Malignant invasion of the cerebrospinal fluid in adult and paediatric patients with haematological and solid malignancies: a monocentric retrospective study.

OBJECTIVES: In this study, we describe the clinical presentation, the cerebrospinal fluid (CSF) characteristics and outcome of children and adults with leptomeningeal invasion due to haematological and solid malignancies. METHODS: Routine CSF samples analyzed from 2008 to 2018 at our institution were retrospectively reviewed for the presence of malignant cells based on cytomorphological analysis. RESULTS: Leptomeningeal invasion was identified in 212 patients: 45 children versus 167 adults, and 92 haematological versus 120 solid malignancies. Leukaemic invasion in childhood was mainly due to ALL, and lymphoma invasion was often due to a high-grade B-cell lymphoma in adults. Metastatic invasion by solid tumours was almost exclusively seen in adults. Patients suffered most frequently from cranial neuropathy and headache (both 32%), while asymptomatic presentations were seen mainly in children (33%) and haematological malignancies (17%). Laboratory CSF parameters often showed an elevated WBC count (87%), total protein (74%) and lactate (76%) and a decreased glucose (77%). These deviations were especially found in solid malignancies (>84%) and adults (>82%). Brain and/or spinal cord imaging was more often suggestive for the leptomeningeal invasion in solid than in haematological malignancies (86% vs. 46%). The 5-year overall survival (OS) rates for patients with haematological and solid malignancies were 21.5% and 5.9%, respectively. The 5-year OS rate for children (55.6%) was significantly better than for adults (3.5%). CONCLUSION: Leptomeningeal invasion is more often asymptomatic, and CSF parameters and imaging are more often normal in children and haematological malignancies than in adults and solid malignancies, possibly leading to underdiagnosis.

Next generation sequencing in therapy-related myeloid neoplasms compared to de novo myeloid neoplasms.

INTRODUCTION: Therapy-related myeloid neoplasms (t-MN) are frequently categorized according to previous therapy or pattern of cytogenetic abnormalities. Our objective was to evaluate and compare the mutational profile of de novo and t-MN by next generation sequencing. METHODS: Sixty-four samples from patients with t-MN, previously treated for a solid tumor (mainly breast), or de novo AML, MDS, MDS/MPN were selected for our study. The library was prepared using diagnostic samples and the TruSight Myeloid sequencing panel targeting 54 genes. Samples were sequenced on a MiSeq. The classification system of the Belgian ComPerMed Expert Panel was used for the biological variant classification. RESULTS: Taking only pathogenic, probably pathogenic variants and variants of unknown significance into account 141 variants in 33 genes were found in 52 of 64 samples (81%; mean number of variants per patient = 2; range = [1-11]; 67 variants in 25 genes in t-MN and 74 variants in 25 genes in de novo MN). Overall, the most frequently detected variants included TET2 (n = 22), TP53 (n = 12), DNMT3A (n = 10) and FLT3, NPM1, RUNX1 (n = 8 each). CONCLUSION: Our study revealed a high variety of variants both in t-MN and de novo MN patients. There was a higher incidence of FLT3 and TP53 variants in t-MN compared to de novo MN.

The integration of Sysmex XN-9100' WPC channel reflex testing in the detection of reactive versus malignant blood samples.

INTRODUCTION: Sysmex XN-9100™ (Sysmex, Kobe, Japan) system has an optional White Progenitor Cell (WPC) channel. While the White Differentiation (WDF) channel reports a combined flag for blasts/abnormal lymphocytes, WPC channel specifies flagging into a separate flag for each cell type or removes the flag entirely. Aim of this study was to evaluate the added value of this WPC channel in the detection of malignant samples. METHODS: Routine blood samples analyzed on Sysmex XE-5000 with flagging for either blasts, abnormal lymphocytes, or atypical lymphocytes (n = 630) were selected for testing on Sysmex XN-9100, resulting in a reflex WPC analysis in 420 samples. All samples were microscopically evaluated with DI-60 digital cell imaging analyzer. RESULTS: WPC reflex testing resulted in a suspect flag ("blasts" and/or "abnormal lymphocytes") in 334 samples, which was confirmed microscopically in 38% (128/334). In all true positive samples, WPC correctly classified the initial WDF flag in either "blasts" flag or "abnormal lymphocytes?" flag in 75%. Only 12% (50/420) of WDF "blasts/abnormal lymphocytes" positive samples became negative after WPC reflex testing. Subgroup analysis showed differences between the "pediatric" versus "adult" groups and the "hematological/chemotherapy" versus "nonhematological/nonchemotherapy" groups in specificity and smear reduction. CONCLUSION: Overall, WPC reflex testing showed good sensitivity (99%); however, the specificity remains poor (29%). Using reflex WPC to the WDF channel resulted in a 12% reduction of the smear review rate. Although the WPC channel offers different interesting advantages, additional topics and a specific workflow should be applied to optimize the use of this channel.

