemogram with advanced clinical parameters by indirect method on Sysmex XN-1000.

Summary:
The CBC+DIFF reference intervals of 68 316 patients aged 18–65 years were determined by indirect method using the non-parametric percentage estimation in Turkish Kastamonu Training and Research Hospital.

L van Pelt J et al. (2022) Clin Chem Lab Med; 60(6): 907:
Reference intervals for Sysmex XN hematological parameters as assessed in the Dutch Lifelines cohort.

Summary:
The publication provides reference intervals for 105 XN parameters (incl. functional and cell activation parameters) based on data of 15,803 healthy individuals from the Lifelines cohort in the Netherlands. The reference intervals were calculated in accordance to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) recommended statistical methods.

Becker M et al. (2022) Int J Lab Hematol; 44(4): 729:
Differences between capillary and venous blood counts in children - A data mining approach.

Summary:
In this multicentric study the differences between capillary and venous bloods were investigated in paediatric samples specifying a delta for the CBC parameters dependant on measurement range of the parameter value, time difference in sampling and age of the patient.

Angelo A et al. (2021) BMC Pediatrics; 21: 275:
Umbilical cord blood hematological parameters reference interval for newborns from Addis Ababa, Ethiopia.

Summary:
This pilot study enrolled 139 umbilical cord blood samples from healthy newborns to establish reference values for the KX-21N. For WBC, RBC, and NEUT significant differences were found between caesarean and natural birth.

Wilson S et al. (2021) Int J Lab Hematol; 43(6): 1394:
Continuous reference curves for common hematology markers in the CALIPER cohort of healthy children and adolescents on the Sysmex XN-3000 system.

Summary:
First study that generated continuous reference intervals (curves) of healthy children and adolescents for 19 haematological XN parameters. Seven parameters required sex-specific reference curves. Continuous reference intervals were found to be accurate estimate of haematological reference ranges over the paediatric age range.

Mrosewski I et al. (2021) Clin Chem Lab Med; 60(3): 408:
Indirectly determined hematology reference intervals for pediatric patients in Berlin and Brandenburg.

Summary:
The study presents indirectly determined CBC reference intervals (RI) for paediatric patients (0-18 years) in Berlin and Brandenburg area in Germany.

Song MY et al. (2021) Int J Lab Hematol; 43(6): 1363:
Establishment of pediatric reference intervals for complete blood count parameters in capillary blood in Beijing.

Summary:
The authors established reference intervals for 22 CBC+DIFF parameters from capillary blood in 6799 children aged 3 months to 18 years from Beijing area in China.

Florin L et al. (2020) Int J Lab Hematol; 42(3): e110:
Establishment of common reference intervals for hematology parameters in adults, measured in a multicenter study on the Sysmex XN-series analyzer.

Summary:
The study provides reference intervals (CBC+DIFF+RET) that could serve as reference values for haematology parameters in adults for laboratories that use the XN-Series analysers.

Bohn MK et al. (2020) Int J Lab Hematol; 42(6): 750:
Complex biological patterns of hematology parameters in childhood necessitating age- and sex-specific reference intervals for evidence-based clinical interpretation.

Summary:
The study establishes a comprehensive paediatric (birth to 21 years) reference intervals for haematology parameters using the XN analyser. The data highlight the dynamic haematological profiles observed in healthy children and adolescents and the need for reference interval stratification by age and sex.

Ianni B et al. (2020) Arch Pathol Lab Med; 145(1):66:
Defining Normal Healthy Term Newborn Automated Hematologic Reference Intervals at 24 Hours of Life Arch Pathol Lab Med; Online ahead of print.

Summary:
Reference intervals on Sysmex XN-Series for normal healthy term new-borns at 23-25 hours of life were prospectively established for CBC, IG%, IG#, IRF, RET-He, IPF and IPF#.

Zierk J et al. (2019) Clin Chem Lab Med; 57(10): 159548:
Next-generation reference intervals for pediatric hematology.

Summary:
The authors determined percentile charts and z-scores for CBC reference intervals from birth to adulthood. A total of 9,576,910 specimens were gathered from ten German facilities and analysed using predominantly Sysmex X-Class and XN-Class analysers and one Beckman Coulter DxH800 analyser.

Arbiol-Roca A et al. (2018) EJIFCC; 29(1): 48:
Reference intervals for a complete blood count on an automated haematology analyser Sysmex XN in healthy adults from the southern metropolitan area of Barcelona.

Summary:
The aim of the study was to establish reference intervals for CBC, DIFF and reticulocytes for a Spanish population. Significant gender differences were found for RBC, PLT, HCT and HGB.

MacQueen BC et al. (2017) J Perinatol; 37(7): 834:
The immature platelet fraction: creating neonatal reference intervals and using these to categorize neonatal thrombocytopenias.

Summary:
Neonatal reference intervals for IPF and IPF# were reported according to gestational age, and during the first 90 days after birth. Moreover, neonates with hyporegenerative thrombocytopenias had lower IPF and IPF# than neonates with consumptive ones.

Ozarda Y et al. (2017) Biochem Med (Zagreb); 27(2): 350:
A nationwide multicentre study in Turkey for establishing reference intervals of haematological parameters with novel use of a panel of whole blood.

Summary:
Using the Cell Dyn and Ruby (Abbott), LH780 (Beckman Coulter) and XT-2000i (Sysmex) analysers, Turkish reference intervals were obtained for CBC-DIFF parameters. Analyser-specific reference intervals were reported for BASO%, BASO#, MCHC, RDW and MPV.

Ko Y et al. (2015) Clin Chem Lab Med; 53(7): 1091:
Reference interval for immature platelet fraction on Sysmex XN hematology analyzer: a comparison study with Sysmex XE-2100.

Summary:
Reference intervals for PLT, IPF% and IPF# were established on the XE- and XN-Series. It was found that the values measured on the XN were higher than on the XE-2100.

Ko Y et al. (2013) Int J Lab Hematol; 35(5): 528:
Establishment of reference interval for immature platelet fraction.

Summary:
The study provides reference intervals for PLT, IPF% and absolute IPF from more than 2,000 healthy individuals and from umbilical cord blood, according to the CLSI guideline. These results could be used as fundamental data for clinical use as well as future research.

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Red Blood Cells

Erythrocyte sedimentation rate (ESR)

Schapkaitz E et al. (2017) Int J Lab Hematol; 39(3):e66-e69:
Evaluation of the InteRRliner automated erythrocyte sedimentation rate analyzer for a large academic laboratory.

Summary:
Indicated by the high correlation coefficient of 0.96 the InteRRliner showed an excellent comparability to the HumaSed ESR method.

Kratz A et al. (2017) Int J Lab Hematol; 39(5): 448:
ICSH recommendations for modified and alternate methods measuring the erythrocyte sedimentation rate.

Summary:
The gold standard for the determination of the erythrocyte sedimentation rate is still the Westergren method. The authors suggest that alternative methods should be accepted when they have been appropriately validated and their results are expressed by comparison with the gold standard.

Extended RBC parameters (HYPO-He / HYPER-He / MicroR / MacroR)

Amir N et al. (2019) Int J Lab Hematol; 41(3): 418:
Percentage of hypochromic red cells as a potential screening test to evaluate iron status in blood donors.

Summary:
HYPO‐He with a cut‐off value of 0.6% is presented as a potential screening parameter with high sensitivity and specificity for evaluating iron status among blood donors, in this study. The authors concluded that the parameter is suitable for screening because of faster turnaround time than biochemical markers.

Schoorl M et al. (2012) Am J Clin Pathol 138: 300:
Efficacy of Advanced Discriminating Algorithms for Screening on Iron-Deficiency Anemia and ß-Thalassemia Trait.

Summary:
The authors conclude that the advanced algorithms, derived from extended RBC parameters provided by the Sysmex XE-5000 analyser, are useful as laboratory devices for anaemia screening.

Persijn L et al. (2012) Ann Hematol 91: 301:
Screening for hereditary spherocytosis in routine practice: evaluation of a diagnostic algorithm with focus on non-splenectomised patients.

Summary:
The authors analysed the hereditary spherocytosis diagnostic tool by Mullier et al. and concluded that it is a useful and working tool but needs fine-tuning to the local patient population.

Mullier F et al. (2011) Ann Hematol 90: 759:
Additional erythrocytic and reticulocytic parameters helpful for diagnosis of hereditary spherocytosis: results of a multicentre study.

Summary:
In this study it is shown that combining several RBC parameters allows to efficiently screen for hereditary spherocytosis even in mild cases.

Urrechaga E et al. (2011) Int J Lab Hematol; 33(1): 30:
The role of automated measurement of red cell subpopulations on the Sysmex XE-5000 analyzer in the differential diagnosis of microcytic anemia.

Summary:
In this study, the new index %microcytic-%hypochromic was the most reliable index in the differential diagnosis of microcytic anaemia due to its high sensitivity and specificity.

Urrechaga E et al. (2011) J Clin Lab Anal; 25(3): 223:
Erythrocyte and reticulocyte parameters in iron deficiency and thalassemia.

Summary:
In this study, Beta-thalassaemia can be recognised through high RBC, small MCV, high %MicroR and moderately increased IRF, whereas iron deficiency shows high RDW and %HYPO-He.

Urrechaga E et al. (2011) Am J Clin Pathol; 135(3): 374:
The role of automated measurement of RBC subpopulations in differential diagnosis of microcytic anemia and β-thalassemia screening

Summary:
In this study, the new index %MicroR-%HYPO-He was the most reliable index in the differential diagnosis of microcytic anaemias due to its high sensitivity and specificity.

Urrechaga E et al. (2009) Clin Chem Lab Med; 47(11): 1411:
Potential utility of the new Sysmex XE 5000 red blood cell extended parameters in the study of disorders of iron metabolism.

Summary:
In this study, the new parameters %HYPO-He /%HYPER-He and %MicroR/%MacroR appear to be sensitive for detecting small changes in the number of red cells with inadequate haemoglobinisation and volume in order to distinguish beta-thalassaemia from iron deficiency anaemia.

General RBC

Tabata M et al. (2024) Clin Chem Lab Med; online ahead of print:
Performance evaluation and user experience of BT-50 transportation unit with automated and scheduled quality control measurements.

Vroemen WHM et al. (2023) Int J Lab Hematol; 45(3): e93:
Hypo-osmolality and its effect on erythrocyte parameters.

Summary:
The authors reported a rare condition affecting erythrocyte parameters. By treating the patient's dehydration and decreased electrolyte concentrations, they showed that plasma hypoosmolality was the rationale behind the increased MCHC (39.6 g/dL), which was not one of the known common causes.

Combaluzier S et al. (2023) Int J Lab Hematol; 45(2): e21:
Detection of unstable haemoglobin variants with Sysmex XN-10.

Summary:
WDF channel of XN analysers shows a decreased fluorescence signal in blood samples of patients with unstable haemoglobin variants causing an abnormal scattergram. The optimal threshold combination to specify unstable haemoglobin variants is LY-SFL < 42 and NE-SFL < 41.2 resulting in a sensitivity of 100% and specificity of 99.9%.

Nivaggioni V et al. (2022) Int J Hematol; 44(2): e84:
Detection of Southern Asian Ovalocytosis with Sysmex XN-10: A complement to the decision tree previously described.

Summary:
The authors expanded the algorithm described in the Nivaggioni et al. 2020 publication with the addition of a step to detect Southeast Asian ovalocytosis (SAO) cases. All SAO samples were correctly classified using the Hypo-He/MicroR ratio, which achieved an AUC of 1.0.

Adam AS et al. (2022) Clin Chem Lab Med; 60(5): e116:
Rare unstable and low oxygen affinity haemoglobin variant, Hb Hazebrouck, detected on Sysmex XN-9000.

Summary:
This is the first case of Hb Hazebrouck, an unstable Hb variant, detected with XN-9000. It shows the same distinctive pattern in the WDF measurement channel as reported in previous cases. This confirms the importance to continue investigations for the presence of 'WBC Abn Scattergram' flag and abnormal scattergram distribution.

Schoorl M et al. (2022) Int J Lab Hematol; 44(6): 1060:
Effects of iron supplementation on microcytic and hypochromic red blood cells during the third trimeste of pregnancy.

Summary:
A study in 145 third trimester pregnant women showed an increase in MicroR and Hypo-He and a decrease in RET-He, RBC-He and Delta-He in women developing iron-deficient erythropoiesis (IDE) (n=39) compared to non-IDE (n=106). After four weeks of iron supplementation in the IDE group, Hypo-He, RET-He and Delta-He showed significant improvements towards their normal reference ranges.

Rosetti M et al. (2021) Br J Haematol; 192: e66:
Parasitised red blood cells misclassified as giant platelets by an automated digital morphology analyser (Sysmex DI-60/ CellaVision): a case report and a retrospective EQA analysis.

Summary:
The DI-60 is not intended to be used for diagnosing malaria, however this study shows how the capturing of abnormal cells by the instrument can aid laboratory technicians to reach a diagnostic conclusion for the patient. The study emphasises the usefulness of remote review.

Van der Vorm L et al. (2021) J Clin Pathol; 76(3): 194:
Performance of the CellaVision DC-1 digital cell imaging analyser for differential counting and morphological classification of blood cell.

Summary:
The accuracy, within-run precision, clinical sensitivity and specificity of the DC-1 were all adequate compared with prespecified acceptance criteria and the DI-60. Altogether the authors state that the DC-1 is a reliable automated cell imaging analyser for the differential white blood cell (WBC) count and morphological classification of both WBCs and red blood cells on peripheral blood smears.

Falvella FS et al. (2020) J Clin Pathol; 73(12): 847:
Validation of the reticulocyte channel of Sysmex XN-9000 system for blood cell count in samples with suspected cold agglutination for use in a total laboratory automation setting.

Summary:
40 samples with increased MCHC (> 37.0 g/dL) due to cold agglutination were tested with two different methods: 1. manual heating at 37°C for two hours and 2. XN RET channel measurement. Both methods equally resolved the falsely altered MCHC and the authors support the implementation of automated reflex tests in Extended IPU to minimise manual operations and shorten the time to result.

Albichr IS et al. (2020) Int J Lab Hematol; 42(5): 573:
Cross-evaluation of five slidemakers and three automated image analysis systems: The pitfalls of automation?

Summary:
Sysmex SP-10 and SP-50 showed in the study an acceptable performance for differential leucocyte counting and a good correlation with haematology analyser results and manual differential on HemaPrep smears. SP-10 and SP-50 showed superior performance compared with the Siemens Advia Autoslider 1, Autoslider 2 and Abbot Alinity Hs slide maker stainers.

Nivaggioni V et al. (2020) Int J Lab Hematol; 42(6): 697:
Use of Sysmex XN-10 red blood cell parameters for screening of hereditary red blood cell diseases and iron deficiency anaemia.

Summary:
A two-step algorithm, based on the XN RBC and reticulocyte parameters, delivers a good prediction and classification between patients with a hereditary RBC disease from iron deficiency anaemia and other patients. The proposed flowchart recommends how to manage MCHC < 36.5 g/dL (22.7 mmol/L) samples in addition to the CBC-O application to assist the diagnosis of RBC diseases. Overall it reaches a very good classification rate of 99.4%, confirmed by an external cohort.

Smit B et al. (2020) Clin Chem Lab Med; 58(11): e295:
Massive hemolysis due to Clostridium perfringens: a laboratory’s perspective.

Summary:
A case report describing laboratory findings in two patients with Clostridium perfringens sepsis. The authors state that massive haemolysis, ghost cells in peripheral blood smear, differences in haemoglobin parameters (total haemoglobin and intraerythrocytic haemoglobin) and distinct microcytic RBC populations may occur as indirect indicators and support early recognition.

Ortiz A et al. (2020) Sysmex J Int; 30(1): 9:
Performance Comparison of Sysmex Hematology Analyzers XN-550 and XN-10.

Summary:
The XN-550 is highly reliable with functionality comparable to the XN-10. It has shown high correlation coefficients and excellent comparative performance in all CBC, DIFF and RET parameters (except BASO%). The overall flagging comparison was excellent among the XN-10, the XN-550 and the manual differential.

Johnson S et al. (2019) Int J Lab Hematol; 41(2): 271:
A CBC algorithm combined with immature platelet fraction is able to identify JAK2 V617F mutation-positive polycythaemia vera patients.

Summary:
The study proposes an algorithm based on CBC and IPF# parameters that allows to identify a cohort of high-likelihood polycythaemia vera (PV) patients and refer them for haematological review. IPF# > 20 × 10e9/L in combination with positive CBC criteria can identify JAK2 V617F mutation-positive PV patients.

Moioli V et al. (2019) Chem Lab Med; 57(12): e324:
Mozhaisk haemoglobin variant effects on leukocyte differential channel using the Sysmex XN series.

Summary:
Case study showing an abnormal WDF scattergram with a decrease of the fluorescence signal, causing the flag 'WBC Abn Scattergram'. In association with the microscopic revision and further genetic analysis an unstable haemoglobin (Hb Mozhaisk) was confirmed.

Jongbloed W et al. (2018) Clin Chem Lab Med; 56(9): e249:
Unstable haemoglobin variant Hb Leiden is detected on Sysmex XN-Series analysers.

Summary:
Case study with an abnormal WDF scattergram observed on the XN-9000 causing the flag "WBC abnormal scattergram" which highlighted the inability to separate the white blood cell population. Further genetic analysis confirmed an unstable haemoglobin.

Huisjes R et al. (2018) Int J Lab Hematol; 40(2): 159:
Digital microscopy as a screening tool for the diagnosis of hereditary hemolytic anemia.

Summary:
Advanced RBC Morphology from CellaVision was used to characterise hereditary haemolytic anaemia. Cutoffs were reported for several RBC abnormalities and showed a high sensitivity and specificity for detection of different conditions in this study.

Cao J et al. (2017) Lab Med; 48(2): 188:
Establishing a Stand-Alone Laboratory dedicated to the Care of Patients with Ebola Virus Disease.

Berda-Haddad Y et al. (2017) Int J Lab Hematol; 39(1): 32:
Increased mean corpuscular haemoglobin concentration: artefact or pathological condition?

Summary:
The use of the optical RBC parameters from the XN-Series saved time and helped in the determination of the cause of increased MCHC, in this study.

Jo S et al. (2017) Int J Lab Hematol; 39(1): e4:
Performance evaluation of recently launched Sysmex XN-550 Automatic Hematology Analyzer.

Summary:
The XN-550 showed a good analytical performance and strong correlation with XE-2100 and XN-3000 analysers for routine CBC parameters.

Teixeira C et al. (2017) Clin Chem Lab Med; 55(11): 243:
Automated detection of unstable hemoglobin variants by Sysmex XE-Series analyzers.

