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Background In ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time, the hypothesis that iron overload in megaloblastic anemia may be related to ineffective erythropoiesis is explored by describing the kinetics of hepcidin, erythroferrone, and growth differentiation factor-15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload. Case presentation An 81-year-old Caucasian male was admitted for fatigue. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease. Vitiligo was observed on both hands. Biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation levels. Megaloblastic anemia was confirmed with undetectable blood vitamin B12 and typical cytological findings like hyper-segmented neutrophils in blood and megaloblasts in bone marrow. The patient received vitamin B12 supplementation. At 3 months, biological parameters reached normal values. Hepcidin kinetics from diagnosis to 3 months inversely correlated with those of erythroferrone and growth differentiation factor-15. Conclusions This case suggests that iron-overload mechanisms of dyserythropoietic anemias may apply to megaloblastic anemias.

The prognostic significance of hypercalcemia in lymphoma has only been studied on small series to date. We conducted a retrospective, monocentric, matched-control study that aimed to compare the outcome of patients diagnosed with any histological subtype of lymphoma associated with hypercalcemia, at diagnosis or relapse, with a group of controls matched for histological and prognostic factors. Sixty-two and 118 comparable patients treated between 2000 and 2016 were included in hypercalcemia and control cohorts, respectively. Hypercalcemia was found mainly at diagnosis (71%) in higher-risk patients (prognosis scores ≥ 3, 76%) and those with diffuse large B cell lymphoma (67.7%), stage III/IV disease (91.9%), and elevated LDH (90.3%). Two-year progression-free survival (PFS) was shorter in the hypercalcemia than control cohort [30.1% (95% confidence interval (95% CI) 18.3–41.9) vs 63.9% (95% CI 5.1–72.7), p

The bone marrow (BM) niche impacts the progression of acute myeloid leukemia (AML) by favoring the chemoresistance of AML cells. Intimate interactions between leukemic cells and BM mesenchymal stromal cells (BM-MSCs) play key roles in this process. Direct intercellular communications between hematopoietic cells and BM-MSCs involve connexins, components of gap junctions. We postulated that blocking gap junction assembly could modify cell–cell interactions in the leukemic niche and consequently the chemoresistance. The comparison of BM-MSCs from AML patients and healthy donors revealed a specific profile of connexins in BM-MSCs of the leukemic niche and the effects of carbenoxolone (CBX), a gap junction disruptor, were evaluated on AML cells. CBX presents an antileukemic effect without affecting normal BM-CD34+ progenitor cells. The proapoptotic effect of CBX on AML cells is in line with the extinction of energy metabolism. CBX acts synergistically with cytarabine (Ara-C) in vitro and in vivo. Coculture experiments of AML cells with BM-MSCs revealed that CBX neutralizes the protective effect of the niche against the Ara-C-induced apoptosis of leukemic cells. Altogether, these results suggest that CBX could be of therapeutic interest to reduce the chemoresistance favored by the leukemic niche, by targeting gap junctions, without affecting normal hematopoiesis.

The coexistence of dual hematological neoplasms is very rare. Sequential or synchronous neoplasms in hematology are an uncommon and complex clinical situation. The aim of the Hemo2 study was to describe the clinical characteristics and analyze the outcome of these patients. We performed a retrospective review of all patients diagnosed with sequential or synchronous hematological malignancies in the university hospital of Tours, between 2007 and 2018. We identified 49 patients in our study, with a prevalence of 0.89%. Sequential and synchronous combinations were found in 36 (73%) and 13 (27%) patients, respectively. One patient presented three sequential neoplasms. The median cumulative incidence was 6 years (95% CI 3–7). Among all neoplasms diagnosed (n = 99), we found 79 lymphoid neoplasms (LNs) (80%) and 20 myeloid neoplasms (MNs) (20%). Sex ratio was 1.88 with 65% of males and 35% of females. The most common LNs were Hodgkin lymphoma (n = 16; 16%) and multiple myeloma (n = 11; 11%). The most frequent MN was essential thrombocythemia (n = 5; 5%). The most common combination was Hodgkin lymphoma and follicular lymphoma in five (10%) patients. The overall survival from the first diagnosis (OS1) at 5 years was 82.4% (95% CI 72.1–94.3). The median overall survival from the second diagnosis (OS2) was 98 months (95% CI 44–NR) and 5-year OS2 was 58.7% (95% CI 45.5–75.7). Median progression-free survival from the second diagnosis (PFS) was 47 months (95% CI 27–NR) with 5-year PFS of 49% (95% CI 35.9–67). OS and PFS did not statistically differ between synchronous and sequential dual neoplasms. In this cohort, that the death relative risk (RR) was significantly lower if the second neoplasm appeared after more than 4 years following the first diagnosis (OR 0.37 (95% CI 0.16–0.90)). The Hemo2study confirmed the rarity of dual hematological neoplasms. In this cohort, HL and FL were the most frequent combinations. Our results may support that synchronous and sequential dual neoplasms bear the same prognosis. Further studies are needed to better characterize these uncommon clinical situations.