A monocentric retrospective study of 138 therapy-related myeloid neoplasms.

As diagnosing therapy-related myeloid neoplasms (t-MN) is often challenging, we reviewed clinicopathological features of t-MN patients. Medical records of 138 patients, diagnosed with t-MN between 1995 and 2017, were reviewed. Of 138 patients, 80 had t-MDS, 53 t-AML, and 5 t-MDS/MPN (age, 22-88 years; median 64 years; male/female ratio, 0.8). The median latency time was 6 years and 5 months. Of 115 patients, 56 patients received cytotoxic-/radiotherapy for a solid tumor, 56 for hematological malignancy, and 3 for an auto-immune disorder, respectively. Another 21 patients had a combination of 2 disorders. Moreover, 2 patients had 3 previous malignancies. Breast cancer was the most prevalent tumor, followed by low-grade B non-Hodgkin lymphoma. Immunophenotyping and immunohistochemistry showed aberrant expression of B-, T-, or NK-cell markers in 21% and 6%, respectively. In 90% of the patients, dysplasia in ≥ 1 lineage was found. KMT2A fusion gene transcripts were seen in 5%. Cytogenetic analysis showed complex karyotypes (31%) and chromosome 5 and/or 7 abnormalities (40%). Almost 82% of the patients died and the median overall survival was about 1 year. Our study confirms that previous therapy for breast cancer is the most important cause of t-MN. KMT2A fusion genes are prevalent and complex karyotypes and/or chromosomes 5 and/or 7 abnormalities are common.

Hemoglobin S monitoring on TOSOH G8 in hemoglobin A1c mode in case of urgent red blood cell exchange.

BACKGROUND: Pre- and post-transfusion hemoglobin S (HbS) levels are used to document the efficacy of red blood cell exchange (RCE) in patients with sickle cell disease (SCD). In case of urgent RCE a 24/7 short turn-around time (STAT) analysis, with the ability to identify and quantify HbS, is warranted. The use of TOSOH G8 (Tosoh Europe) is evaluated for this purpose, using the variant HbA1c mode. METHODS: Analytical performance of the HbS analysis on TOSOH G8 in variant HbA1c mode was evaluated, including assessment of imprecision and linearity for HbS. In addition, a comparison study between TOSOH G8 and Minicap Flex Piercing (FP) system CZE (Sebia) using 32 HbS samples (HbS range: 9%-93%) was carried out to evaluate analytical and clinical concordance. RESULTS: Total HbS imprecision was 1.77% and 0.31% for a sickle cell trait and a sickle cell anemia sample, respectively. An acceptable linearity (HbS range: 6%-88%) was observed (R2  > .99). Passing-Bablok regression analysis showed a significant proportional bias; however, a good analytical concordance (r > .95) was found. Our results suggested that TOSOH G8 underestimated HbS results compared with those of Minicap FP system (mean difference: -3.54%), especially in samples with a high HbS concentration. CONCLUSION: Hemoglobin S results obtained with TOSOH G8 in variant HbA1c mode are clinically acceptable to monitor urgent RCE. The observed underestimation will not alter clinical decision-making.

Clinicopathological characteristics of de novo and secondary myeloid sarcoma: A monocentric retrospective study.

OBJECTIVE: Diagnosing myeloid sarcoma remains challenging, and we aimed to provide clinicopathological features to facilitate diagnosis. METHOD: Clinicopathological data from 41 patients with de novo and 31 with secondary myeloid sarcoma were reviewed. RESULTS: Most de novo cases presented with isolated myeloid sarcoma (n = 19) or myeloid sarcoma with concurrent acute myeloid leukemia (n = 15). Most secondary cases presented after acute myeloid leukemia (n = 11), myeloproliferative neoplasm (n = 9), or myelodysplastic syndrome (n = 8). Most frequent localizations were skin and lymph nodes. Immunohistochemistry showed immature and/or aberrant antigenic expression in 29% of de novo and 39% of secondary cases. Most genetic abnormalities were RUNX1-RUNX1T1 (n = 4), CBFB-MYH11 (n = 2), KMT2A-MLLT3 (n = 2), and JAK2 V617F (n = 2) mutations in de novo myeloid sarcoma, and BCR-ABL1 (n = 5) and KMT2A rearrangements (n = 2) in secondary cases. A complex karyotype was seen in 17% of de novo and 39% of secondary cases. Most prevalent treatment was induction chemotherapy followed by consolidation chemotherapy (n = 10) or allogeneic stem cell transplantation (n = 9) for de novo and radiotherapy (n = 11) for secondary cases. CONCLUSION: De novo myeloid sarcoma mostly presented isolated. Lesions were often localized at skin and lymph nodes. Genetic aberrations frequently involved core-binding factor rearrangements in de novo cases and a complex karyotype in secondary cases.