Summary:
The authors tested 9 samples with known unstable HGB variants and reported that only the XE-2100 flagged the samples in contrast to the SIEMENS Healthineers ADVIA.

Tailor H et al. (2017) Int J Lab Hematol; 39(6): 585:
Evaluation of the Sysmex XN-550, a Novel Compact Haematology analyser from the XN-L ® series, compared to the XN-20 system.

Summary:
Samples from adult patients (N=202) were measured on the XN-550 and compared with an XN-20. Good correlations and low bias were observed for all parameters except for BASO%. PLT-O from the XN-550 showed no significant bias compared to PLT-F from the XN-20.

Tamigniau A et al. (2017) Ann Biol Clin (Paris); 75(3): 285:
From XE-2100 to XN-9000, from SIS Standard to GFHC recommendations for slide review: potential impact on review rate and turnaround time.

Summary:
Changing from the XE-2100 to XN-9000 and implementing the Biomedical Validation ruleset led to a significant reduction in review rate (from 35.8% to 25.9%) and TAT. In this hospital this resulted in a cost reduction of 7000 Euros over 6 months.

Geara C et al. (2016) Int J Lab Hematol; 38(1): e10:
Comparative study of quantitative performances between the new Sysmex XN-L (XN-550) haematology analyser and the XN-9000 in a routine laboratory.

Summary:
The XN-Series and XN-L Series were compared; correlations were good and the study showed that the XN-L Series provided the same high quality as the XN-Series.

Summary:
Using the biomedical validation criteria, 21.3% of samples triggered a smear review. Modification of four criteria by the authors reduced the number of smears from 21.3% to 15.0% without loss of clinical value.

Summary:
In this study the XP-300 showed very good precision and linearity results, comparable with the XN-3000 analyser.

Egele A et al. (2016) Int J Lab Hematol; 38(5): e98:
Classification of several morphological red blood cell abnormalities by DM96 digital imaging.

Summary:
The authors report the cutoff values for most of the RBC abnormalities that can be detected by the Advanced RBC Morphology software.

Arneth B et al. (2015) J Clin Lab Anal; 29(3): 175:
Technology and New Fluorescence Flow Cytometry Parameters in Hematological Analyzers.

Summary:
This paper gives a good overview of the technology behind the XE-Series and the benefits of flow cytometry and automatic cell counting. In this study the XE-5000 delivers faster accurate results than older analysers.

Jo SY et al. (2015) Int J Lab Hematol; 37(2): 155:
Performance evaluation of the new hematology analyzer Sysmex XN-series.

Summary:
A good correlation was found between the XN- and XE-Series for all parameters. The XN-Series dramatically reduced the smear rate (by 58%). Even at counts below 500/µL the XN provided an accurate WBC count using the Low WBC mode.

Egele A et al. (2015) Int J Lab Hematol; 37(6): e153:
Automated detection and classification of teardrop cells by a novel RBC module using digital imaging/microscopy.

Summary:
The authors report excellent detection of teardrop cells in samples from patients with myelofibrosis and MDS, using the Advanced RBC Morphology software.

Ferrero-Vacher C et al. (2015) Annales de Biologie Clinique; 73(6): 729:
Utilisation des paramètres érythrocytaires Sysmex dans un cas d’hémolyse sévère (Erythrocytic parameters Sysmex in a case of severe haemolysis).

Summary:
Case report of severe haemolytic anaemia with cold agglutinins, identified by increased MCHC and qualitative alarms. The RBC-O and HGB-O parameters from the RET channel, and the RBC most frequent volume (R-MFV) allowed to report the correct results.

Tabe Y et al. (2015) Clin Chem Lab Med; 53(2): 281:
Performance evaluation of the digital cell imaging analyzer DI-60 integrated into the fully automated Sysmex XN hematology analyzer system.

Summary:
This performance evaluation of the digital imaging analyser DI-60 showed a good agreement between results from the DI-60 and manual microscopy. In addition, blasts were correctly classified with 95% sensitivity and 99% specificity.

Genevieve F et al. (2014) feuillets de Biologie; VOL LVI N° 317:
Smear microscopy revision: propositions by the GFHC.

Hotton J et al. (2013) Am J Clin Pathol; 140: 845:
Performance and Abnormal Cell Flagging Comparisons of Three Automated Blood Cell Counters: Cell-Dyn Sapphire, DxH-800, and XN-2000.

Summary:
Repeatability, linearity and carryover was good for all tested analysers, and correlation between the analysers was good for HGB, MCV, PLT and WBC.
Quotes: "The XN showed a higher sensitivity than the SAPH and DxH for all flags of interest." "For the first time, we have decreased the slide review for our laboratory from 20% with the SAPH to 9.3% with the XN."

Wang H et al. (2013) Clin Lab; 59: 217:
Use of RBC-O and S-MCV Parameters of Sysmex XE-2100 in a Patient with RBC Cold Agglutination.

Summary:
A combination of sample dilution and the use of RBC parameters from the RET channel on the XE-2100 is described to obtain accurate RBC parameters from samples with RBC cold agglutination without heating of the sample.

Godon A et al. (2012) Ann Biol Clin 2012; 70(2): 155:
Anomalies et erreurs de détermination de l’hémogramme avec les automates d’hématologie cellulaire Partie 3. Hémoglobine, hématies, indices érythrocytaires, réticulocytes.

Summary:
A summary report about potential interferences of CBC parameters with focus on situations leading to abnormal HGB, RBC and MCV, resulting in abnormal calculated RBC indices, e.g. MCHC.

Urrechaga E et al. (2011) J Clin Lab Anal; 25: 223:
Erythrocyte and reticulocyte parameters in iron deficiency and thalassemia.

Summary:
In this study beta-thalassaemia was recognised through high RBC, small MCV, high %MicroR and moderately increased IRF, whereas iron deficiency showed high RDW and %HYPO-He.

Malaria-infected RBC (MI-RBC)

Khartabil TA et al. (2022) Malaria J; 21: 119:
Fast detection and quantification of Plasmodium species infected erythrocytes in a non-endemic region by using the Sysmex XN-31 analyzer.

Summary:
In this study from the Netherlands the XN-31 exhibits a positive and negative predictive value of 100% while three out of 112 samples showed abnormal scattergrams. In a set of 920 samples with RBC abnormalities abnormal scattergrams occurred in 50% at a false positive rate of 4.6%. Sickle cell disease was the most frequent underlying condition. However, with a review of the scattergram, false positives can be well distinguished from true positives.

Komaki-Yasuda K et al. (2022) Malaria J; 21: 229:
Clinical performance testing of the automated haematology analyzer XN‐31 prototype using whole blood samples from patients with imported malaria in Japan.

Summary:
In the present study the low malaria mode and pre-diluted mode of the XN-31p (prototype) analyser showed similar sensitivity (97%/94%) and same specificity (100%). Changes in parasitaemia during treatment monitoring were concordant in 4 out of 6 cases between microscopy and XN-31p, whereas in 2 cases were deviated.

Kayange M et al. (2022) Malaria J; 21: 299:
Automated measurement of malaria parasitaemia among asymptomatic blood donors in Malawi using the Sysmex XN-31 analyser: could such data be used to complement national malaria surveillance in real time?

Summary:
The authors found that malaria prevalence in blood donors in Malawi (endemic area), measured by XN-31, correlated with seasonal and local prevalences of the disease as known from household survey. Age, location, and collection month were significant predictors of malaria positivity in males, whereas in females only location was significant.

Kagaya W et al. (2022) Malaria J; 21: 252:
Potential application of the haematology analyser XN-31 prototype for field malaria surveillance in Kenya.

Summary:
The authors investigated the feasibility of a hub-and-spoke model for malaria diagnosis by XN-31p. Identical results for presence of malaria were found between capillary and venous blood, also short-term storage under chilled conditions, simulating storage and transport of the suggested hub-and-spoke model, had no adverse effect.

Picot S et al. (2022) Parasite; 29: 31:
Diagnostic accuracy of fluorescence flow-cytometry technology using Sysmex XN-31 for imported malaria in a non-endemic setting.

Summary:
In a study conducted in the University Hospital in Lyon, France the XN-31 analyser exhibited a sensitivity of 100%, specificity of 98.4%, NPV of 100% and PPV of 96.5% when compared to microscopy. Correlation of XN-31 and microscopy regarding parasitaemia and species identification was deemed excellent. The authors consider XN-31 as a more efficient screening tool than LAMP and RDT during patient follow-up.

Zuluaga‐Idárraga L et al. (2021) Malaria Sci Rep; 11(1): 5268:
Performance of the hematology analyzer XN‑31 prototype in the detection of Plasmodium infections in an endemic region of Colombia.

Summary:
The XN-31 prototype (XN-31p) was evaluated against qPCR exhibiting a sensitivity of 90.0% and a specificity of 99.8%, thus similar to the performance of microscopy and Rapid Diagnostic Test (RDT). Sensitivity of XN-31p is inferior to microscopy and RDT in detecting P. falciparum, however, sensitivity and specificity for detecting P. vivax is similar to both. Results in a small number of samples indicate similar diagnostic accuracy in capillary blood as in venous blood.

M’Baya B et al. (2021) Vox Sang; 117(3): 346:
Evaluation of the Sysmex XN-31 automated analyser for blood donor malaria screening at Malawi Blood Transfusion Services.

Summary:
The malaria detection rate in 5,281 donor blood samples from malaria endemic area (Malawi) was significantly higher using XN-31 (11.6%) when compared with routine microscopy (6.5%). The latter only detected 22% of samples with low parasitaemia (< 100 parasites/μL). The XN-31 had superior sensitivity to routine microscopy (100% vs. 75%) whilst maintaining excellent specificity (98.9%).

Pillay E et al. (2019) Malaria J; 18(1): 15:
Evaluation of automated malaria diagnosis using the Sysmex XN-30 analyser in a clinical setting.

Summary:
The novel technology of the Sysmex XN-30 provides a robust, rapid, automated and accurate platform for diagnosing malaria. It allows precise recognition and demonstrated a sensitivity and specificity of 100% for malaria parasitaemia detection in this study.

Post A et al. (2019) BMC Medicine; 17(1): 103:
The XN-30 hematology analyzer for rapid sensitive detection of malaria: a diagnostic accuracy study.

Summary:
The novel technology of the Sysmex XN-30 provides a robust, rapid, automated and objective platform for diagnosing and quantifying malaria. The XN-30 ensures the prompt initiation of the malaria treatment and the malaria anaemia together with the reliable treatment monitoring in this study.

Tougan Tet al. (2018) Malaria J; 17(1): 59:
An automated haematology analyzer XN-30 distinguishes developmental stages of falciparum malaria parasite cultured in vitro.

Summary:
Using a modified algorithm, the XN-30 research analyser could be used to recognize cultured red blood cells infected with different developmental stages of Plasmodium falciparum parasites. In addition, purified merozoites and gametocytes could be detected. The analyser may therefore be useful for research studies done on the malaria parasite.

Dumas C et al. (2018) J Clin Pathol; 71(7): 594:
Automated Plasmodium detection by the Sysmex XN hematology analyzer.

Summary:
The study describes abnormal WDF scattergrams on the XN-Series for samples from patients infected with malaria. Most WDF scattergrams were not affected by Plasmodium falciparum infections but about 50% of non-falciparum infections caused scattergram abnormalities.

Nucleated red blood cells (NRBC)

Sahni D et al. (2024) Pediatr Cardiol; 45(3): 513:
Nucleated Red Blood Cell Counts Differentiate Cardiac from Respiratory Causes of Cyanosis at Birth.

Summary:
In a multivariate analysis, the authors found that NRBC discriminated hypoxia due to congenital heart disease (CHD; n=80) from hypoxia due to respiratory disease (RD; n=109) in term neonates within the first 12 h of life (AUC 0.914). Sensitivity was 0.938 and specificity 0.881 with a cut-off value of 1.07 x 10^9 NRBC/L.

Piggott K et al. (2021) Cardiol Young; 32(7):1048:
Nucleated red blood cells as a biomarker for mortality in neonates following cardiac surgery.

Summary:
In this retrospective single centre study in neonates an NRBC value of ≥ 10/100 WBC following cardiac surgery and an elevated NRBC value in the 14-day period post-cardiac surgery was associated with mortality (AUC of 0.9 and 0.914).

Hüseyin N et al. (2021) Am J Emerg Med; 46: 335:
Nucleated red blood cells as predictor of all-cause mortality in emergency department.

Summary:
A retrospective analysis of 204 samples from emergency department patients showed that NRBC was higher in patients that died compared to the ones that were discharged. NRBC was an independent predictor for mortality, with an AUC of 0.95, and a cut-off > 0 NRBC/μL had a sensitivity of 94.1% and specificity of 82.3%.

Morton SU et al. (2020) A Pediatr Neonatol; 61(6): 592:
Association of nucleated red blood cell count with mortality among neonatal intensive care unit patients.

Summary:
Neonatal ICU patients with NRBC count >0 had a significantly higher risk of mortality, and time to mortality decreased with higher NRBC counts. The authors claim that NRBC counts may be useful in refining prognostic models for neonates.

Valina O et al. (2020) Sysmex J Int; 30(1): 1:
Evaluation of the Automated Nucleated Red Blood Cell (NRBC) Enumeration on Sysmex XN Analyser in Preterm and Term Neonates.

Summary:
The authors compare manual NRBC count to an automated counting by XN-Series analyser for neonates, which correlates well. In addition, the mean NRBC count on different postnatal days were analysed and reference values have been stated.

Menk M et al. (2018) Ann Intensive Care; 8(1): 42:
Nucleated red blood cells as predictors of mortality in patients with acute respiratory distress syndrome (ARDS): an observational study.

Summary:
The study results confirmed previous findings in critically ill patients suggesting that NRBC are equally predictive of mortality in acute respiratory distress syndrome (ARDS). NRBC-positive patients were found to require longer treatment with mechanical ventilation, extra-corporal gas exchange and had prolonged ICU stay when compared with NRBC-negative patients.

Monteiro Junior JG et al. (2015) PLoS One; 10(12): e0144259:
Nucleated Red Blood Cells as Predictors of All-Cause Mortality in Cardiac Intensive Care Unit Patients: A Prospective Cohort Study.

Summary:
Quote: ‘The presence of NRBC (XE-2100) was associated with a higher ICU mortality (49.4% vs 21.7%, P<0.001) as well as in-hospital mortality (61.4% vs 33.3%, p = 0.001).’

Cremer M et al. (2015) Early Hum Dev; 91(10): 559:
Nucleated red blood cells as marker for an increased risk of unfavorable outcome and mortality in very low birth weight infants.

Summary:
This study of 438 low birth weight infants indicates that an NRBC count obtained 24-120 h after birth can serve as a surrogate marker for later severe morbidity and mortality. The optimal cut-off value was 2x10^9/L with 83% sensitivity and 75% specificity.

Tantanate C et al. (2014) Int J Lab Hematol; 37(3): 341:
Performance evaluation of the automated nucleated red blood cell enumeration on Sysmex XN analyser.

Summary:
The authors suggested that NRBC counts from the XN-Series could replace manual counts. The precision of the XN-Series was superior and a small bias (manual counts slightly higher than NRBC counts from the XN-Series) was only observed for NRBC counts above 200/100 WBC, in this study.

Parco S et al. (2013) J Blood Med; 4: 23:
Public banking of umbilical cord blood or storage in a private bank: testing social and ethical policy in northeastern Italy.

Summary:
An excellent correlation was found between manual NRBC counts and NRBC counts from the XE-2100 (r2 = 0.94) in umbilical cord blood. The authors suggest using this number to correct the WBC count and thereby guarantee an adequate WBC concentration for blood banking of umbilical cord blood.

Pipitone S et al. (2012) Clin Chem Lab Med; 50(10): 1857:
Evaluation of automated nucleated red blood cells counting on Sysmex XE-5000 and Siemens ADVIA 2120.

Summary:
The results show excellent analytical performances for the XE-5000, with high accuracy and precision. In agreement with previous studies, the authors also showed that despite similar performance in terms of analytical imprecision, the overall correlation with microscopy is higher for XE-5000 than for ADVIA 2120, i.e., correlation coefficient 0.97 vs. 0.67 and AUC 0.97 vs. 0.73, respectively.

Gasparović V et al. (2012) Coll Antropol; 36(3): 853:
Nucleated red blood cells count as first prognostic marker for adverse neonatal outcome in severe preeclamptic pregnancies.

Summary:
In this study, an increased count of nucleated red blood cells in preterm new-borns born from pregnancies with severe preeclampsia seems to be the first significant marker for detecting adverse neonatal outcome.

Danise P et al. (2011) Clin Chem Lab Med; 50(2): 357:
Evaluation of nucleated red blood cells in the peripheral blood of hematological diseases.

Summary:
NRBC were found in nearly all onco-haematological diseases in this study at diagnosis and frequently during therapy. They were absent at remission.

Kuert S et al. (2011) Clin Chem Lab Med; 49(2): 257:
Association of nucleated red blood cells in blood and arterial oxygen partial tension.

Summary:
In this study, the NRBC count is an independent risk indicator of poor prognosis and mortality, NRBC-positive patients required a longer stay in the intensive care unit.

Danise P et al. (2009) Clin Chem Lab Med; 47(12): 1539:
Nucleated red blood cells and soluble transferrin receptor in thalassemia syndromes: relationship with global and ineffective erythropoiesis.

Summary:
The authors found that the NRBC count helps defining ineffective erythropoiesis in thalassaemia patients and supporting transfusion management.

Stachon A et al. (2007) Crit Care; 11(3): R62:
Nucleated red blood cells in the blood of medical intensive care patients indicate increased mortality risk: a prospective cohort study.

Summary:
In this study, the NRBC count is one indicator of mortality ─ persistence (observed in daily screenings) and high concentration are both indicators for poor prognosis.

Stachon A et al. (2006) Clin Chem Lab Med; 44(8): 955:
Poor prognosis indicated by nucleated red blood cells in peripheral blood is not associated with organ failure of the liver or kidney.

Summary:
The NRBC count is one indicator of mortality independent of other in this study analysed factors such as kidney or liver failure.

Stachon A et al. (2006) Clin Chim Acta; 366(1-2): 329:
Daily monitoring of nucleated red blood cells in the blood of surgical intensive care patients.

Summary:
NRBC count is an early indicator of mortality – daily screening is recommended, by the authors.

Wang F-S et al. (2003) Clin Lab Haematol; 25(1): 17:
Development and clinical application of nucleated red blood cell counting and staging on the automated haematology analyser XE-2100.

Summary:
In this study, the NRBC count correlated well with flow cytometry.

Stachon A et al. (2002) J Lab Clin Med; 140(6): 407:
Nucleated red blood cells indicate high risk of in-hospital mortality.