The bone marrow (BM) microenvironment plays a crucial role in the development and progression of leukemia (AML). Intracellular reactive oxygen species (ROS) are involved in the regulation of the biology of leukemia-initiating cells, where the antioxidant enzyme GPx-3 could be involved as a determinant of cellular self-renewal. Little is known however about the role of the microenvironment in the control of the oxidative metabolism of AML cells. In the present study, a coculture model of BM mesenchymal stromal cells (MSCs) and AML cells (KG1a cell-line and primary BM blasts) was used to explore this metabolic pathway. MSC-contact, rather than culture with MSC-conditioned medium, decreases ROS levels and inhibits the Nrf-2 pathway through overexpression of GPx3 in AML cells. The decrease of ROS levels also inactivates p38MAPK and reduces the proliferation of AML cells. Conversely, contact with AML cells modifies MSCs in that they display an increased oxidative stress and Nrf-2 activation, together with a concomitant lowered expression of GPx-3. Altogether, these experiments suggest that a reciprocal control of oxidative metabolism is initiated by direct cell&ndash, cell contact between MSCs and AML cells. GPx-3 expression appears to play a crucial role in this cross-talk and could be involved in the regulation of leukemogenesis.

Clonal hematopoiesis (CH) of indeterminate potential has been described in blood samples from large series of patients. Its prevalence and consequences are still not well understood because sequencing methods vary and because most studies were performed in cohorts comprising individuals with nonhematologic diseases. Here, we investigated the frequency of CH in 82 paired bone marrow and blood samples from carefully selected healthy adult volunteers. Forty-one genes known to be mutated in myeloid malignancies were sequenced with a 1% threshold of detection. In bone marrow samples, clones were found in almost 40% of healthy volunteers more than 50 years old. The most frequent mutations were found in DNMT3A and TET2, with 1 individual carrying 3 variants. Variant allele frequencies were highly concordant between blood and bone marrow samples. Blood parameters were normal except for those in 2 individuals: 1 had a mild macrocytosis and 1 had a mild thrombocytosis. Furthermore, no morphologic abnormalities or dysplasia were detected when bone marrow smears were carefully evaluated. Individuals with CH differed from others by age (62.8 vs 38.6 years; P < .0001) and platelet count (294 vs 241 ×109/L; P = .0208), the latter being no more significant when removing the 2 individuals who carried the JAK2 p.V617F mutation. These results confirm that CH is a very common condition in healthy adults over 50 years old. Consequently, the detection of driver myeloid mutations should be interpreted with caution in the absence of cytologic abnormalities in the blood and/or the bone marrow.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for transformation in secondary acute myeloid leukemia. This study focused on the redox metabolism of bone marrow (BM) cells from 97 patients compared with 25 healthy controls. The level of reactive oxygen species (ROS) was quantified by flow cytometry in BM cell subsets as well as the expression level of 28 transcripts encoding for major enzymes involved in the antioxidant cellular response. Our results highlight increased ROS levels in BM nonlymphoid cells and especially in primitive CD34posCD38low progenitor cells. Moreover, we identified a specific antioxidant signature, dubbed “antioxidogram,” for the different MDS subgroups or secondary acute myeloblastic leukemia (sAML). Our results suggest that progression from MDS toward sAML could be characterized by 3 successive molecular steps: (1) overexpression of enzymes reducing proteic disulfide bonds (MDS with

Abernethy malformation is a rare congenital anomaly of the portal vein where the portal blood bypasses the liver. We report the first case of a patient with Abernethy malformation and tetralogy of Fallot associated with nodular regenerative hyperplasia and focal nodular hyperplasia (FNH), which finally evolved to a giant hepatocellular-cholangiocarcinoma (HCC-CC) of the liver, successfully resected. (Hepatology 2016;64:1800-1802).