Isolated sulfite oxidase deficiency.

Isolated sulfite oxidase deficiency (ISOD) is a life-threatening, autosomal recessive disease characterized by severe neurological impairment. As no long-term effective treatment is available, distinction from other treatable diseases, such as molybdenum cofactor deficiency (MoCD) type A, should be made. We reviewed 47 patients (45 previously reported in the literature). Cases were reviewed for consanguinity, sex, age at onset, death, clinical findings (including spasticity, seizures, psychomotor retardation, feeding difficulties, ectopia lentis, microcephaly), laboratory findings [urinary sulfite, S-sulfocysteine (in plasma and urine), plasma cystine, total homocysteine, uric acid, and oxypurines in urine] and radiological findings (including cerebral/cerebellar atrophy, cystic white matter changes, ventriculomegaly). We also aligned the published SUOX gene mutations to the reference sequence NM_000456.2. Onset occurred mostly during the first 72 h of life (57%) and within the first year of life in all but two patients (96%). All patients presented with neurological abnormalities, such as neonatal axial hypotonia and/or peripheral hypertonia (100%), (pharmacoresistant) seizures (84%), or developmental delay (97%). Feeding problems were also common. As found in our review, measurement of homocysteine in plasma, amino acids in plasma/urine, and sulfite in fresh urine supports the diagnosis of ISOD. Analysis of uric acid (plasma) and oxypurines (urine) is useful to rule out MoCD. In all patients in whom brain magnetic resonance imaging/computed tomography (MRI/CT) was performed, brain abnormalities were found. The purpose of this literature review is to provide a thorough overview of clinical, neuroimaging, biochemical, and genetic findings of patients with ISOD.

Performance of strip-based glucose meters and cassette-based blood gas analyzer for monitoring glucose levels in a surgical intensive care setting.

BACKGROUND: We verified the analytical performance of strip-based handheld glucose meters (GM) for prescription use, in a comparative split-sample protocol using blood gas samples from a surgical intensive care unit (ICU). METHODS: Freestyle Precision Pro (Abbott), StatStrip Connectivity Meter (Nova), ACCU-CHEK Inform II (Roche) were evaluated for recovery/linearity, imprecision/repeatability. The GMs and the ABL90 (Radiometer) blood gas analyzer (BGA) were tested for relative accuracy vs. the comparator hexokinase glucose-6-phosphate-dehydrogenase (HK/G6PDH) assay on a Cobas c702 analyzer (Roche). RESULTS: Recovery of spiked glucose was linear up to 19.3 mmol/L (347 mg/dL) with a slope of 0.91-0.94 for all GMs. Repeatability estimated by pooling duplicate measurements on samples below (n=9), in (n=51) or above (n=80) the 4.2-5.9 mM (74-106 mg/dL) range were for Freestyle Precision Pro: 4.2%, 4.0%, 3.6%; StatStrip Connectivity Meter: 4.0%, 4.3%, 4.5%; and ACCU-CHEK Inform II: 1.4%, 2.5%, 3.5%. GMs were in agreement with the comparator method. The BGA outperformed the GMs, with a MARD of 3.9% compared to 6.5%, 5.8% and 4.4% for the FreeStyle, StatStrip and ACCU-CHEK, respectively. Zero % of the BGA results deviated more than the FDA 10% criterion as compared to 9.4%, 3.7% and 2.2% for the FreeStyle, StatStrip and ACCU-CHEK, respectively. For all GMs, icodextrin did not interfere. Variation in the putative influence factors hematocrit and O2 tension could not explain observed differences with the comparator method. CONCLUSIONS: GMs quantified blood glucose in whole blood at about the 10% total error criterion, proposed by the FDA for prescription use.