Summary:
The authors revealed that NRBC are often an only transient observation, but they indicate a poor prognosis, whether transient or persistent.

Briggs C et al. (2000) Clin Lab Haematol; 22(6): 345:
New quantitative parameters on a recently introduced automated blood cell counter - the XE 2100.

Summary:
The automated NRBC count was highly correlated with the manual reference count (r2=0.97). In this study the ‘optical’ platelet count significantly improves the reliability of low platelet counts.

RBC fragments (FRC)

Hisasue M et al. (2021) Clin Lab; 67(1): 15:
Modification of the Algorithm Used by Automated Hematology Analyzer XN-3000 Improves Specificity in the Detection of Schistocytes.

Summary:
A retrospective analysis in 1,026 blood samples showed that the 'Fragments?' flag had a sensitivity of 100% and a specificity of 41.6% in detecting schistocytes. Combination of the flag and the research parameter FRC% balanced the performance of the analyser (sensitivity 86.5%, specificity 70.3%).

Lesesve JF et al. (2015) Int J Lab Hematol; 37(5): 583:
Fragmented red cells reference range for the Sysmex XN®-series of automated blood cell counters.

Summary:
Normal values were determined on the XN-Series for the percentage fragmented red blood cells, FRC%: 0.14 +/- 0.35% (mean 0%). It was also found that HYPO-He correlates with FRC% so, samples with both a high HYPO-He and FRC% should be interpreted with care.

Hervent AS et al. (2015) Int J Lab Hematol; 37(5): 588:
Evaluation of schistocyte analysis by a novel automated digital cell morphology application.

Summary:
This performance evaluation showed that the CELLAVISION Advanced RBC Software Application is easy to use and provides a sensitive and reproducible measurement of schistocytes in peripheral blood.

Lesesve JF et al. (2012) Int J Lab Hematol; 34(6): 566:
Fragmented red blood cells automated measurement is a useful parameter to exclude schistocytes on the blood film.

Summary:
The automated FRC count offered a better degree of certainty than microscopy to exclude the presence of fragmented RBC in this study.

Abe Y et al. (2009) Clin Appl Thromb Hemost; 15(3): 257:
The effectiveness of measuring for fragmented red cells using an automated hematology analyzer in patients with thrombotic microangiopathy.

Summary:
In conclusion, the FRC level was a simple and useful marker for thrombotic microangiopathy (TMA), and an FRC level of 1.2% was recommended by the authors as the cut-off value for the diagnosis of TMA.

Imoto S et al. (2005) Lab Hematol; 11(2): 131:
Usefulness of sequential automated analysis of fragmented red blood cells for the differential diagnosis of TTP-hemolytic uremic syndrome following allogeneic hematopoietic cell transplantation.

Summary:
In this study, sequential monitoring of FRC% was a reliable marker for a specific type of complication (TTP-HUS; thrombotic thrombocytopenic purpura haemolytic uraemic syndrome) after allogeneic haematopoietic precursor cell transplantation.

Banno S et al. (2005) Clin Lab Haematol; 27(5): 292:
Quantification of red blood cell fragmentation by the automated hematology analyzer XE-2100 in patients with living donor liver transplantation.

Summary:
The determination of FRC% by the XE-2100 enables early diagnoses and monitoring of TTP (thrombotic thrombocytopenic purpura) or TMA (thrombotic microangiopathy) in this study.

Reference intervals

Bildirici A et al. (2023) Turk J Biochem; 48(4): 388:
Determination of reference intervals of hemogram with advanced clinical parameters by indirect method on Sysmex XN-1000.

L van Pelt J et al. (2022) Clin Chem Lab Med; 60(6): 907:
Reference intervals for Sysmex XN hematological parameters as assessed in the Dutch Lifelines cohort.

Becker M et al. (2022) Int J Lab Hematol; 44(4): 729:
Differences between capillary and venous blood counts in children - A data mining approach.

Angelo A et al. (2021) BMC Pediatrics; 21: 275:
Umbilical cord blood hematological parameters reference interval for newborns from Addis Ababa, Ethiopia.

Bahr TM et al. (2021) J Pediatr; 236: 95:
Neonatal Reference Intervals for the CBC Parameters “Micro-R” and “HYPO-He”: Sensitivity Beyond the Red Cell Indices for Identifying Microcytic and Hypochromic Disorders.

Summary:
The authors created retrospectively neonatal reference intervals for MicroR% and HYPO-He. They can be measured as part of a neonate’s CBC with no additional phlebotomy volume or run-time and can identify microcytic and hypochromic disorders even when the red cell indices are normal.

Song MY et al. (2021) Int J Lab Hematol; 43(6): 1363:
Establishment of pediatric reference intervals for complete blood count parameters in capillary blood in Beijing.

Summary:
The authors established reference intervals for 22 CBC+DIFF parameters from capillary blood in 6799 children aged 3 months to 18 years from Beijing area in China.

Mrosewski I et al. (2021) Clin Chem Lab Med; 60(3): 408:
Indirectly determined hematology reference intervals for pediatric patients in Berlin and Brandenburg.

Summary:
The study presents indirectly determined CBC reference intervals (RI) for paediatric patients (0-18 years) in Berlin and Brandenburg area in Germany.

Summary:
The study provides reference intervals (CBC+DIFF+RET) that could serve as reference values for haematology parameters in adults for laboratories that use the XN-Series analysers.

Ianni B et al. (2020) Arch Pathol Lab Med; 145(1):66:
Defining Normal Healthy Term Newborn Automated Hematologic Reference Intervals at 24 Hours of Life.

Summary:
Reference intervals on Sysmex XN-Series for normal healthy term newborns at 23-25 hours of life were prospectively established for CBC, IG%, IG#, IRF, RET-He, IPF and IPF#.

Zierk J et al. (2019) Clin Chem Lab Med; 57(10): 159548:
Next-generation reference intervals for pediatric hematology.

Summary:
The aim of the study was to establish reference intervals for CBC, DIFF and reticulocytes for a Spanish population. Significant gender differences were found for RBC, PLT, HCT and HGB.

Reticulocyte haemoglobin equivalent (RET-He/RBC-He)

Czempik PF et al. (2023) Sci Rep; 13(1): 5264:
Iron deficiency in sepsis patients managed with divided doses of iron dextran: a prospective cohort study.

Summary:
The authors found that RET-He quickly normalized in sepsis and septic shock patients under intravenous iron treatment. Increase in RET-He was seen after 4 days of starting the treatment, which was the first measuring point, while HGB levels remained constant. Additionally immature reticulocyte subpopulations showed variations within the same monitoring period, indicating erythropoietic activity.

Almashjary MN et al. (2022) J Clin Med; 11(19): 5675:
Reticulocyte Hemoglobin-Equivalent Potentially Detects, Diagnoses and Discriminates between Stages of Iron Deficiency with High Sensitivity and Specificity.

Summary:
The authors found that RET-He predicted ID/IDA with a sensitivity of 92.7%/90.6% and specificity of 97.9%/92.3% using serum ferritin as a reference. Also RET-He predicted early stages of ID better than RDW and gave indications of iron therapy success after 7 days, whereas HGB was not changed yet.

De Leur K et al. (2022) Int J Lab Hematol; 45(1): 96:
The alternative Thomas-plot: A new tool for effective anemia diagnostics.

Summary:
The authors developed and validated an alternative version of the Thomas plot, plotting RET-He against transferrin/log (ferritin) instead of soluble transferrin receptor/log (ferritin). It was concluded that the alternative Thomas plot delivered similar results in sub-categorising IDA and in reducing the number of anaemias of unknown causes. In the overall distribution of anaemia cases a shift from IDA in the Thomas plot to functional IDA in the alternative Thomas plot was observed.

Hoenemann C et al. (2021) iMedPupJournals; 5(1): 154:
Reticulocyte Haemoglobin as a Routine Parameter in Preoperative Iron Deficiency Assessment

Summary:
The authors of the review recommend RET-He as a routine preoperative parameter to identify patients at risk for latent iron deficiency. RET-He helps to proactively avoid complications during surgery and prevent extended hospitalisation. In contrast to other biochemical parameters it is much cheaper and already available in many hospitals.

Neef V et al. (2021) J Con Med 10: 3506:
The Reticulocyte Hemoglobin Equivalent as a Screening Marker for Iron Deficiency and Iron Deficiency Anemia in Children

Summary:
The study shows that the cut-off value for RET-He to screen for ID was 33.5 pg (sensitivity 90.7%; specificity 35.8%) and 31.6 pg (sensitivity 90.6%; specificity 50.4%) to screen for IDA.

Hoenemann C et al. (2021) J Clin Med; 10(18): 4250:
Reticulocyte and Erythrocyte Hemoglobin Parameters for Iron Deficiency and Anemia Diagnostics in Patient Blood Management. A Narrative Review.

Summary:
This review paper summarises literature with regards to Patient Blood Management. It focuses on RET-He and Delta-He in the context of pre-, during-, and postoperative patient management for anaemia in elective surgeries. They present the advantages in septic patients compared to classical anaemia parameters, and also explain their roles in ICIS and COVID-19 prognostic score.

Auerbach M et al. (2021) Mayo Clin Proc; 96(6): 1510:
Using Reticulocyte Hemoglobin Equivalent as a Marker for Iron Deficiency and Responsiveness to Iron Therapy.

Summary:
Data from CBC and RET-He were able to identify patients with iron deficiency anaemia (RET-He <30.7 pg, 68.2% sensitivity and 69.7% specificity) and determine the need for and the responsiveness to intravenous iron defined as an HGB increase of 1.0 g (RET-He <28.5 pg and HGB <10.3 g/dL, 84% sensitivity and 78% specificity).

Kumar U et al. (2020) J Lab Physicians; 12(1): 15:
Role of Reticulocyte Parameters in Anemia of First Trimester Pregnancy: A Single Center Observational Study

Summary:
A prospective study on first trimester pregnant women revealed that RET-He values were different among normal, borderline and true anaemia, and RET-He <27.8 pg had an AUC of 0.93 for diagnosis of IDA with a sensitivity of 93%.

Bahr TM et al. (2020) J Perinatol; 41(3): 619:
Reconciling markedly discordant values of serum ferritin versus reticulocyte hemoglobin content.

Summary:
In a multicentric study discordances between RET-He and serum ferritin were found in rare cases. 15 out of 16 of these discordances had a low RET-He and high serum ferritin and 13 out of the 15 had a confirmed or suspected infection or inflammation.

Morton SU et al. (2020) Pediatr Qual Saf; 5(2): e258:
Screening With Reticulocyte HemoglobinIncreased Iron Sufficiency Among NICU Patients

Summary:
The authors found that implementation of an iron supplementation guideline utilizing RET-He values can improve iron sufficiency even for heterogeneous out-born neonatal intensive care unit patient populations. Normal RET-He range was defined as 27–38 pg based on published literature and expert consensus.

Chinudomwong P et al. (2020) J Clin Lab Anal; 34(6): e23225:
Diagnostic performance of reticulocyte hemoglobin equivalent in assessing the iron status.

Summary:
RET-He (n = 953) was investigated in a variety of conditions, involving inflammation, and its diagnostic performance was evaluated in assessing the iron status, in this study. Iron deficiency anaemia (IDA) can be ruled out at a cut-off ≥30 pg. For RET-He <30 pg the study proposed a diagnostic algorithm to identify/distinguish between IDA and non-ID anaemia.

Tantawy AA et al. (2019) J Pediatr Hematol Oncol; 42(3): e147:
Reticulocyte Hemoglobin Content (Ret He): A Simple Tool for Evaluation of Iron Status in Childhood Cancer.

Summary:
The authors suggest that RET-He could be considered an easy and affordable tool for assessment of iron deficiency anaemia (IDA) in children with cancer during chemotherapy. Due to the influence of underlying inflammatory conditions, it is judged in this study to be a more reasonable test than conventional iron parameters.

Levy S et al. (2018) Int J Lab Hematol; 40(6): 683:
The clinical utility of new reticulocyte and erythrocyte parameters on the Sysmex XN 9000 for iron deficiency in pregnant patients.

Summary:
This study demonstrates the clinical efficacy of RET-He, %Hypo-He and %Micro-R for detecting ID in nonanemic pregnant patients. The authors point out that this is as well a cost-effective alternative.

Tiwari A et al. (2018) Vox Sang. 2018; 113(7): 639:
Applying newer parameter Ret-He (reticulocyte haemoglobin equivalent) to assess latent iron deficiency (LID) in blood donors-study at a tertiary care hospital in India.

Summary:
The authors concluded that RET -He can be used as a routine screening test to detect latent iron deficiency in blood donors. This could provide an opportunity to make appropriate and timely interventions like dietary changes or drug supplementation.

Jarc E et al. (2017) Zdrav Vestn (Slovenian Med J); 86(1-2): 19:
Comparison of erythrocyte and reticulocyte indices for the diagnosis of iron deficiency.

Summary:
In this study, reticulocytes indices (Sysmex RET-He and Siemens CHr) were directly comparable. RET-He showed a slightly better predictive power for iron deficiency identification in IDA. Hypo-He (Sysmex) and %HYPO (Siemens) were not exchangeable, the authors recommended to use them for long-term iron deficiency evaluation.

Wirawan R et al. (2017) Acta Med Indones; 49(1): 34:
Concordance between Reticulocyte Hemoglobin Equivalent and Reticulocyte Hemoglobin Content in CKD Patients Undergoing Hemodialysis.

Summary:
A very strong correlation (r=0.91) and a good concordance was found between RET-He and CHr with a mean bias of 0.5 pg in chronic kidney disease patients undergoing haemodialysis. The authors concluded that RET-He and CHr can both be used for assessing iron status.

Toki Y et al. (2017) Int J Hematol; 106(1): 116:
Reticulocyte hemoglobin equivalent as a potential marker for diagnosis of iron deficiency.

Summary:
In this publication, RET -He was shown to be a clinically useful marker for determining iron deficiency in the general population and can also be used for the evaluation of the efficacy of iron administration.

Weimann A et al. (2016) Clin Lab; 62(4): 667:
Delta-He, Ret-He and a New Diagnostic Plot for Differential Diagnosis and Therapy Monitoring of Patients Suffering from Various Disease-Specific Types of Anemia.

Summary:
A diagnostic plot using RET-He and Delta-He was developed based on differences between different patient groups suffering from anaemia. The authors showed several case examples to demonstrate the clinical utility of this plot for therapy monitoring.

Buttarello M et al. (2016) Clin Chem Lab Med; 54(12): 1939:
Evaluation of the hypochromic erythrocyte and reticulocyte hemoglobin content provided by the Sysmex XE-5000 analyzer in diagnosis of iron deficiency erythropoiesis.

Summary:
In this study, RET-He and %Hypo-He, measured on the XE-5000, allowed identification of patients with iron deficiency, especially those who had already developed anaemia. RET-He had a better sensitivity, presumably because it is more responsive to iron deficiency.

Urrechaga E et al. (2016) Int J Lab Hematol; 38(4): 360:
Percentage of hypochromic erythrocytes and reticulocyte hemoglobin equivalent predictors of response to intravenous iron in hemodialysis patients.

Summary:
In this study, HYPO-He and RET-He presented as being reliable parameters for the study of erythropoiesis status in haemodialysis patients.

Al-Ghananim RT et al. (2016) J Clin Lab Anal; 30(4): 326:
Reticulocyte Hemoglobin Content During the First Month of Life in Critically Ill Very Low Birth Weight Neonates Differs From Term Infants, Children, and Adults.

Summary:
In this study, RET-He values from the XE-2100 were lower in very low birth weight infants than in term infants, children, and adults. RET-He was 31.8 pg within 24 hr after birth and subsequently declined to a steady-state level of 28.4 pg.

Archer N et al. (2015) Crit Rev Clin Lab Sci.; 52(5): 256.:
Diagnosis of iron-deficient states.

Summary:
This review gives an overview of the haematological, biochemical and genetic markers for identifying iron deficiency. RBC-He, RET-He, Delta-e, HYPO-He and MicroR are mentioned besides the standard RBC indices.

Peerschke EI et al. (2014) Am J Clin Pathol; 142:(4): 506:
Using the Hemoglobin Content of Reticulocytes (RET-He) to Evaluate Anemia in Patients With Cancer.

Summary:
According to the present study, RET-He values above 31 or 32 pg could be used to rule out iron deficiency in cancer patients. The use of RET-He would have reduced the number of biochemical iron studies by 66% (from 209 to 70).

Urrechaga E et al. (2013) Int J Lab Hematol; 35:(2): 144:
Erythrocyte and reticulocyte indices in the assesment of erythropoiesis activity and iron availability.

Summary:
In this study, RET-He and %HYPO-He are helpful in assessing erythropoiesis and iron status.

Schoorl M et al. (2012) Hematology Reports; 4:(4): e24:
Effects of iron supplementation on red blood cell hemoglobin content in pregnancy.

Summary:
In this study, RET-He and RET-He/RBC-He ratio are sensitive markers for screening when a decrease in red blood cell haemoglobin content is observed and for monitoring short-term effects of iron supplementation. The authors recommend integrating these parameters into the protocol for anaemia screening and monitoring during pregnancy.

Schoorl M et al. (2012) Int J Lab Hematol; 34(4): 390:
Temporary impairment of reticulocyte haemoglobin content in subjects with community-acquired pneumonia.

Summary:
In patients with community-acquired pneumonia, acute inflammation at an early-stage results in decreased RET-He levels reflecting acute erythropoietic dysfunction.

Fernandez R et al. (2010) Anesthesiology 112(5): 1211:
Low Reticulocyte Hemoglobin Content Is Associated with a Higher Blood Transfusion Rate in Critically Ill Patients: A Cohort Study.

Summary:
The authors conclude that low reticulocyte haemoglobin content (RET-He) is common at admission at ICU in nonanaemic patients and it is associated with higher RBC transfusion requirements than in patients with normal RET-He values (39.1 % vs. 12.8 %, P = 0.02).

Maier-Redelsperger M et al. (2010) Blood Cell Mol Dis; 45:(4): 289:
Strong association between a new marker of hemolysis and glomerulopathy in sickle cell anemia.

Summary:
The authors created a special algorithm by combining RBC-He, RET-He, and lactate dehydrogenase and used it as a marker for haemolysis which presented a strong correlation with albuminuria in sickle cell anaemia patients.

Jonckheere S et al. (2010) Acta Haematol; 124:(1): 27:
Erythrocyte indices in the assessment of iron status in dialysis-dependent patients with end-stage renal disease on continuous erythropoietin receptor activator versus epoetin beta therapy.

Summary:
Due to fluctuations of iron status parameters, a fixed time point should be used for iron status monitoring during erythropoietin therapy.