Introduction Moderate anemia affects a substantial fraction of the elderly population and blood smear analysis can help to guide towards a diagnosis of myelodysplastic syndrome (MDS). Nevertheless, in medical laboratories, review of blood smear is realized only if there is quantitative or qualitative flag on the complete blood count (CBC). Consequently, the suspicion of MDS could be delayed because of the absence of systematic blood smear triggering, this smear being crucial to induce the diagnosis process by cytological analysis of bone marrow aspiration. The DxH 800 Hematology Analyzer measures and calculates 126 cytological parameters based on photometry, impedance or light scatter. These parameters regroup 23 standard CBC parameters and 103 unexploited "research parameters". The goal of our study was to create an original mathematical model using "research parameters" to determine a Suspicion Score of MDS which triggers blood smear examination and consequently the process of identification of subclinical patients suffering from MDS. Methods This study compared the 126 parameters measured by the Beckman-Coulter DxH 800 Hematology Analyzer from peripheral blood samples of MDS patients and healthy volunteers. MDS cohort was composed of 101 patients of the university hospital of Tours (9 MDS-SLD, 28 MDS-MLD, 8 MDS-RS-SLD, 8 MDS-RS-MLD, 20 MDS-EB-1, 19 MDS-EB-2, 9 5q-). The cohort of healthy volunteers included 88 aged-matched subjects from HEALTHOX and PLASMYC protocols (ClinicalTrials.gov # NCT02789839 and # NCT02809222, respectively). The "research parameters" contained Research Use Only (RUO) parameters and Cell Population Data (CPD). CPD were composed of 98 parameters measured by Volume Conductivity Scatter (VCS) module. The parameters derived from reticulocytes, which require a specific prescription, were excluded. Statistical analyses were performed using Rstudio version 1.0.153. The normal distribution of values was studied by Shapiro-Wilk tests (p-value0.05). Means comparisons were performed by Wilcoxon and Student tests. Principal component analysis (PCA) was performed using FactoMineR. The logarithmic logistic regression was done thanks to the glm() function of the stats package. The general linear model was obtained by using logistic regression with weighted parameters and was validated by split-sample strategy (10,000 repeats). Samples were divided into two groups ("learning" and "test" groups) randomly mixing MDS patients and healthy volunteers. The "learning" group (n=130) allowed to build the model and the "test" group (n=59) was used to validate it. Results After mono-parametric and multi-parametric comparisons, 10 parameters were selected to establish the model of interest according to the best contributions at the first axe of PCA, the best correlations at two first axes of PCA and the most significant p-values (parameters described in the Table: MN.LALS.NNRBC, MN.LMALS.NNRBC, MN.UMALS.NNRBC, SD.MALS.NE, SD.UMALS.NE, SD.V.NE, MN.MALS.NE, SD.AL2.NE, SD.AL2.MO, SD.V.MO ). In order to determine the Suspicion Score of MDS (SS-MDS), the 10 selected parameters were weighted during split sampling strategy by logistic regression. After repeat of 10,000 split-samples, the SS-MDS determined using weighted parameters was validated with average efficiency of 92.3%. For each parameter, the median of weighting coefficients was used in the mathematical model: "SS-MDS = ΣCi.Pi + intercept" with "Ci: weighting coefficient of parameter i" and "Pi: parameter i value". On the whole cohort, SS-MDS induced "MDS" flag for 11 MDS patients (red points in the Figures) for which conventional CBC algorithms failed to generate flag spreading peripheral blood smear. By fixing the threshold at -1.5, the sensitivity and specificity of SS-MDS were 100% and 92%, respectively. Moreover, the positive and negative predictive values were 93.5% and 100%, respectively. Conclusions The incidence of MDS increases with aging and the early diagnosis enables optimal care of these diseases. The Beckman-Coulter DxH 800 HematologyAnalyzer is widely used over the world. We propose in this study the clinical use of 10 unexploited "research parameters" to early detect subclinical MDS by selective triggering of blood smear examination. A prospective/multicentric study will allow the optimization of SS-MDS. Figure. Figure. Disclosures No relevant conflicts of interest to declare.