Leers MP et al. (2010) Int J Lab Hematol; 32(6 Pt 2): 572:
The value of the Thomas-plot in the diagnostic work up of anemic patients referred by general practitioners.

Summary:
The authors recommended the Thomas-plot as helpful in diagnosing patients referred from general practitioners and differentiating functional iron deficiency from classical iron deficiency.

Schoorl M et al. (2010) Ned Tijdschr Klin Chem Labgeneesk; 35: 206 / Reprinted in Sysmex J Int; 20(1): 12:
Changes in red blood cell hemoglobinization during pregnancy.

Summary:
In this study, RET-He is a useful sensitive and early indicator of iron status in the second half of pregnancy and should ideally be measured in combination with zinc protoporphyrin and IRF.

Van Wyck DB et al. (2010) Am J Kidney Dis; 56:(3): 540:
Analytical and biological variation in measures of anemia and iron status in patients treated with maintenance hemodialysis.

Summary:
This study showed that RET-He could prove superior to transferrin saturation (TSAT) and ferritin in monitoring iron status of haemodialysis patients due to a lower biological variation.

Maconi M et al. (2009) Scand J Clin Lab Invest; 69(3): 365:
Erythrocyte and reticulocyte indices in iron deficiency in chronic kidney disease: comparison of two methods.

Summary:
RET-He and CHr correlate and agree well in evaluating CKD patients needing iron support, in this study.

Miwa N et al. (2009) Int J Lab Hematol 32(2): 248:
Usefulness of measuring reticulocyte hemoglobin equivalent in the management of haemodialysis patients with iron deficiency.

Summary:
RET-He is equivalent to CHr and useful in managing haemodialysis patients with iron deficiency as it responds more rapidly than HGB, in this study.

Mast A et al. (2008) Am J Hematol; 83:(4): 307:
Reticulocyte hemoglobin content.

Summary:
The authors concluded that reticulocyte haemoglobin can be used to differentiate iron deficiency from other causes of anaemia and as an early marker to monitor the therapy.

Thomas C et al. (2006) Med Oncol; 23:(1): 23:
The diagnostic plot: A concept for identifying different states of iron deficiency and monitoring the response to epoetin therapy.

Summary:
A review article about anaemia of chronic disease, markers for iron deficiency and the ‘Thomas plot’, that includes RET-He. Results from a small study with 26 six critically-ill patients receiving epoetin therapy were also discussed. The ‘Thomas plot’ could predict the response to therapy to those patients that had increased erythropoietic activity after treatment.

Brugnara C et al. (2006) Clin Lab Haematol; 28:(5): 303:
Reticulocyte hemoglobin equivalent (Ret He) and assessment of iron-deficient states.

Summary:
In dialysis patients the authors identified RET-He as a reliable marker of cellular haemoglobin content and suggested it usage to identify iron-deficient states. RET-He and CHr presented a good agreement in this study.

Schoorl M et al. (2006) Clin Lab; 52:(11-12): 621:
Erythropoiesis activity, iron availability and reticulocyte hemoglobinization during treatment with hemodialysis and in subjects with uremia.

Summary:
In this study, biochemical parameters reflecting functional iron availability and haematological parameters reflecting haemoglobinisation are interdependent.

Thomas L et al. (2005) Clin Chem Lab Med; 43(11): 1193:
Reticulocyte hemoglobin measurement -- comparison of two methods in the diagnosis of iron-restricted erythropoiesis.

Summary:
A study in 474 anaemic patients showed that RET-He and CHr had an excellent correlation (r=0.92). RET-He could replace CHr in the original ‘Thomas plot’, resulting in an agreement rate of 94.7%.

Canals C et al. (2005) Haematologica; 90(8): 1133:
Clinical utility of the new Sysmex XE 2100 parameter - reticulocyte hemoglobin equivalent - in the diagnosis of anemia.

Summary:
According to the present study RET-He may be useful to support differential diagnosis of iron deficiency anaemia vs anaemia of chronic disease and could also be helpful in the identification of thalassaemia patients.

Buttarello M et al. (2004) Am J Clin Pathol; 121:(4): 489:
The new reticulocyte parameter (RET-Y) of the Sysmex XE 2100: its use in the diagnosis and monitoring of posttreatment sideropenic anemia.

Summary:
The authors concluded that RET-Y closely correlates with CHr and can be used for diagnosis and early monitoring after the administration of intravenous iron.

Reticulocytes (RET/IRF)

Equey T et al. (2022) Int J Lab Hematol; 44(1): 112:
Standardization of reticulocyte counts in the athlete biological passport: A practical update.

Summary:
The study confirms the tendency of a small positive bias for the RET% value determination when switching from XT/XE to XN technology. The proposal of a model allows a suitable comparison of data in the Athletic Biological Passport for the range of RET% encountered in anti-doping.

Feugray G et al. (2022) Front Med; 9: 858911:
Assessment of Reticulocyte and Erythrocyte Parameters From Automated Blood Counts in Vaso-Occlusive Crisis on Sickle Cell Disease.

Summary:
The authors developed an algorithm to predict the probability of a vaso-occlusive crisis (VOC) on sickle cell disease (SCD) patients within the following year. A reticulocyte count (RET) of > 189.4 x10^9/L and a medium fluorescence reticulocytes (MFR) of > 19.75% presented a sensitivity of 81.8% and a specificity of 88% to predict VOC in patients with SCD at steady state.

Jeppesen JS et al. (2021) Drug Test Anal; 13(7): 1331:
Immature reticulocytes are sensitive and specific to low-dose erythropoietin treatment at sea level and altitude.

Summary:
IRF and IRF/RBC ratio changes identified 90% of study participants treated with a micro-dose of recombinant human erythropoietin at sea level during and after the exposure period with a specificity of >99%.

Jiang H et al. (2019) Clin Chem; 65(7): 1251:
Interferents of Automated Reticulocyte Analysis Integrated with Relevant Clinical Cases.

Summary:
XN-9000 showed high agreement with the manual counting method (r = 0.956) in a cohort of 510 samples. The analyser was able to correctly count RET% and RET# in presence of most interferences or indicate result unreliability in severe cases.

La Gioia A et al. (2018) J Clin Pathol; 71(8): 729:
Short preheating at 41°C leads to a red blood cells count comparable to that in RET channel of Sysmex analysers in samples showing cold agglutination.

Summary:
Detailed evaluation of the RET channel in terms of resolving cold-agglutinins. It provides comparable results like traditional manual 37°C/2h pre-treatment and therefore, the authors recommended it to shorten the TAT.

Summary:
In this study, both IRF% and IPF% measured on an XE-5000 predicted neutrophil and platelet recovery, respectively.

Yesmin S et al. (2011) Bangladesh Med Res Council Bull 37(2): 57:
Immature reticulocyte fraction as a predictor of bone marrow recovery in children with acute lymphoblastic leukaemia on remission induction phase.

Summary:
In 52% of paediatric ALL patients, IRF% values rose before NEUT# values during recovery after chemotherapy. Therefore, the authors concluded that monitoring of both parameters may be beneficial.

Goncalo AP et al. (2011) Transplant Proc; 43: 24:
Predictive value of immature reticulocyte and platelet fractions in hematopoietic recovery of allograft patients.

Summary:
In this study, immature platelet (IPF) and immature reticulocyte fraction (IRF) were presented as early and readily available assessment methods for post-transplant bone marrow recovery.

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Urinalysis

Biochemistry

Nah et al. (2021) Annals of Public Health Reports 5(1):152-159:
Screening of Chronic Kidney Disease in Primary Health: Comparison of the Urine Dipstick Albumin-to-Creatinine Ratio and Dipstick Proteinuria.

Summary:
The aim of this study was to compare test strip ACR with proteinuria for CKD screening in a primary healthcare setting. This cross-sectional study included 88,479 specimens with ACR and proteinuria was measured on the UC-3500 automated urine test strip analyser. In conclusion, the CKD risk category using test strip proteinuria was underestimated compared to the ACR-based CKD risk category, suggesting a recommendation of the use of test strip ACR for CKD screening in primary healthcare settings.

Currin et al. (2021) BMC Nephrology 22:103:
Diagnostic accuracy of semiquantitative point of care urine albumin to creatinine ratio and urine dipstick analysis in a primary care resource limited setting in South Africa.

Summary:
This study evaluated the diagnostic accuracy of the semi-quantitative albumin-creatinine ratio (ACR) measurement on the UC-1000 at the point of care by determining the sensitivity, specificity, positive predictive value, and negative predictive value of the ACR. The prevalence of albuminuria in the study cohort was 11.6% and accompanied by underlying diseases such as diabetes and hypertension. The performance showed of the ACR measurement showed a sensitivity of 0.79, a specificity of 0.84, a positive predictive value of 0.39 and a negative predictive value 0.97. The sensitivity improved, if including additional information, such as underlying diseases and age. In summary, the study demonstrated a good NPV for ACR at the point of care, offering the potential for frequent screening of risk group patients and reliable rule-out of albuminuria, if screening for CKD.

Oyaert M and Delanghe JR (2019) J Clin Lab Anal 33(5):e22870:
Semiquantitative, fully automated urine test strip analysis.

Summary:
This study evaluated the analytical and diagnostic performance of the UC-3500 for the presence of glucose, protein, albumin, leukocyte esterase, and hemoglobin peroxidase activity and ordinal scale results in comparison to the analysis of urine sediments using the UF-5000 as well as in comparison to wet clinical chemistry using the Roche cobas® 8000. Especially for detection of glycosuria, proteinuria and albuminuria, a perfect agreement between the reflectance data of the UC-3500 and immunochemistry results has been obtained. This allows the UC-3500 to provide a high‐throughput first‐level screening method for urinalysis which acts as a reliable sieving system to reduce the workload for further validation methods. Especially the albumin measurement fulfills optimum criteria for trueness allowing a reliable, semiquantitative detection of albumin.

Salinas et al. (2019) Clin Chem Lab Med 57(2):204-209:
Urinary albumin strip assay as a screening test to replace quantitative technology in certain conditions.

Summary:
This study aims to evaluate the diagnostic performances of a test strip for measuring ACR for differentiating patients who are candidates for subsequent albumin quantification, and to evaluate the economic effects of its implementation. In conclusion, the detection of albumin and the albumin:creatinine ratio (ACR) is a suitable screening strip test to identify pathological albuminuria for further confirmation through quantitative methods. The performance of the test strip and its workflow benefits do not only foster economic savings, but also elucidates the potential for frequently screening of risk group patients.

Oyaert M et al. (2018) Clin Chem Lab Med 56(7):1126-1132:
Quantitative urine test strip reading for leukocyte esterase and hemoglobin peroxidase.

Summary:
This study investigates diagnostic accuracy of the Sysmex UC-3500 automated urine chemistry analyzer based that uses CMOS sensor technology for leukocyte esterase and hemoglobin peroxidase results. In addition, the influence of urinary dilution, haptoglobin, urinary pH and ascorbic acid on the test results has been assessed. In conclusion, CMOS technology allows to obtain high quality test strip results for assessing WBC and RBC in urine. Quantitative peroxidase and leukocyte esterase are complementary with flow cytometry and have an added value in urinalysis, which may form a basis for expert system development.

Delanghe JR et al. (2017) Clin Chim Acta 471:107-112:
Sensitive albuminuria analysis using dye-binding based test strips.

Summary:
Delanghe and colleagues investigated the potential of the CMOS sensor technology of the UC-3500 for obtaining quantitative albuminuria results in comparison to clinical wet chemistry using the cobas® 8000 immunochemistry analyser. For albumin, this study revealed a limit of detection of 5.5 mg/l, respecting limits for screening for albuminuria in patients at risk of CKD. A strong or good correlation between strip reflectance data and albuminuria creatinine, respectively, potentially allows quantification of albuminuria and ACR by dye-binding test strip.

Bladder Cancer

Shukuya et al. (2023) Practical Laboratory Medicine 23:e00328:
Comparison of the clinical performance of the Atyp.C parameter of the UF-5000 fully automated urine particle analyzer with that of microscopic urine sediment analysis.

Summary:
This study shows that a combination of UF-5000 analysis and microscopic examination of urine sediment improves Atyp.C detection in urine sediment analysis. These results suggest that Atyp.C measured by UF-5000 could be a useful parameter in routine testing of urine samples.

Karaburun et al. (2023) J Med Syst 47(1):41:
Investigation of Atypical Cell Parameter in the Surveillance of Patients with NMIBC; Initial Outcomes of a Single Center Prospective Study.

Summary:
In this prospective study, the Atyp.C parameter demonstrated a potential use in the surveillance of NMIBC patients, showing significantly different values in malignant and non-malignant individuals, as well as between those with high- and low-grade recurrence.

Aydin O (2021) Turk J Biochem; Diagnostic Pathology 16:9:
Atypical cells parameter in Sysmex UN automated urine analyzer: feedback from the field.

Summary:
This study investigates the research parameter “Atypical cells” parameter in context of automated urinalysis to detect cellular atypia as a potential indicator of bladder cancer. In total, 50, mainly female samples with higher than 1 atypical cell/μL result were included in the study with one case of a high-grade urothelial carcinoma. The positive case provided evidence for the capability of the UF-Series to detect atypical cells in urine. The negative cases presented clues that probable vulvovaginal contamination and crowded specimens could be deceptive for this parameter.

Ren C et al. (2020) Diagn Pathol 15(1):77:
Investigation of Atyp.C using UF-5000 flow cytometer in patients with a suspected diagnosis of urothelial carcinoma: a single-center study.

Summary:
This study evaluated the predictive power of the UF-5000 research parameter ‘Atypical Cells’ for patients with a suspected diagnosis of urothelial carcinoma. In total, urinary specimens of 128 patients that were enrolled for urinary cytology analysis were included in this investigation and analysed on the UF-5000, aiming to evaluate its performance in identifying atypical or malignant urothelial cells. The UF-5000 findings were in agreement with cytopathology in 73 % of the investigated cases. Using follow-up histologic diagnosis of urothelial carcinoma with or without urinary tract cytology (UTCy) as a reference standard the sensitivity and specificity were calculated with 59 % and 82.1 %, respectively. This resulted in a positive predictive value of 75.0% and a negative predictive value of 68.8%. In conclusion, the ‘Atypical Cells’ parameter bears the potential of an accessory test for urothelial carcinomas in context of routine urinary diagnostics, that might help to identify high-risk patients that require more specific follow-up and medical treatment.

Tınay İ et al. (2020) Bull Urooncol 19(1):17-19:
“Atypical Cell” Parameter in Automated Urine Analysis for the Diagnosis of Bladder Cancer: A Retrospective Pilot Study.

Summary:
This study evaluated the application of the UF-5000 and its research parameter ‘Atypical Cell’ in supporting the diagnosis of bladder cancer in a retrospective manner in a heterogenous study population. With an acceptable sensitivity of 75 % and a specificity of 100 %, the UF-5000 demonstrated potential value for diagnostic decisions on follow-up cystoscopy for patients with low-risk non-muscle invasive bladder cancer (NMIBC). For patients with high-risk NMIBC, sensitivity and specificity values are lower, but comparable or even better, if compared to cytology. The authors thus revealed the potential to avoid invasive procedures on patient side and to save costs for unnecessary treatments. To further investigate and validate the presented findings, a prospective study is in preparation.

Aydin O et al. (2020) Turk J Biochem; aop:
Atypical cells in Sysmex UN automated urine particle analyzer: a case report and pitfalls for future studies.

Summary:
The UF-4000 automatically detected atypical cells in the urine specimen of a 73-year old individual with recurrent high-grade urothelial carcinoma in an outpatient setting, which was confirmed by manual microscopy, demonstrating the potential of the UF-Series to detect malignancies.

Body fluid

Baran and Ilki (2023) Clin Lab 69(4):
Evaluation of Sysmex UF-5000-BF Module for Sterile Body Fluids. An Alternative for Conventional Methods?

Summary:
This study highlights the capabilities of the UF-Series Body Fluid mode in automated detection of bacterial cells for rapid prediction of positive body fluid culture results. For CSF, pleural and CAPD fluids, the bacteria count showed a sensitivity of 100 % and a NPV of 100 %, allowing the direct rule-out of negative samples with impact on prevention of unnecessary antibiotic treatments in the sense of antimicrobial stewardship, especially in combination with MALDI-TOFF mass spectrometry for rapid pathogen identification.

Siatkowski M et al. (2022) Clin Chim Acta 531:152-156:
Performance evaluation of UF-4000 body fluid mode for automated body fluid cell counting.

Summary:
This study evaluated the performance of the UF-4000 body fluid mode in comparison to manual light microscopy for ascitic, CSF, pleural, synovial and CAPD fluids. The investigation was executed under real operating conditions within a microbiology laboratory setup and revealed an excellent performance for WBC and RBC counting, reaching 100 % sensitivity and 100 % specificity for most fluids. Especially for ascites the body fluid mode showed the potential to rule-out infections in urgent situations. The outcome of this study highlights the potential of the UF-series body fluid mode for partial replacement of manual body fluid assessment methods. Manual methods might be still required for some cases with abnormal WBC cell counts and scattergram distributions, but overall, positive workflow impacts have been observed.

Dossou N et al. (2022) Microbiology Spectrum 10(1):e0183021:
Evaluation of Flow Cytometry for Cell Count and Detection of Bacteria in Biological Fluids.

Summary:
In the light of diagnostic pathway efficiency for the analysis of body fluids in context of monitoring effusion-causing diseases and the diagnosis of infectious diseases, this study aimed to evaluate the analytical performance (I) of the UF-4000 and the XN-10 as methods for the cytological analysis of different body fluids in comparison to manual counting chambers and manual leukocyte differential counts and (II) of the UF-4000 s a method for the microbiological analysis in comparison with direct Grams staining (DGS) and/or the conventional cultures. Three optimal cut-off values have been defined for the prediction of DGS-positivity for peritoneal (465.0 bacteria/μL), synovial (1200.0 bacteria/μL), and cerebrospinal fluids (17.2 bacteria/μL) with maximum sensitivity and highest negative predictive values. In conclusion, bacterial counts, obtained by flow cytometry on the UF-4000 correlate with direct Gram staining and culture results. The body fluid mode of the UF-Series could thus be used to improve upstream of routine microbiological workflows, aiming the improvement and acceleration of the diagnosis of infectious diseases in biological fluids.

Seghezzi M et al. (2021) Diagnosis (Berl). Online ahead of print.:
Performance evaluation of automated cell counts compared with reference methods for body fluid analysis.

Summary:
This study aimed to evaluate the analytical performance of the UF-5000 body fluid mode in comparison to manual microscopy and the body fluid mode of the XN-1000 for different types of non-CSF body fluids. In conclusion, the UF-5000 body fluid mode shows a very good performance for differential counts of cells in ascitic, pleural and synovial and is thus a suitable and reliable tool in automated body fluid analysis.

Cho J et al. (2020) Ann Lab Med 40(2):122-130:
Performance Evaluation of Body Fluid Cellular Analysis Using the Beckman Coulter UniCel DxH 800, Sysmex XN-350, and UF-5000 Automated Cellular Analyzers.

Summary:
Different types of body fluid specimen were examined using manual counting and three the automated cellular analysers XN-350, UF-5000 and UniCel DxH 800. Additionally, 2,779 BF analysis results were retrospectively reviewed. All three analysers showed good agreement for total nucleated cell (TNC) and red blood cell (RBC) counts, except for the RBC count in CSF samples using the UniCel DxH 800. However, variable degrees of differences were observed during differential cell counting. In conclusion, the three automated analysers showed good analytical performances and proper reflex and interpretation guidelines can help to utilise the generated data.

Koo M et al. (2019) J Lab Med Qual Assur 2019; 41(3): 172-178:
Comparison of Red Blood Cell, White Blood Cell and Differential Counts between UF-5000 System and Manual Method.

Summary:
Analysis of body fluids provides important information for assessing various medical conditions. This study aims to validate the analytical and diagnostic performance of the UF-5000 for the analysis of different body fluids. The performance of RBC counts, WBC counts and differentiation of leucocytes was assessed in comparison to light microscopy for ascitic, pleural, and cerebrospinal and other body fluids. In conclusion, the body fluid application on the UF-5000 proved to be an effective and automated alternative to chamber counting in laboratory routine analysis, thereby enhancing laboratory workflow and clinical effectiveness.

Seghezzi M et al. (2017) Clin Chim Acta. 473:133-138:
Preliminary evaluation of UF-5000 Body Fluid Mode for automated cerebrospinal fluid cell counting.

Summary:
This study evaluated the body fluid mode of the UF-5000 for analysis of CSF in comparison to microscopy. The UF-5000 showed a high diagnostic accuracy for TNC, WBC and RBC counts, as well as high sensitivities and specificities and confirmed a low limit of detection for the RBCs. In conclusion, the UF-5000 body fluid mode offers rapid and accurate quantification of cells, including bacterial cells in CSF samples in clinically relevant concentration ranges, allowing the replacement of microscopy for CSF samples without abnormal cell counts or scattergrams.

General / Review

Debunne et al. (2023) Clin Chem Lab Med, oap:
Urine transfer devices may impact urinary particle results: a pre-analytical study.

Summary:
In this study, the group of Prof. Delanghe investigated the effect of different urine collection methods and the associated urine transfer tubes on urine test strip and particle results. Three different transfer tubes (BD, Greiner, Sarstedt vacuum and Sarstedt aspiration) were used, in comparison to direct measurement on the UF-5000 and UC-3500 analysers. Whereas there were no significant differences found in the test strip results, transfer of urine samples to the secondary tubes affected their particle counts. Clinically significant reductions in counts of renal tubular epithelial cells and hyaline casts were observed using the BD and Greiner transfer tubes and in counts of pathological casts using the BD, Greiner and Sarstedt vacuum tubes. The results of this study indicate that the use of urine transfer tubes may impact counts of fragile urine particles. Clinical laboratories need to be aware about the variation that urine collection methods can induce on urine particle counts.

Antimicrobial Resistance Collaborators (2022) Lancet 399:629-655:
Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis.

Summary:
Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous publications have estimated the effect of AMR on incidence, deaths, hospital length of stay, and health-care costs for specific pathogen–drug combinations in select locations. To our knowledge, this study presents the most comprehensive estimates of AMR burden to date.

Oyaert M et al. (2022) Clin Chem Lab Med, oap:
Improving clinical performance of urine sediment analysis by implementation of intelligent verification criteria.

Summary:
In this study, urinary diagnostic data, obtained from urinary test strip analysis on the UC-3500 and urinary flow cytometry on the UF-5000 are combined with intelligent verification criteria, aiming to evaluate improvements in diagnostic performance in context of combination of diagnostic data. In summary, the implementation of intelligent verification and review rules improved the diagnostic performance of urinary flow cytometry.

Oyaert M and Delanghe JR (2019) Ann Lab Med 39(2):15-22.:
Progress in Automated Urinalysis.

Summary:
This publication is a comprehensive review of the current status of automated urinalysis, highlighting the potential quantitative reading of urinary test strips using CMOS technology for albuminuria testing and the value of urinary flow cytometry for the differentiation of urinary microorganisms, screening for urinary tract infections and clinical decision support in a variety of nephrological and urological diseases. In addition, progress in automated urinary microscopy and the improved pathogen identification by MALDI-TOF mass spectrometry is reflected and an outlook into future technologies, such as laboratory-on-a-chip approaches, use of microfluids and mobile applications is given.

MICROBIOLOGY & ANTIMICROBIAL RESISTANCE

Chen Y et al. (2023) J Infect Chemother 29(7):667-672:
Combination of UC-3500 and UF-5000 as a quick and effective method to exclude bacterial urinary tract infection.

Summary:
This study evaluated the performance of the combination of the UC-3500 and the UF-5000 in screening for bacterial urinary tract infection (UTI). Applying cut-off values of 32.20/μL (male) and 39.15/μL (female) for WBC as well as 22.35/μL (male) and 127.25/μL (female) for BACT allowed effective determination of urinary tract infections. The combiation of WBC, BACT and LEU in a joint screening programs were identified as suitable approach to rapidly and effectively exclude bacterial UTI.

Wang H et al. (2023) PLoS One 18(2):e0281118:
Accuracy of the Sysmex UF-5000 analyzer for urinary tract infection screening and pathogen classification.

Summary:
This study aimed to investigate the screening performance of the UF-5000 for UTI and the BACT Info flag for discrimination of Gram-positive and Gram-negative pathogens. The decision curve showed that urinary bacteria had a higher predictive benefit than WBC with a sensitivity and specificity of the decision tree were 0.69 and 0.95, respectively. The flag of Gram-negative had a positive predictive value (PPV) of 0.93 in patients with urine bacteria > 1367 /μl. In conclusion, urine bacteria determined by the UF-5000 had higher screening performance and greater benefit than WBC. A decision tree can be used to improve the screening performance of routine urinary parameters. The flag of Gram-negative is a reliable indicator to confirm gram-negative bacteria infection in UTI patients.

Yanılmaz Ö & İlki AA (2022) New Microbiologica 45(4):292-295:
Performance of Sysmex UF-5000 for candiduria screening.

Summary:
This study evaluated the performance of the UF-5000 for the assessment of candidurias to detect or exclude fungal infections by applying the yeast-like cell (YLC) parameter. If compared to Candida culture, the use of a cut-off of 5 YLC/µl resulted in an excellent diagnostic performance with 100 % sensitivity, 95 % specificity a negative predictive value of 100 % and a positive predictive value of 66 %. In conclusion, the performance of the YLC parameter allows the exclusion of candidurias with positive impact on laboratory workflows and antimicrobial stewardship.

Szmulik M et al. (2022) Front Cell Infect Microbiol 12:936854:
A novel approach to screening and managing the urinary tract infections suspected sample in the general human population.

Summary:
This study evaluated the performance of laboratory indicators of UTI on digital imaging (Iris iQ®200 ELITE) and fluorescence flow cytometry (UF-5000) urinalysis instruments, as well as by dip stick testing. For the prediction of urine culture results for UTI, based on WBC and/or BACT, a good diagnostic performance has been observed with a sensitivity of 100 % and a specificity of 83.7 %, resulting in a negative predictive value of 100 % and a s positive predictive value of 75 %. This outcome further highlights the capabilities of the UF-series to rule-out UTIs and to positively improve laboratory workflows in context of UTI.

Chun TTS et al. (2022) Front Cell Infect. Microbiol. 12:936854:
The diagnostic value of rapid urine test platform UF-5000 for suspected urinary tract infection at the emergency department.

Summary:
This study evaluated the diagnostic utility of the UF-5000 for the prediction of UTIs at the emergency department in comparison to dipstick and urine culture. The results of this study highlight the capability of the UF-5000 to predict negative urine culture and to support the laboratory UTI diagnostic pathway, thereby clearly outperforming dip stick assessment with improved predictive values. In addition, the performance of the ‘BACT Info’ flag, especially for Gram negatives with a concordance of 96.2 %, if compared to urine culture might support clinical decisions.

Torres-Sangiao E et al. (2022) Antibiotics 11(5):663:
Direct Urine Resistance Detection Using VITEK 2.

Summary:
This study evaluated the combination of different diagnostic technologies including urine flow cytometry, MALDI-TOF mass spectrometry and automated antibiotic susceptibility testing to reduce the time for reporting UTI-positive samples and proposing a suitable antibiotic susceptibility profile. The aim is to allow fast and precise treatment, thereby minimising the risk for antimicrobial resistance. In this context, the UF-5000 was used to select samples, suspected to be positive for UTI, here BACT counts ≥ 150 cells/mL and the ‘Gram Negative?’ flag were used. After confirmation by MALDI-TOF mass spectrometry, samples positive for E. coli were subjected to AST on VITEK 2. In summary, this study proposes a combination of diagnostic techniques to foster a rapid diagnosis of UTI without the need for long-lasting urine cultures.

Christy P et al. (2022) Int J Nephrol: eCollection 2022:
Comparison of Laboratory Diagnosis of Urinary Tract Infections Based on Leukocyte and Bacterial Parameters Using Standardized Microscopic and Flow Cytometry Methods.

Summary:
This study evaluated a reduction of laboratory turn-around-time for suspected urinary tract infections using the UF-5000 urinary flow cytometry using bacteria and leucocyte counts in comparison to the Shih-Yung microscopy method. In conclusion, urinary flow cytometry showed a very good performance in detecting acquired symptomatic UTIs and a high agreement with culture results.

Kim et al. (2022) Clin Lab 68(12):
Clinical Usefulness of BACT Count and BACT-Info Flag of UF-5000 for Screening for Urinary Tract Infection and Prediction of Gram-Negative Bacteria.

Summary:
In need of a rapid and reliable screening test for (UTI), helping to reduce the turn-around time and to rule out negative results of urine culture, this study assessed the performance of the BACT count and the BACT-Info flag of the UF-5000. The authors recommend the use of a combination of BACT count (685.3/µL) and BACT-Info for UTI assessment, which appeared to be more appropriate for Gram-negative bacteria, and could support the selection of selecting empirical treatment.

Gilboe HM ET AL. (2021) PLoS ONE 16(7): e0254064:
Rapid diagnosis and reduced workload for urinary tract infection using flow cytometry combined with direct antibiotic susceptibility testing.

Summary:
This study evaluated the potential impact of urinary flow cytometry of the UF-5000 on the rapid identification of culture negative and contaminated samples prior to culture plating and on the prediction of positive samples for antibiotic susceptibility testing. Using a cut-off value with bacterial count ≥100,000/mL and WBCs ≥10/μL, urinary flow cytometry predicted 42.1% of samples with non-significant growth and for 52/56 positive samples containing Gram negative bacteria direct Antibiotic Susceptibility Testing (dAST) was identical to routine testing. Overall, there was concordance in 555/560 tested antibiotic combinations. In conclusion, flow cytometry offers improvements in UTI diagnostics by reducing the response times and workloads for negative samples on the day of arrival and by predicting Gram-positive samples for Antibiotic Susceptibility Testing (AST), allowing a same day report of antibiotic susceptibility profiles.

Alenkaer LK et al. (2021) Scand J Clin Lab Invest 81(5):379-384:
Evaluation of the Sysmex UF-5000 fluorescence flow cytometer as a screening platform for ruling
out urinary tract infections in elderly patients presenting at the Emergency Department.

Summary:
This study evaluated the potential of the UF-5000 to rule-out UTI in elderly patients. Using a patient group-specific cut-off value of 108 CBU/L an NPV of 0.92 has been achieved, allowing to rule-out clinically irrelevant cases, potentially saving up to 36% of ordered urine. Due to the quick availability of results, compared to urine culture, the UF-5000 also offers the possibility to better guide the prescription of antibiotics.

Mancini S et al. (2020) J Antimicrob Chemother 75(11):3218-3229:
Evaluation of standardized automated rapid antimicrobial susceptibility testing of Enterobacterales-containing blood cultures: a proof-of-principle study.

Summary:
In this study, the preparation of standardized bacterial inocula for Enterobacterales-containing clinical blood cultures and the automated assessment of data of a rapid antimicrobial susceptibility testing (RAST) is reported, aiming to accelerate antibiotic therapy decisions. The UF-4000 was used to enumerate bacteria to adjust the inocula to 106 cfu/mL. Disc diffusion plates were automatically streaked, incubated for 6, 8 and 18 h and imaged automatically. In conclusion, with the standardized and automated RAST method, consistent AST data from blood cultures containing Enterobacterales can be generated after 6–8 h of incubation and subsequently confirmed by standard reading of the same plate after 18 h.

Ippoliti R et al. (2020) Microbiologyopen 9(3):e987.:
UF-5000 flow cytometer: A new technology to support microbiologists' interpretation of suspected urinary tract infections.

Summary:
This case study aimed to describe the adoption of UF-5000 in context of the microbiology diagnostic pathways to investigate suspected urinary tract infections (UTIs). In conclusion, the UF-5000 can provide information improve the identification of both contamination and colonization, thus reducing inappropriate antibiotic prescriptions. An implementation of this technology thus allows the supply of sustainable treatments by hospitals, especially in context of the reduction of unnecessary use of antibiotics in false-positive results, obtained by reference methods.

Oyaert M et al. (2020) Clin Chem Lab Med 58(4):597-604:
Renal Tubular Epithelial Cells Add Value in the Diagnosis of Upper Urinary Tract Pathology.

Summary:
Oyaert and colleagues evaluated the analytical performance characteristics of renal tubular epithelial cells (RTECs) and transitional epithelial cells (TECs) on the Sysmex UF-5000 urine sediment analyser, as well as the diagnostic performance of these parameters to differentiate between lower and upper UTI. In comparison to transitional epithelial cells (TEC), increased urinary levels of renal tubular epithelial cells (RTEC) demonstrated a good potential to serve as a marker for the diagnosis of upper UTI and outperforms α1-micrglobulin in the discrimination between upper and lower UTI. However, the diagnostic performance of these parameters is strongly depending on proper sample handling.

Wagner K et al. (2019) J Glob Antimicrob Resist 19:8-13:
Evaluation of the AID AmpC line probe assay for molecular detection of AmpC Enterobacterales.

Summary:
This study investigated the use of commercially AID AmpC line probe assays for analysis of antibiotic resistance by detection of plasmid-mediated blaAmpC β-lactamase genes in Enterobacterales, which proofed to be an accurate, sensitive and easy-to-use test that can be readily implemented in any diagnostic laboratory. In this context, the UF-5000 has been demonstrated to be a reliable tool to judge samples, sent for molecular testing, for the presence of bacteriuria and to reduce the number of unnecessary molecular testing.

Öğüş E et al. (2019) ASMS 3(6):88-92:
Compatibility of the Results of an Automated Urine Analyzer with Urine Culture.

Summary:
This study evaluated the incidence of leukocyte esterase and nitrite positivity, leukocyte and bacterial counts in urine and Gram positive and negative bacterial results interpreted by the UF-5000 for compliance with urine culture results. Incorrect results for the Gram status in comparison to urine culture was obtained for three Gram-positive and three Gram-negative samples. Rates of leucocyte esterase, nitrite positivity, leukocyte and bacterial counts were higher in Gram negative group. In conclusion, especially Gram-negative bacterial interpretation obtained from the UF-5000 be beneficial for rapid typing of bacteria and early treatment in urinary tract infections.

De Rosa R et al. (2018) Clin Chim Acta 484:171-178:
Evaluation of the new Sysmex UF-5000 fluorescence flow cytometry analyser for ruling out bacterial urinary tract infection and for prediction of Gram-negative bacteria in urine cultures.

Summary:
De Rosa and colleagues investigated the potential of the UF-5000 to rule-out urinary tract infections and its ability to predict the presence of Gram-negative bacteria in urine samples with a request for urine culture in context of a suspected urinary tract infection. With neglectable carry-over and cross-contamination, the UF-5000 demonstrated a high screening performance for urinary tract infections with a high sensitivity and NPV for the bacteria using a cut-off of ≥58/μl. The ‘Gran Neg?’ flag predicted Gram negative urine cultures with good sensitivity and high specificity. In conclusion, the UF-5000 represents a reliable tool for ruling-out urinary tract infections with high diagnostic accuracy and offers the possibility to detect Gram-negative bacteria in very high agreement with urine culture. Further investigations might reveal the potential for the Gram information for targeted antibiotic.

Kim SY et al. (2018) J Clin Microbiol 56(8):e02004:
Rapid Screening of Urinary Tract Infection and Discrimination of Gram-Positive and Gram-Negative Bacteria by Automated Flow Cytometric Analysis Using Sysmex UF-5000.

Summary:
Kim and colleagues evaluated the performance of the UF-5000 in context of UTI screening, aiming to reduce unnecessary urine culture and improve the determination of antibiotic treatments. The performance to discriminate Gram-negative bacteria was superior to that for Gram-positive bacteria with high sensitivity and specificity in ≥105 CFU/ml monobacterial samples. In conclusion, the UF-5000 demonstrated a potential utility for the rapid screening of negative bacterial cultures, depending on the respective patient population, requiring cut-off optimization.

Duyeal Song et al. (2018) Ann Clin Microbiol 21(4):75-79:
Selection of Unnecessary Urine Culture Specimens Using Sysmex UF-5000 Urine Flow Cytometer.

Summary:
This study investigated the potential of the UF-5000 to support the reduction of unnecessary urine cultures by ruling-out bacterial and fungal urinary tract infections. Applying urinalysis cut-off values of 50/µl and 100/l for bacteria and YLC, respectively, 84 out of 126 requested urine cultures were negative and could have been ruled-out by the UF-5000. In conclusion, the bacteria and yeast-like cell counts delivered by the UF-5000 could be used to predict negative cultures and reduce the load of urine cultures by around 10% without sacrificing positive cultures.

Kawamura K et al. (2017) Jap J Med Technol 66(5):516-523 [Article in Japanese]:
Evaluation of automated urine particle analyzer, UF-5000, as a screening tool to identify Gram stainability of urinal pathogens.

Summary:
Kawamura and colleagues evaluated the performance of the UF-5000 with regards to the provision on information on the Gram status of bacterial cells via the BACT-info flag in comparison to conventional methods including Gram staining and quantitative bacterial culture. In summary, the UF-5000 presented in 83.2 % of UTI cases a Gram information, in line with classical Gram staining. The UF-5000 exhibited a high positive predictive value (93.3%) for both Gram negative staining and culture results. Thus, the UF-5000 using BACT-info shows great promise in screening for UTI pathogens and further improvements of judgement algorithms might make the Gram judgement even more reliable.

Geerts N et al. (2016) Clin Chim Acta 452:173–176:
Cut-off values to rule out urinary tract infection should be gender-specific.

Summary:
This study investigated the potential of urine flow cytometry of the UF-5000 to rule-out urinary tract infections and to reduce the load of urine culture samples. Applying cut-off value of >200 bacteria/μl, a sensitivity of 93.0%, a specificity of 63.5% and an NPV of 96.2% has been obtained. As a result, the culturing of 49% of all samples could be avoided. In addition, the data was retrospectively analyzed to determine if the introduction of gender-specific cut-off values could improve screening results. The obtained receiver operator curves are indeed significantly different when gender specific cut-offs were used. When an NPV of 95% is considered acceptable the unisex cut-off value of >200bacteria/μl can be used for women (NPV 94.9%), but the cut-off value for men could be raised to >400bacteria/μl without diminishing the NPV (NPV 95.0%).

Medicoeconomics

Herráez Carrera Ó and Jarabon Bueno MDM (2020) Pharmacoecon Open 10(22) [Online ahead of print]:
Cost analysis of the automated examination of urine with the Sysmex UN-SeriesTM in a Spanish population.

Summary:
This study aimed to investigate the potential of the Sysmex UN-Series to reduce high financial costs and high and time-consuming laboratory workloads of current urinalysis practice. By investigating more than 90,000 handled urine samples of a 10-year period, including financial data and alternative costs of reference and test scenarios, potential average cost savings of 340,000 € per year was identified for the use of automated urine examination, compared to the current urinalysis practice. On top, the UN-Series has the potential to reduce the annual working hours of laboratory personnel to up to 1615 hours. In conclusion, the implementation of the UN-Series within routine practice in clinical laboratories could minimise costs, provide substantial savings for investment, improve laboratory procedures and could contribute to synergy between clinical analysis and microbiology laboratories.

Nephrology

Cho H Y et al. (2022) Ann Lab Med 42(2):160-168:
Diagnostic Characterisation of Urinary Red Blood Cell Distribution Incorporated in UF-5000 for Differentiation of Glomerular and Non-Glomerular Hematuria.

Summary:
This study evaluated the potential of the UC-3500/UF-5000 to screen for Lupus nephritis, a common glomerular disease. The investigation revealed an excellent agreement for the accuracy for assessing the protein-to-creatinine ratio by the UC-3500, if compared to clinical chemistry and good agreement for the detection and quantification of RTECs by the UF-5000, if compared to manual microscopy. RTECs have been shown to be significantly elevated in Lupus nephritis patients. The data highlight a good screening capability for increased protein-to creatinine ratios (specificity of 97.5 % and an a PPV of 96.46 %) or elevated RTEC and protein-to-creatinine ratios (specificity of 97.5 % and an a PPV of 94.03 %). Sensitivity (95.97 %) and NPV (96.24 %) were highest in case only one parameter was positive. In conclusion, the UN-2000 (UC-3500 and UF-5000) can be used to screen for Lupus nephritis.

Chen Y et al. (2022) BMC Nephrology 23:328:
Sysmex UN2000 detection of protein/creatinine ratio and of renal tubular epithelial cells can be used for screening lupus nephritis.

Mizuno G et al. (2021) Clin Chem Lab Med 59(9):1547–1553:
Evaluation of red blood cell parameters provided by the UF-5000 urine auto-analyzer in patients with glomerulonephritis.

Summary:
This study investigates the potential the UF-5000 for interpretation of morphological information of glomerular RBC by using the UF-5000 RBC-related parameters small RBC (UF-%sRBC) and Lysed-RBC in context of glomerulonephritis in comparison to time-consuming and labour-intensive microscopic examination of haematuria. The data indicate that the UF-%sRBC and Lysed-RBC values differed significantly between glomerulonephritis and non-glomerulonephritis cohorts. Cut-off values have been defined for UF-%sRBC as >56.8% (AUC = 0.649; SE = 94.1%; SP = 38.1%; PPV = 68.3%; NPV = 82.1%) and for Lysed-RBC as >4.6/μL (AUC = 0.708; SE = 82.4%; SP = 56.0%; PPV = 72,6%z, NPV = 69.1%). In conclusion, the applied cut-off values for the UF-5000 RBC parameters UF-%sRBC and Lysed-RBC demonstrated sufficient diagnostic performance to support the diagnosis of glomerulonephritis.

Performance Evaluation / Comparison

Demirel OU et al. (2022) Medicine Science 11(1):367-371:
Comparison of Sysmex UF-5000 flow cytometer and Fuchs-Rosenthal chamber urine sediment analysis.

Summary:
This study evaluated the diagnostic performance of urine sediment analysis performance of the Sysmex UF-5000 flow cytometer with the manual Fuchs-Rosenthal counting chamber. In summary, flow cytometry urinalysis is a promising area compared to the manual reference method. Urinalysis automation reduces TAT, laboratory workloads and workforce and the need for microscopic review.

Yis et al. (2022) Clin Lab 69(3):
Performance Evaluation of Urine Osmolality Measurement on Sysmex UF-5000 and the Effect of Molecules and Particles in Urine.

Summary:
This study evaluated the analytical performance of osmolality measurement of the UF-5000, to examine the effect of different molecules and particles in the urine on the osmolality measurement. Considering the good accessibility of the automated routine complete urine analyser, UF-5000 can be considered to determine whether urine osmolality is within reference or should be measured by methods based on colligative properties. Thus, referral of patients to a clinic that uses the colligative measurement method may be used more effectively.

Yang et al. (2021) BMC Urol 21:24:
A performance comparison of the fully automated urine particle analyzer UF-5000 with UF-1000i and Gram staining in predicting bacterial growth patterns in women with uncomplicated urinary tract infections.

Summary:
This study aims to compare the performance of the new UF-5000 and the UF-1000i and Gram staining for determining bacterial patterns in urine samples. Mid-stream urine samples of women with symptoms suggestive of urinary tract infection were collected for gram staining, urine analysis and urine cultures. Bacterial patterns were classified using the UF-1000i, the UF-5000 and Gram staining. The collected data revealed a sensitivity/specificity of the UF-1000i of 81.8/91.1% for gram-negative rods and 23.5/96.9% for cocci/mixed. The sensitivity/specificity of the UF-5000 was 80.0/88.2% for gram negative rods and 70.0/86.5% for gram-positive cocci. In conclusions, the UF-5000 demonstrated good sensitivity and specificity for Gram-negative bacilli and demonstrated an improved sensitivity for detecting Gram-positive cocci compared with the UF-1000i.

Enko D et al. (2020) Clin Chem Lab Med 58(2):268-273 [Online version from 2019]:
Comparison of the diagnostic performance of two automated urine sediment analyzers with manual phase-contrast microscopy.

Summary:
Enko and colleagues demonstrate that the analytical performance of the UF-5000 is in strong concordance with manual phase-contrast microscopy and clearly outperforming the Roche cobas® u 701 module. This study included a broad spectrum of urine sediment pathologies, thereby proving the UF-5000 to be a reliable tool for automated urine sediment analysis in daily clinical practice.

Kucukgergin C et al. (2019) Scand J Clin Lab Invest. 79(7):468-474.:
Performance of automated urine analyzers using flow cytometric and digital image-based technology in routine urinalysis.

Summary:
This study evaluates the analytical performances of the UF-5000 and the Dirui FUS-200, to manual microscopy. Thereby, all available urinalysis aspects and sediment results were investigated within one hour after sample collection. Accurate results have been obtained from both analytical systems, the FUS-200 and the UF-5000, as good linearity without carry- over has been shown. Overall, the UF-5000 demonstrated better agreement in classification of WBCs, RBCs, ECs, positively affecting the morphologic recognition and enumeration of cells.

Cho J et al. (2019) Clin Chem Lab Med 57(11):1744-1753:
Comparison of five automated urine sediment analyzers with manual microscopy for accurate identification of urine sediment.

Summary:
This study evaluated the analytical and diagnostic performance of the Sysmex UF-5000, the Roche cobas® u 701 module, the URiSCAN PlusScope and the Iris iQ200SPRINT and the SIEMENS UAS800 in comparison to manual microscopy. Each automated urine sediment analyzer has certain distinct features, in addition to the common advantages of reducing the burden of manual processing. Therefore, laboratory physicians are encouraged to understand these features, and to utilize each system in appropriate ways, considering clinical algorithms and laboratory workflow.

Bakan E et al. (2018) Biochem Med (Zagreb) 28(2):020712:
Evaluation of the analytical performances of Cobas 6500 and Sysmex UN-Series automated urinalysis systems with manual microscopic particle counting.

Summary:
This study compared the diagnostic performance of the UF-5000 and the Roche cobas® u 701 module to manual microscopy. Comparing the quantification of WBCs and RBCs, the UF-5000 obtained the better sensitivities and specificities and showed high agreement with manual microscopy. In conclusion, the UF-5000 is a reliable tool for urine sediment analysis, but pathological samples should be confirmed by microscopy.

Previtali G et al. (2017) Clin Chim Acta 472:123-130:
Performance evaluation of the new fully automated urine particle analyser UF-5000 compared to the reference method of the Fuchs-Rosenthal chamber.

Summary:
Previtali and colleagues evaluated the analytical performance of the Sysmex UF-5000 for urine sediment samples compared manual particle counting using the Fuchs-Rosenthal chamber. The study demonstrated high linearity performances for RBCs, WBCs and epithelial cells, as well as high negative predictive values and good sensitivities and specificities for all parameters, especially those of clinical relevance. The authors conclude a high potential of the UF-5000 and its fluorescence flow cytometry technology to investigate urine sediment particles related to pathological conditions of the kidneys and the urinary tract.

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White Blood Cells

Flagging

Ramiah J L et al. (2023) Afr J Lab Med; 12(1): 2140:
Performance of the automated Sysmex XN-3000 analyser for detecting white blood cell abnormalities in South Africa.

Summary:
A comparison study between WBC flagging and microscopic evaluation in 250 samples (45% haematologic malignancies) showed that 'Blasts?' and 'Abn Lympho?' had a sensitivity of 96.3% and 90% respectively, and a specificity of 84.9% and 96.3%. Low WBC count, chemotherapy, presence of malignancy and/or infection were factors that were associated with discrepant results between flagging and microscopy.

Dedeene L et al. (2022) Int J Lab Hematol; 44(4): e153:
"Smart” WPC reflex testing enables optimal use of the WPC channel in the detection of malignant blood samples using Sysmex XN-9100.

Summary:
In this follow-up publication of Blomme S et al. 2021, the authors have adjusted the criteria for WPC reflex testing. The revised workflow resulted overall in a 40% reduction in the number of WPC reflex tests and a 16% reduction in smear reviewing in a routine set-up.

Blomme S et al. (2021) Int J Lab Hematol; 43(2): 191:
The integration of Sysmex XN-9100’ WPC channel reflex testing in the detection of reactive versus malignant blood samples.

Summary:
In this study the WPC reflex testing showed excellent sensitivity (99%), but low specificity (29%). Using reflex WPC to the WDF channel resulted in a 12% reduction of the smear review rate. The authors suggested workflow for the optimal use of the WPC channel in a routine setting.

Moioli V et al. (2020) Scand J Clin Lab Invest; 80(1): 55:
A specific abnormal scattergram of peripheral blood leukocytes suggestive for the presence of proerythroblast.

Summary:
In this publication two cases of myeloproliferative disorder patients are described. Abnormal cell clusters in the WNR, WDF and WPC scattergrams were present. In oncological patients, this likely indicates the presence of proerythroblasts as a symptom of an erythroid leukaemia and therefore the XN scattergrams were suggested to support a rapid stratification.

Paridaens H et al. (2019) Ann Biol Clin (Paris); 77(4): 422:
Can the 72-hour rule based on "Blast/Abn Lymph" flag on Sysmex XN-10 optimize the workflow in hematology laboratory?

Summary:
The authors verified GFHC rules for reducing unnecessary smears and even extended the rules for further smear reduction when using XN analysers. The very good sensitivity (93%) and specificity (94%) of the Blast/Abn Lympho? flag was confirmed in line with smear reduction of 5.7% and associated cost reduction.

Schuff-Werner P et al. (2016) Clin Chem Lab Med; 54(9): 1503:
Performance of the XN-2000 WPC channel-flagging to differentiate reactive and neoplastic leucocytosis.

Summary:
The XN-1000 demonstrated an excellent performance for differentiation between neoplastic and reactive leukocytosis.

Ulset R J et al. (2014) Clin Lab; 60(12): 1961:
“Aged Sample” Software on Automated Routine Hematology Analyzer Enables Differentiation Between Pathological and Non-Pathological WBC Flagging in Aging Samples.

Summary:
'Aged Sample Identifier' software not only detects and labels samples that are ageing or were stored under suboptimal conditions, but also prevents false positive flagging.

Hotton J et al. (2013) Am J Clin Pathol; 140: 845:
Performance and Abnormal Cell Flagging Comparisons of Three Automated Blood Cell Counters: Cell-Dyn Sapphire, DxH-800, and XN-2000.

Briggs CJ et al. (2011) Am J Clin Pathol; 136: 309:
Improved Flagging Rates on the Sysmex XE-5000 Compared With the XE-2100 Reduce the Number of Manual Film Reviews and Increase Laboratory Productivity

Summary:
The increased specificity of the XE-5000 eMM (efficient multichannel messaging) flagging reduces the number of manual film reviews, particularly for blast and abnormal lymph flags.

General WBC

Tabata M et al. (2024) Clin Chem Lab Med; online ahead of print:
Performance evaluation and user experience of BT-50 transportation unit with automated and scheduled quality control measurements.

Fujimaki K et al. (2024) Pract Lab Med; 39: e00370:
Performance evaluation of the new Sysmex XR-Series haematology analyser.

Summary:
The XR analyser had very good analytical performance, and highly comparable results to the predecessor XN analyser in all investigated parameters, flags and workflow aspects. The correlation coefficients between the two systems for the parameters tested were greater than 0.909. High sensitivities for the detection of abnormal cells were observed for the ‘Blasts/Abn Lympho?’ flag (XN: 100%, XR: 99.0%) and WPC abnormal flags (‘Blasts?’ or ‘Abn Lympho?‘) (XN: 97.0%, XR: 96.0%).

Coutaz C et al. (2024) J Clin Lab Anal; 38(4): e25017:
Evaluation of the Sysmex XQ-320 three-part differential haematology analyser and its flagging capabilities.

Summary:
The XQ-320 showed excellent analytical performance in selected categories. A method comparison with XN-9000 and XP-300 in a cohort of 493 samples enriched with abnormalities showed correlation values greater than 0.94 for the majority of the 20 reportable parameters, with better results than XP-300. Specific parameter patterns on XQ-320 could differentiate abnormal samples that were only identified by the extensive XN-9000 flagging algorithms.

Kaneda M et al. (2024) J Infect Chemother; 30(10): 983:
Time-dependent changes in cell population data obtained using Sysmex XN-series hematology analyzer in bacterial infections.

Summary:
A study in patients with acute bacterial infection that developed sepsis (n=25) showed that NE-WY peaked on d0, the starting point of antibiotic treatment, and was then gradually decreasing on d1 and d3, when all patients improved. NE-WY also correlated with the blood bacterial load on d0 and d1 in PCR-proven infections irrespective of the sepsis status (n=22).

Akbari P et al. (2023) Nat Commun; 14(1): 5023:
A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology.

Summary:
The authors performed the first genome-wide association study to investigate the genetic basis of 63 blood cell morphological traits (Sysmex parameters). They identified key cellular proteins associated with disease aetiologies (e.g. multiple sclerosis) and highlighted the importance of genetic factors in influencing blood cell parameters (e.g. ZFPM2 gene expression for platelet granularity).

Bouriche L et al. (2023) Int J Lab Hematol; 46(2): 286:
Detection of dysplasia in peripheral blood: Proposal of an algorithm to detect myelodysplastic syndromes and chronic myelomonocytic leukemias on a high-speed technical platform using the Sysmex XN™ analyser.

Summary:
A decision tree utilising the MDS-CBC and mono-dysplasia scores had a 94.4% sensitivity and 91.4% specificity in identifying MDS (n=18) and CMML (n=18) samples within a cohort of 749. Routine implementation of the tree compared to using the recommended cytopenia or monocytosis criteria in over 25,000 samples significantly reduced the smear workload.

Dai Q et al. (2023) Clin Chem Lab Med; 61(7): e131:
Spurious low WBC count in the WNR channel of Sysmex XN-9000 hematology analyzer in a case with leukocyte aggregation.

Summary:
A sample of an 11-year-old girl infected with Cryptococcus neoformans led to discrepancies between WNR and WDF channel results, correctly identified by the XN-9000, due to excessive hyaluronic acid produced from the pathogen.

Ho SF et al. (2023) Diagnostics (Basel); 13(14): 2445:
Exploring Extended White Blood Cell Parameters for the Evaluation of Sepsis among Patients Admitted to Intensive Care Units.

Summary:
The authors observed a specific pattern of CBC parameters (including EIP) and biochemical parameters (CRP, PCT and IL-6) in a small cohort of sepsis (n=30) and non-sepsis (n=23) ICU patients. The combination of certain CBC parameters and EIP was effective in predicting worse outcome. The AUC for the combined parameters (AUC=0.918) was highest compared to the classical markers (SOFA Score = 0.631; CRP = 0.611; PCT= 0.639; IL-6= 0.531).

Vanrenterghem M et al. (2023) Int J Lab Hematol; 45(5): 625:
Carcinocythemia in metastatic breast cancer detected by high fluorescent signals on an automated Sysmex XN-9100 hematological cell counter.

Summary:
This case report describes a patient with suspected microangiopathic haemolytic anaemia (prominence of NRBCs, RET# 0.379 x 10^12/L), 4-5% schistocytes, elevated LDH (1823 U/L)) together with suspicious high fluorescence cells. Smear results and other tests have proven the presence of circulating non-haematological malignant tumour cells, a rare phenomenon called carcinocythaemia.

Pozdnyakova O et al. (2022) J Clin Pathol; 76(9): 624:
Beyond the routine CBC: machine learning and statistical analyses identify research CBC parameter associations with myelodysplastic syndromes and specific underlying pathogenic variants.

Summary:
A predictive model to identify myelodysplastic syndrome (MDS) samples (n=102) from cytopenic (n=145) or other control samples (n=484) was created using haematology parameters. The model had AUC 0.98, sensitivity 90%, specificity 96% and NPV 99%. Neutrophil parameters and IPF were found to have high predictive value for the model.

Zhu J et al. (2022) BMC Cancer; 22(1): 972:
Machine learning-based improvement of MDS-CBC score brings platelets into the limelight to optimize smear review in the hematology laboratory.

Summary:
A two-step algorithm, triggered by cytopenia, and utilising the MDS-CBC score and IPF, correctly separated myelodysplastic (MDS) samples (n=168) from other non-clonal cytopenic samples (n=357) with a sensitivity of 88.7% and a specificity of 95.8%. The algorithm had a 96.4% classification rate for MDS and 95.8% for the cytopenic controls.

Debus J et al. (2021) Clin Chem Lab Med; 59(7): e285:
A case of methaemoglobinaemia interference on the WDF channel on Sysmex XN-Series analysers.

Summary:
This report is about a case of acquired methaemoglobinaemia resulting in “WDF abnormal scattergram” flagging on XN-1000 and XE-2100. Interferences were shown to be reduced in the course of therapy. The authors suggested interferences with the reagent reaction in line with existing literature.

Comar SR et al. (2021) Int J Lab Hematol; 43(6): e280:
Early detection of Candida parapsilosis sepsis in peripheral blood as a result of cytografic changes on the Sysmex XN-3000 hematology analyzer.

Summary:
A case review that describes specific WNR and WDF scattergram patterns of a patient with Candida parapsilopsis sepsis. The authors propose careful overall observation of all information provided by the automated blood count including thorough analysis of scattergrams that might enable early diagnosis of invasive fungal infection.

Ortiz A et al. (2020) Sysmex J Int; 30(1): 9:
Performance Comparison of Sysmex Hematology Analyzers XN-550 and XN-10.

Urrechaga E et al. (2018) J Clin Pathol; 71(3): 259:
Role of leucocytes cell population data in the early detection of sepsis.

Summary:
Cell population data (CPD) were different between control and sepsis patients in both study (n=719) and validation (n=272) groups. The authors calculated the NEMO score (NE-SFL, MO-X) and classified three statistically significant risk groups (mild (≤3), moderate (4≤NEMO≤5) and high (≥6) risk of sepsis) with an AUC of 0.98 in the study and 0.955 in the validation group.

Boutault R et al. (2018) Br J Haematol; 183(5): 736:
A novel complete blood count-based score to screen for myelodysplastic syndrome in cytopenic patients.

Summary:
The authors suggested an MDS-CBC multiparametric score as a screening tool for MDS patients by combining absolute neutrophil count (ANC), mean corpuscular volume (MCV), and median neutrophil complexity width of dispersion (Ne-WX). The score had a sensitivity of 86% and a specificity of 88% in the leading cohort.

Cao J et al. (2017) Lab Med; 48(2): 188:
Establishing a Stand-Alone Laboratory Dedicated to the Care of Patients With Ebola Virus Disease.

Summary:
The XP-300 showed very good precision and linearity results in this study, comparable with the XN-3000 analyser.

Takagi Y et al. (2015) Microscopy (Oxf); 64(5): 305:
Comparison of optical data from flow cytometry and microscopy of leukocytes after exposure to specific reagents.

Summary:
Flow cytometry software and electron microscopy methods were used to confirm the positions and fluorescence intensity of WBC populations in the XN-WDF scattergram.

Seo JY et al. (2015) Int J Lab Hematol; 37(2): 155:
Performance evaluation of the new hematology analyzer Sysmex XN-series.

Tabe Y et al. (2015) Clin Chem Lab Med; 53(2): 281:
Performance evaluation of the digital cell imaging analyzer DI-60 integrated into the fully automated Sysmex XN hematology analyzer system.

Arneth B et al. (2015) J Clin Lab Anal; 29(3): 175:
Technology and New Fluorescence Flow Cytometry Parameters in Hematological Analyzers.

Bruegel M et al. (2015) Clin Chem Lab Med 53(7): 1057:
Comparison of five automated hematology analyzers in a university hospital setting: Abbott Cell-Dyn Sapphire, Beckman Coulter DxH 800, Siemens Advia 2120i, Sysmex XE-5000, and Sysmex XN-2000.

Summary:
A comparison of Abbott, Beckman Coulter, Siemens and Sysmex analysers found superior flagging performance of the XN-2000, especially for blasts and variant lymphocytes. Otherwise, the analysers were comparable.

Genevieve F et al. (2014) Feuillets de Biologie VOL LVI N° 317:
Smear microscopy revision: propositions by the GFHC.

Kawauchi S et al. (2013) Sysmex J Int; 23(1): 1:
The Positions of Normal Leukocytes on the Scattergram of the Newly Developed Abnormal Cell-detection Channel of the XN-Series Multi-parameter Automated Hematology Analyzers.

Summary:
Using purified leukocyte populations, the paper confirms the position of those populations within the WPC scattergrams. Interestingly, two populations of lymphocytes with a different resistance to WPC reagents were found.

Briggs C et al. (2012) J Clin Pathol; 65: 1024:
Performance evaluation of the Sysmex haematology XN modular system.

Summary:
In this study the XN showed reduced sample turnaround time and reduced number of blood film reviews compared to the XE-2100 without loss of sensitivity and with more precise and accurate results for both platelets and low WBC counts.

Van Hecke I et al. (2010) Acta Clin Belg; 65: 248:
Evaluation of the Sysmex pocH-1001 haematology analyser in an outdoor oncology service.

Summary:
In this study, Sysmex pocH-100i produces reliable results in the normal and in the lower ranges. The authors concluded that in a well-controlled management plan the Sysmex pocH-100i is suitable for near patient testing in oncology.

Whisler S et al. (2005) Lab Hematol; 11: 107:
Performance Evaluation of the Sysmex pocH-100i Automated Hematology Analyzer.

Summary:
Performance evaluation of the poch-100i and comparison with KX-21N and XE-2100 showed excellent results in this study. A reference range for a healthy population was also established by the authors.

Briggs C et al. (2003) Lab Hematol; 9(4): 225:
Performance evaluation of a New Compact Hematology Analyzer, the Sysmex pocH-100i.

Summary:
Performance evaluation of the pocH-100i and comparison with KX-21N showed excellent results. This study illustrates the clinical potential for use for accurate CBC results in a low-volume laboratory or in near-patient testing environment.

Granulocytes

Costa RM et al. (2024) Clin Chem Lab Med; online ahead of print:
Early diagnosis of severe illness in an outpatient – the Sysmex XN’s neutrophil reactivity parameter.

Summary:
In this case report from a patient with lung cancer, routine CBC results were in line with patient history, except for a high NEUT-RI value. Further investigation revealed early-stage peritonitis, which was asymptomatic likely due to cancer medication.

Mantovani EMA et al. (2023) Diagnostics (Basel); 13(10): 1781:
The Potential Role of Neutrophil-Reactive Intensity (NEUT-RI) in the Diagnosis of Sepsis in Critically Ill Patients: A Retrospective Cohort Study.

Summary:
In this study, NEUT-RI showed an AUC of 0.826 in differentiating septic (n=46) from nonseptic (n=50) patients on admission to the ICU. Its negative predictive value (87.4%) was superior to that of PCT (83.9%) and CRP (86.6%) but not significantly influenced by renal failure. The authors concluded that NEUT-RI values, together with clinical signs and currently used inflammatory biomarkers, could be useful in the early diagnosis of sepsis.

Fedorov K et al. (2023) Life (Basel); 13(3): 623:
Identifying Neutrophil Extracellular Traps (NETs) in Blood Samples Using Peripheral Smear Autoanalyzers.

Summary:
The authors revealed that the smudge cell category of CellaVision may contain two distinct populations of leukocytes: degenerated lymphocytes and neutrophils exhibiting Neutrophil Extracellular Traps (NETs). This study suggests NET-like smudge cells are not an artifact of smear preparation, are identified in the high SFL area of the WNR scattergram, and express NETs markers identifiable with immunohistochemistry and flow cytometry.

Li S et al. (2022) BMC Pulm Med; 22(1): 107:
Neutrophil side fluorescence: a new indicator for predicting the severity of patients with bronchiectasis.

Summary:
Unlike NEUT# and PCT, NEUT-SFL correlates significantly with Bronchiectasis Severity Index score in this study. The cut-off 42.15 FI for NEUT-SFL presents an AUC of 0.813 with a sensitivity of 67.1% and a specificity of 82.1%.

Lemkus L et al. (2022) PLoS ONE; 17(2): e0262938:
The utility of extended differential parameters as a biomarker of bacteremia at a tertiary academic hospital in persons with and without HIV infection in South Africa.

Summary:
In a cohort of bacterial infection patients NE-SFL presented as the best extended differential parameter in identifying bacteraemia in HIV positive patients (AUC = 1) whilst in HIV negative patients IG% performed best (AUC = 0.79). The study revealed a significant correlation to neutrophil CD64 expression which adds scientific validity to NE-SFL as a marker for neutrophil activation.

Cetin N et al. (2022) Pediatr Nephrol; 38(1): 219:
Immature granulocytes as biomarkers of inflammation in children with predialysis chronic kidney disease.

Summary:
A retrospective analysis in 57 children with predialysis chronic kidney disease (CKD) showed that IG%, IG#, WBC#, NEUT#, and NLR were higher compared to healthy children. IG parameters were also higher in stage 4 CDK compared to stage 2 and 3. IG% and IG# could predict the presence of inflammation with an AUC of 0.838 (sensitivity 74.2%) and 0.799 (sensitivity 70.8%) respectively in this cohort.

Lu Q et al. (2022) J Hemat; 15(1): 1:
Evaluation of immature granulocyte parameters in myeloid neoplasms assayed by Sysmex XN hematology analyzer.

Summary:
An analysis of 1,412 blood samples showed that IG% from an XN-Series analyser correlated well with manual microscopy in both myeloid neoplasms (n=388, r=0.83) and non-haematopoietic neoplasms (n=524, r=0.86). IG parameters correctly indicated the presence of immature granulocytes in myeloid neoplasm patients (sensitivity 75% for IG# and 81% for IG%).

Bhansaly P et al. (2022) Indian J Crit Care Med; 26(2): 216:
Evaluation of Immature Granulocyte Count as the Earliest Biomarker for Sepsis.

Summary:
The authors found that IG% and IG# gave an earlier indication of the onset of sepsis than serum procalcitonin and lactate. An increase in IG%/# was found in patients up to 24h before the onset of sepsis according to Sepsis-3 criteria.

Kim H et al. (2021) Int J Lab Hematol; 43(2): e54:
Screening of myelodysplastic syndrome using cell population data obtained from an automatic hematology analyzer.

Summary:
In a study of 63 patients with myelodysplastic syndrome (MDS), RBC, PLT, NE-FSC and NE-SSC exhibited the highest correlation with the disease (AUC from 0.87 to 0.94). The authors propose a combined interpretation of these four parameters for identifying MDS (one out of four cutoff criteria had to be fulfilled).

Güngör A et al. (2021) Postgrad Med;133(7):817:
Utility of biomarkers in predicting complicated appendicitis: can immature granulocyte percentage and C-reactive protein be used?

Summary:
In this study, the best parameters for prediction of complicated appendicitis were found to be IG% (cutoff > 0.35, AUC 0.82, sensitivity 85.4, specificity 61.5) and CRP (cutoff > 33.9, AUC 0.82, sensitivity 75.7, specificity 73.0).

Porizka M et al. (2019) Interact Cardiovasc Thorac Surg; 28(6): 845:
Immature granulocytes as a sepsis predictor in patients undergoing cardiac surgery.

Summary:
Porizka et al. investigated the ability of IG, Procalcitonin (PCT), WBC, body temperature and combinations in a cohort of cardiac surgery patients for the ability to identify sepsis. IG and PCT exhibited an AUC of 0.71 and 0.72, whereas in combination AUC increased to 0.8. IG is presented as a valuable additional parameter to PCT that improves sepsis identification in this special patient cohort.

Ustyantseva M et al. (2019) Sysmex Journal International; 29(1): 8:
Innovative Technologies in the Evaluation of the Neutrophil Functional Activity in Sepsis.
* Free online after free registration

Summary:
The study revealed significantly higher values of neutrophil fluorescence intensity (NEUT-RI) in critically ill patients with sepsis (NEUT-RI = 70 FI) compared to the non-septic control group (NEUT-RI = 53 FI). Furthermore, strong correlations between the levels of NEUT-RI and generally recognized biomarkers of sepsis (PCT, CRP) were found.

Huang Y et al. (2019) J Crit Care; 50: 303:
Immature granulocytes: A novel biomarker of acute respiratory distress syndrome in patients with acute pancreatitis.

Summary:
In patients with acute pancreatitis, immature granulocytes (IG%) could facilitate the identification of patients with a high risk for developing acute respiratory distress syndrome (ARDS). The authors present IG% as a potential indicator of ARDS incidence with predictive power similar to (or greater than) other biomarkers.

Stiel L et al. (2019) Thromb Res; 183: 153:
First visualization of circulating neutrophil extracellular traps using cell fluorescence during human septic shock-induced disseminated intravascular coagulation.

Summary:
The authors reported direct visualisation of circulating neutrophils extracellular traps (NETs) in patients with septic shock induced disseminated intravascular coagulation (DIC). The previously reported in vivo relevance of NEUT-SFL in NETosis was confirmed.

Ünal Y et al. (2018) Ulus Travma Acil Cerrahi Derg; 24(5): 434:
A new and early marker in the diagnosis of acute complicated appendicitis: immature granulocytes.

Summary:
WBC, neutrophil-to-lymphocyte ratio (NLR), IG# and IG% showed significant changes in patients with acute appendicitis compared to simple appendicitis, while changes in IG# were most prominent.

Delabranche X et al. (2017) J Crit Care; 47(3): 313:
Evidence of Netosis in Septic Shock-Induced Disseminated Intravascular Coagulation.

Summary:
In this study neutrophil fluorescence intensity (NEUT-RI) in blood samples of patients with septic shock exhibited significantly higher values in septic shock-induced disseminated intravascular coagulation (DIC) patients compared to non-DIC septic shock patients (70.0 vs. 50.7 FI).

Ronez E et al. (2017) Scand J Clin Lab Invest; 77(6): 406:
Usefulness of thresholds for smear review of neutropenic samples analyzed with a Sysmex XN-10 analyzer.

Summary:
A multi-center study showed that 1031 smear reviews triggered by isolated neutropenic samples (NEUT# < 1.5 G/L) resulted in the detection of only one positive sample (containing blasts). The authors recommend using a lower cutoff of 1.0 G/L for smear review.

Hampson P et al. (2017) Ann Surg; 265(6): 1241:
Neutrophil Dysfunction, Immature Granulocytes, and Cell-free DNA are Early Biomarkers of Sepsis in Burn-injured Patients: A Prospective Observational Cohort Study.

Summary:
Neutrophil and IG counts correlated with sepsis risk in burn patients. The authors propose the interpretation considering also other markers such as the phagocytic index and cell free DNA.

Stiel L et al. (2016) Crit Care Med; 44(11): e1132:
Neutrophil Fluorescence: A New Indicator of Cell Activation During Septic Shock-Induced Disseminated Intravascular Coagulation.

Summary:
In this study neutrophil fluorescence (NEUT-RI) above 57.3 FI demonstrated a sensitivity of 90.9 % and a specificity of 80.6 % for disseminated intravascular coagulation in patients with septic shock.

Park SH et al. (2015) Int J Lab Hematol; 37(2): 190:
Sepsis affects most routine and cell population data (CPD) obtained using the Sysmex XN-2000 blood cell analyzer: neutrophil-related CPD NE-SFL and NE-WY provide useful information for detecting sepsis.

Summary:
NE-SFL and NE-WY parameters showed significantly increased values in sepsis patients compared to the normal control group.

Ha SO et al. (2015) Scand J Clin Lab Invest; 75(1): 36:
Fraction of immature granulocytes reflects severity but not mortality in sepsis.

Summary:
In this study cohort sepsis patients with an IG count on the XE-2100 of more than 0.5 % were more likely to suffer from severe sepsis or septic shock, while WBC, CRP and PCT did not correlate with sepsis severity.

Wiland EL et al. (2014) Acta Paediatr; 103(5): 494:
Adult and child automated immature granulocyte norms are inappropriate for evaluating early-onset sepsis in newborns.

Summary:
A study on the XE-5000 showed that IG counts were increased during the first 2 days after birth. Therefore, the authors conclude that the use of adult and child norms for IG% is not appropriate for newborns as supportive information in the diagnosis of sepsis.

Nierhaus A et al. (2013) BMC Immunology 14: 8:
Revisiting the white blood cell count: immature granulocytes count as a diagnostic marker to discriminate between SIRS and sepsis - a prospective, observational study.

Summary:
"Direct quote: Our findings demonstrate that sepsis is associated with an increased immature granulocyte count. The IG count can differentiate between patients with an infection and those who are not infected, particularly within the first critical hours after an initial SIRS alert. Using ROC analysis we found the IG count a superior biomarker for sepsis compared to C-reactive protein, lipopolysaccharide binding protein and interleukin-6."

Cimenti C et al. (2012) Clin Chem Lab Med; 50: 1429:
The predictive value of immature granulocyte count and immature myeloid information in the diagnosis of neonatal sepsis.

Summary:
The study concludes that, automated detection of IG# and IMI# represents a fast, accurate and less labour-intensive method compared to a manual smear review and could improve screening and monitoring for early onset sepsis in neonates.

Zimmermann M et al. (2011) Clin Chem Lab Med; 49: 1193:
Granularity Index of the SYSMEX XE-5000 hematology analyzer as a replacement for manual microscopy of toxic granulation neutrophils in patients with inflammatory diseases.

Summary:
The Granularity Index (GI) was shown to correlate well with the degree of toxic granulation of neutrophils. The GI is a parameter calculated from automated, standardised measurements. The authors suggest that it should replace the time-consuming and subjective microscopic procedure.

Le Roux G et al. (2010) Int J Lab Hematol; 32: e237:
Routine diagnostic procedures of myelodysplastic syndromes: value of a structural blood cell parameter (NEUT-X) determined by the Sysmex XE-2100™.

Summary:
The authors present NEUT-X and the calculated granularity index GI as helpful in the screening for myelodysplastic syndromes (MDS) with increased sensitivity without increasing unnecessary smears.

Furundarena J et al. (2010) Int J Lab Hematol; 32: 360:
The utility of the Sysmex XE-2100 analyzer's NEUT-X and NEUT-Y parameters for detecting neutrophil dysplasia in myelodysplastic syndromes.

Summary:
In this study the parameters NEUT-X and NEUT-Y were used to detect neutrophil dysplasia arising from MDS and chronic myelomonocytic leukaemia (CMML).

Linssen J et al. (2008) Cytometry B (Clin Cytometry); 74: 295:
Automation and validation of a rapid method to assess neutrophil and monocyte activation by routine fluorescence flow cytometry in vitro.

Summary:
In this study fluorescence flow cytometry was shown to measure activation steps of monocytes and polymorphonuclear neutrophils to defined external stimuli. This may potentially be applied as a screening and surveillance method for inflammatory diseases.

Fernandes B (2007) Am J Clin Pathol; 128: 454:
Automated enumeration of immature granulocytes.

Summary:
The results indicate that the automated IG count can replace the manual morphology count and is superior to it.

Ansari-Lari A et al. (2003) Am J Clin Pathol 120: 795:
Immature granulocyte measurement using the Sysmex XE-2100. Relationship to infection and sepsis.

Summary:
In this study the automated IG count matched the manual IG count very well. At significantly elevated levels, it is was shown to be a very specific predictor of sepsis. Multiparameter algorithms might be more successful at lower concentrations.

Briggs C et al. (2000) Clin Lab Haematol; 22: 345:
New quantitative parameters on a recently introduced automated blood cell counter – the XE 2100.

Summary:
The IG count correlated with visual counts thus potentially improving screening and monitoring of various pathological conditions and reducing turnaround time.

Haematopoietic Progenitor Cells (HPC)

Brochier A et al. (2024) Clin Chem Lab Med; 62(7): e160:
The added value of automated HPC count: detecting clinically important interferences on the flow cytometric CD34+ cell count.

Summary:
This case report of a peripheral T-cell lymphoma patient describes discrepancies between CD34+ flow count results and HPC count. The clinician decided to initiate apheresis due to increasing HPC counts, because the CD34+ was zero. Investigation of the discrepancy revealed background staining from the patient's plasma in the flow cytometric CD34+ cell count, obscuring the CD34+ stem cells. The authors emphasised the added value of the HPC as complementary method to flow cytometry.

Lavalleye T et al. (2024) Transfusion; online ahead of print:
Method comparison between hematopoietic progenitor cell and CD34+ cell counts in hematopoietic stem cell collection.

Summary:
A study in allogeneic and autologous stem cell transplantation donors (n=133 samples) showed that HPC had a varying performance to predict the optimal apheresis starting point (AUC from 0.737 to 0.954). By applying a positive and a negative cut-off for adequate or inadequate stem cell mobilisation respectively, 81% of CD34+ flow cytometry measurements would have been saved in healthy donors, 63% in lymphoma patients, and 24% in multiple myeloma patients.

Reberšek K et al. (2021) J Clin Apher; 36(6): 870:
Hematopoietic progenitor cell counting can optimize peripheral blood stem cell apheresis process.

Summary:
This study in autologous and allogeneic stem cell donors showed that HPC correlated well with CD34+ cell count, had a very good diagnostic accuracy to identify the apheresis starting point (AUC 0.852), and to predict both an insufficient (AUC 0.884) or sufficient (AUC 0.769) harvest.

Mishra S et al. (2020) Int J Lab Hematol; 43(1): 76:
A study to compare Hematopoietic Progenitor Cell count determined on a next-generation automated cell counter with flow cytometric CD34 count in peripheral blood and the harvested peripheral blood stem cell graft from autologous and allogenic donors.

Summary:
A study on allogeneic and autologous donors showed that HPC had a very good correlation with CD34+ count in peripheral blood and in the final harvest product, and was an efficient predictor for the optimal time of harvesting of stem cells.

Dima F et al. (2020) Blood Transfus; 18(1): 67:
Assessment of haematopoietic progenitor cell counting with the Sysmex® XN-1000 to guide timing of apheresis of peripheral blood stem cells.

Summary:
The HPC mode was shown to assess the timing of apheresis and thus improve the apheresis workflow by reducing CD34 tests. The parameter demonstrates excellent diagnostic accuracy in different donor subsets, high precision and a very good correlation with CD34.

Furundarena JR et al. (2020) Int J Lab Hematol; 42(2): 170:
Evaluation of the predictive value of the hematopoietic progenitor cell count using an automated hematology analyzer for CD34+ stem cell mobilization and apheresis product yield.

Summary:
The authors established two decision trees using haematopoietic progenitor cells count for decision making in autologous transplants. One for optimising the rational use of plerixafor in poor mobilisers and the second for decision on the optimal starting point of apheresis.

Grommé M et al. (2017) Transfusion; 57(8): 1949:
Multicenter study to evaluate a new enumeration method for hematopoietic stem cell collection management.

Summary:
In this study, HPC correlates well with the gold standard of CD34 flow cytometry during stem cell mobilisation phase to determine apheresis start time, during apheresis for real-time monitoring and for QC of the final stem cell harvest.

Park SH et al. (2015) Ann Lab Med; 35(1): 146:
The New Sysmex XN-2000 Automated Blood Cell Analyzer More Accurately Measures the Absolute Number and the Proportion of Hematopoietic Stem and Progenitor Cells Than XE-2100 When Compared to Flow Cytometric Enumeration of CD34(+) Cells.

Summary:
In this study, HPC counts from the XN-Series were more accurate than counts from the XE-Series when compared to CD34 flow cytometry.

Peerschke El et al. (2015) Transfusion; 55(8): 2001:
Evaluation of new automated hematopoietic progenitor cell analysis in the clinical management of peripheral blood stem cell collections.

Summary:
In this study, automated haematopoietic progenitor cell analysis was presented as a functional equivalent of CD34 analysis and may be a surrogate for CD34 analysis to predict optimal timing of stem cell collections from mobilised peripheral blood.

Tanosaki R et al. (2014) Int J Lab Hematol; 36(5): 521:
Novel and rapid enumeration method of peripheral blood stem cells using automated hematology analyzer.

Summary:
This study found that CD34-positive cells fall in the area where stem cells locate in the WPC scattergram. The final yield of collected CD34-positive cells could be predicted from the HPC value in pre-apheresis blood and apheresis products.

Low WBC mode

SEO JY et al. (2015) Int J Lab Hematol; 37(2): 155:
Performance evaluation of the new hematology analyzer Sysmex XN-series.

Tanaka Y et al. (2014) Int J Hematol. 36(4): e50:
Elimination of interference by lipids in the Low WBC mode in the automated hematology analyzer XN-2000.

Summary:
The study shows that potential interferences by the contamination of lipids have been eliminated in the two leukocyte channels of the XN-series, particularly compared to non-fluorescent methods. Furthermore, the new Low WBC mode showed better precision for leukopenic samples than the whole blood (WB) mode.

Lymphocytes

Kallen ME et al. (2024) J Hematop; online ahead of print:
Carvykti CAR T‑cell morphology in cellavision peripheral smear reviews.

Summary:
The authors report on four patients and their lymphocyte morphology of CAR T-cell expansion in the context of CAR T-cell therapy. CellaVision DM9600 confirmed the expansion of atypical lymphocytes (CAR T-cells) with kinetics very similar to those reported by Faude S 2021.

Lesesve JF et al. (2022) Mediterr J Hematol Infect Dis; 14(1): e2022024:
CAR-T Cells Microscopic and Phenotypic Identification in the Peripheral Blood.

Summary:
The case study of a woman with large B-cell lymphoma treated with CAR-T cells highlights the value of close monitoring of treatment progress after CAR-T cell infusion with WDF channel. WDF scattergrams and peripheral blood smear found atypical lymphocytes that could represent the proliferating CAR-T cells.

Rutkowska E et al. (2021) Cells; 10(1): 82:
Usefulness of the New Hematological Parameter: Reactive Lymphocytes RE-LYMP with Flow Cytometry Markers of Inflammation in COVID-19.

Summary:
A study on patients with viral infections showed that RE-LYMP% correlated with the presence of plasmablasts (activated B cells). RE-LYMP also correlated with activation markers on CD4+ and CD8+ T cells in COVID-19 (CD8+ CD45RO+) or other infections (CD38+ and HLA-DR+).

Urrechaga E et al. (2021) Scand J Clin Lab Invest; 81(5): 394:
Leukocyte differential and reactive lymphocyte counts from Sysmex XN analyzer in the evaluation of SARS-CoV-2 infection.

Summary:
The prospective observational study aimed to assess the diagnostic performance in distinguishing SARS-CoV-2 infections from other viral or bacterial infections in emergency room (ER) patients presenting with fever. NLR > 3.3 and RE-LYMP >0.6% correctly distinguished 95.6% of SARS-CoV-2 infection patients in the validation group (bacterial and viral infected ER patients).

Tantanate C et al. (2018) Lab Med; 49(4): 362:
Performance Evaluation of High Fluorescence Lymphocyte Count: Comparability to Atypical Lymphocyte Count and Clinical Significance.

Summary:
An analysis of 320 blood samples showed that the HLFC parameter from the XN-3000 was higher in samples with infection (n=229), and correlated well with the atypical lymphocytes from the microscopic examination (r=0.865 for counts, and r=0.893 for percentages). HFLC predicted the presence of atypical lymphocytes in the blood smear with an 80% sensitivity in this study.

Henriot I et al. (2017) Int J Lab Hematol; 39(1): 14:
New parameters on the hematology analyzer XN-10 (SysmexTM) allow to distinguish childhood bacterial and viral infections.

Summary:
The study investigated new parameters from the Sysmex XN in children with fever. The authors found that the parameter AS-LYMP was significantly higher in children with viral infections. The parameter AS-LYMP (AUC=0.83) had the same discrimination power as procalcitonin (AUC=0.82) to distinguish between bacterial and viral infections in this cohort.

Sale S et al. (2016) J Clin Lab Anal; 30(5): 779:
Detection of Apoptotic Lymphocytes Through Sysmex XN-1000 As a Diagnostic Marker for Mononucleosis Syndrome.

Summary:
The authors propose a new algorithm that integrates the 'Atypical Lympho?' flag, lymphocyte structural parameters (LY-WX, LY-WY, LY-WZ) and presence of events in area of the FCS-SSC and SFL-SSC scattergrams and could aid in the diagnosis of infectious mononucleosis.

Oehadian A et al. (2015) Int J Lab Hematol; 37(6): 861:
New parameters available on Sysmex XE-5000 hematology analyzers contribute to differentiating dengue from leptospirosis and enteric fever.

Summary:
This study investigated how detection of atypical lymphocytes, high-fluorescent lymphocytes and immature granulocytes on the XE-5000 supports the differentiation between common causes of febrile illnesses with thrombocytopenia in dengue areas.

Brisou G et al. (2015) J ClinLab Anal: 29(2): 153:
Alarms and Parameters Generated by Hematology Analyzer: New Tools to Predict and Quantify Circulating Sezary Cells.

Summary:
Combining the 'Blasts/Abn Lympho?' flag with the LY-X and LY-Y parameters it was possible to differentiate Sezary patients from control patients (sensitivity 89%; specificity 98%) or from patients with chronic lymphoproliferative diseases (sensitivity 89%; specificity 94%). The proposed algorithm may alert the microscopist that a sample likely contains Sezary cells.

Van Mirre E et al. (2011) Clin Chem Lab Med; 49: 685:
Sensitivity and specificity of the high fluorescent lymphocyte count-gate on the Sysmex XE-5000 hematology analyzer for detection of peripheral plasma cells.

Summary:
The Sysmex XE-5000 is suitable for screening blood samples for the presence of elevated numbers of plasma cells in peripheral blood.

Linssen J et al. (2007) Cytometry B (Clin Cytometry) 72: 157–166. Reprinted in: Sysmex J Int 19(1): 19–25.:
Identification and quantification of high fluorescence-stained lymphocytes as antibody synthesizing/secreting cells using the automated routine hematology analyzer XE-2100.

Summary:
This study demonstrates that the Sysmex high-fluorescence lymphocyte count quantifies activated B-lymphocytes with high precision and reliability in patients without haematological systemic diseases, thus providing a potential screening and monitoring tool for a suspected infection.

Monocytes

Cornet E et al. (2024) Int J Lab Hematol; online ahead of print:
Applicability of mono dysplasia score on the new Sysmex XR analyzer range to predict diagnosis of chronic myelomonocytic leukaemia.

Summary:
A study of 316 patients with monocytosis showed that a mono-dysplasia score > 0.16 calculated on XR-Series could differentiate CMML samples (n=22) from reactive monocytosis cases (n=294) with an AUC of 0.994, sensitivity 100% and specificity of 95.2%.

Kouame H et al. (2023) AHRJ; 6(3): 104:
Monocytosis / Monocytic Dysplasia: Testing a New Diagnostic Tool Using Sysmex XN Analyzer Parameters.

Summary:
A study in 263 patients with monocytosis (≥1x10^9/L and >10%) showed that the mono-dysplasia score (described in Schillinger F et al. 2018) had a sensitivity of 100% and a specificity of 96.4% in identifying samples with monocytic dysplasia.

Zhu J et al. (2019) Int J Lab Hematol; 41(6): 782:
A hierarchical approach in the diagnostic workflow of chronic myelomonocytic leukemia: Pivotal role of the "Mono-dysplasia-score" combined with flow cytometric quantification of monocyte subsets.

Summary:
The authors set up a workflow for monocytosis samples including Mono-dysplasia score, smear review and flow cytometry. The proposed mono-dysplasia score was shown to be a valuable filter for reducing the number of smears without losing sensitivity for CMML suspicious samples.

Buoro S et al. (2018) Int J Lab Hematol; 40(5): 577:
Evaluation and comparison of automated hematology analyzer, flow cytometry, and digital morphology analyzer for monocyte counting.

Summary:
Comparison of the XN-9000, CyFlow Space System and DI-60 compared with OM (optical microscopy) for the monocyte count revealed a better performance and higher values for flow cytometry than OM and DI-60 which have also a higher imprecision. The authors conclude also that the absolute monocyte count may be more reliable.

Schillinger F et al. (2017) Scand J Clin Lab Invest; 78(3):159:
A new approach for diagnosing chronic myelomonocytic leukemia using structural parameters of Sysmex XN analyzers in routine laboratory practice.

Summary:
The study presents a score derived from Sysmex XN parameters that identifies possible CMML samples by excluding reactive monocytes. This reduces the smear review workload.

Mazumdar R et al. (2013) Leukemia Research; 37(6): 614:
The automated monocyte count is independently predictive of overall survival from diagnosis in chronic lymphocytic leukaemia and of survival following first-line chemotherapy.

Summary:
A monocyte count >0.91 ×109/L at the time of diagnosis was associated with a shortened overall and treatment-free survival in CLL patients in this cohort.

Reference intervals

Bildirici A et al. (2023) Turk J Biochem; 48(4): 388:
Determination of reference intervals of hemogram with advanced clinical parameters by indirect method on Sysmex XN-1000.

Mrosewski I et al. (2023) Clin Chem Lab Med; 61(6): 1116:
Indirectly determined reference intervals for automated white blood cell differentials of pediatric patients in Berlin and Brandenburg.

Summary:
The study presents indirectly determined WBC differential reference intervals (RI) for paediatric patients (0-18 years) in Berlin and Brandenburg area in Germany. No RI for DIFF parameters are available for children < 7 months.

L van Pelt J et al. (2022) Clin Chem Lab Med; 60(6): 907:
Reference intervals for Sysmex XN hematological parameters as assessed in the Dutch Lifelines cohort.

Becker M et al. (2022) Int J Lab Hematol; 44(4): 729:
Differences between capillary and venous blood counts in children—A data mining approach.

Angelo A et al. (2021) BMC Pediatrics; 21: 275:
Umbilical cord blood hematological parameters reference interval for newborns from Addis Ababa, Ethiopia.

Dockree S et al. (2021) EBioMedicine; 74: 102715:
White blood cells in pregnancy: reference intervals for before and after delivery

Summary:
The study established pregnancy-specific reference intervals for WBC subtypes for use between 8-40 weeks of gestational age and 7-21 days postnatally based on 80,637 blood measurements from 24,318 women from the UK.

Mrosewski I et al. (2021) Clin Chem Lab Med; 60(3): 408:
Indirectly determined hematology reference intervals for pediatric patients in Berlin and Brandenburg.

Summary:
The study presents indirectly determined CBC reference intervals (RI) for paediatric patients (0-18 years) in Berlin and Brandenburg area in Germany.

Song MY et al. (2021) Int J Lab Hematol; 43(6): 1363:
Establishment of pediatric reference intervals for complete blood count parameters in capillary blood in Beijing.

Summary:
The authors established reference intervals for 22 CBC+DIFF parameters from capillary blood in 6799 children aged 3 months to 18 years from Beijing area in China.

Summary:
The study provides reference intervals (CBC+DIFF+RET) that could serve as reference values for haematology parameters in adults for laboratories that use the XN-Series analysers.

Bohn MK et al. (2020) Int J Lab Hematol; 42(6): 759:
Complex biological patterns of hematology parameters in childhood necessitating age- and sex-specific reference intervals for evidence-based clinical interpretation.

Zierk J et al. (2019) Clin Chem Lab Med; 57(10): 1595:
Next-generation reference intervals for pediatric hematology.

Summary:
The aim of the study was to establish reference intervals for CBC, DIFF and reticulocytes for a Spanish population. Significant gender differences were found for RBC, PLT, HCT and HGB.

Ozarda Y et al. (2017) Clin Chem Lab Med; 57(1): 30:
Verification of reference intervals in routine clinical laboratories - practical challenges and recommendations.

Summary:
The opinion paper summarises guidelines and approaches for the verification of reference intervals (RI) in routine clinical laboratories. It gives definitions for common terms, refers to examples and covers challenges such as RI for geriatric and paediatric populations.

Cornet E et al. (2015) Int J of Lab Hematol.: 37(5): e123:
Contribution of the new XN-1000 parameters NEUT-RI and NEUT-WY for managing patients with immature granulocytes.

Summary:
Normal values were determined on the XN-Series for the structural neutrophil parameters NEUT-GI, NEUT-RI and NEUT-WY. In addition, it was shown that NEUT-RI and NEUT-WY can be used to predict IG% values within a 72 h time frame.

Zimmermann M et al. (2015) Clin Lab; 61: 235:
Detection and quantification of hypo- and hypergranulated neutrophils on the new Sysmex XN hematology analyzer: establishment of an adapted reference interval for the neutrophil-granularity-intensity compared to XE-technology in adult patients.

Summary:
The reference intervals for NEUT-GI (XN-Series) and NEUT-X (XE-series) were determined using 246 blood-healthy control patients: 140.91 - 160.46 channels and 129.20 - 142.33 channels, respectively. Neutrophil granularity was higher in ICU patients.

Roehrl MHA et al. (2011) Arch Pathol Lab Med; 135: 471:
Age-dependent reference ranges for automated assessment of immature granulocytes and clinical significance in an outpatient setting.

Summary:
The use of appropriate reference ranges makes the IG count a powerful haematologic parameter for outpatient care that is associated with differential diagnoses that are distinctly characteristic of that setting.

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