An improved index for diagnosis and mortality prediction in malignancy-associated hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. Classification and regression tree and receiver-operating curve analyses were used to identify the most useful diagnostic and prognostic parameters and to optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3900 U/mL) and ferritin (>1000 ng/mL) best identified HLH-2004-defining features (sensitivity, 84%; specificity, 81%). Moreover, this combination, which we term the optimized HLH inflammatory (OHI) index, was highly predictive of mortality (hazard ratio, 4.3; 95% confidence interval, 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk who were not defined as having HLH according to HLH-2004/HScore. Finally, the OHI index shows diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies patients with HM and an inflammatory state associated with a high mortality risk and warrants further prospective validation.

Heart valve disease in primary antiphospholipid syndrome.

OBJECTIVES: Antiphospholipid syndrome (APS)-associated heart valve disease (HVD) is well described. Nonetheless, limited data exist on clinical parameters associated with the course of primary APS (pAPS) patients with HVD. The goal of this study was to assess clinical features and related outcomes in patients with APS associated HVD. METHODS: In this multicentre retrospective study, we identified 33 pAPS patients with HVD (pAPS-HVD group) and compared their clinical course with 128 pAPS patients with normal heart valves on echocardiography (pAPS-control group). RESULTS: pAPS-HVD patients had more cerebrovascular events 56.3% vs 25% (p= 0.005) and livedo reticularis 24.2% vs 7.8% (p= 0.013) than pAPS-controls. Furthermore, catastrophic-APS (CAPS) (12.1% vs 2.4%, p= 0.034), recurrent thrombosis (33.3% vs 4.7%, p< 0.001), and need for advanced therapy (i.e. IVIG, plasmapheresis or rituximab) were more frequent in pAPS-HVD patients. Anti-B2GPI-IgG. [84.8% vs 63.2% (p= 0.034)], anti-cardiolipin IgG [90.9% vs. 64.8% (p= 0.005)] and triple positive aPL [75.8% vs 56.5% (p= 0.047)] were commoner in pAPS-HVD patients vs pAPS-controls. Ten of the 33 patients with pAPS-HVD underwent valve surgery which was associated with male gender, smoking, arterial limb ischaemia and livedo reticularis. CONCLUSION: pAPS-HVD patients had a more severe APS clinical course including CAPS and thrombotic events as well as with specific serology namely IgG isotype aPL antibodies and triple positivity. Our data suggest that pAPS-HVD represents a high-risk subgroup of APS patients.

A Case of Chronic Lymphocytic Leukemia Complicated by Hemophagocytic Lymphohistiocytosis: Identifying the Aberrant Immune Response.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that may complicate hematologic malignancies. HLH and malignancies have common clinical features, and HLH diagnostic criteria (HLH-2004/Hscore) were not validated in this specific population. We describe a case of a 72-year-old patient with a history of chronic lymphocytic leukemia stable for over 10 years who presented with fever and cytopenia. After excluding infectious etiologies and the progression of her disease, HLH was diagnosed. The patient was treated with etoposide, dexamethasone, intravenous immunoglobulin, and rituximab. Despite initial clinical improvement, the patient deteriorated and developed pulmonary aspergillosis and CNS involvement that reflected uncontrolled HLH. The patient died 45 days after her presentation. An unusual feature of this case was that HLH was not triggered by infection, disease transformation, or treatment. This case emphasizes the challenges of differentiating the development of overwhelming HLH from other complications associated with hematologic malignancy.

Nuclear αvß3 integrin expression, post translational modifications and regulation in hematological malignancies.

αvß3 integrin, a plasma membrane protein, is amply expressed on an array of tumors. We identified nuclear αvß3 pool in ovarian cancer cells and were interested to explore this phenomenon in two rare and aggressive types of leukemia, T-cell acute lymphoblastic leukemia (T-ALL) and Mast cell leukemia (MCL) using Jurkat and HMC-1 cell lines, respectively. Moreover, we collected primary cells from patients with chronic lymphocytic leukemia (CLL, n = 11), the most common chronic adult leukemia and used human lymphoblastoid cell lines (LCL) generated from normal B cells. Nuclear αvß3 integrin was assessed by Western blots, confocal microscopy, and the ImageStream technology which combines flow-cytometry with microscopy. We further examined post translational modifications (phosphorylation/glycosylation), nuclear trafficking regulation using inhibitors for MAPK (U0126) and PI3K (LY294002), as well as nuclear interactions by performing Co-immunoprecipitation (Co-IP). αvß3 integrin was identified in all cell models within the nucleus and is N-glycosylated. In primary CLL cells the ß3 integrin monomer is tyrosine Y759 phosphorylated, suggesting an active receptor conformation. MAPK and PI3K inhibition in Jurkat and CLL cells led to αvß3 enhancement in the nucleus and a reduction in the membrane. The nuclear αvß3 integrin interacts with ERK, Histone H3 and Lamin B1 in Jurkat, Histone H3 in CLL cells, but not in control LCL cells. To conclude, this observational study provides the identification of nuclear αvß3 in hematological malignancies and lays the basis for novel cancer-relevant actions, which may be independent from the membrane functions.

Prolonged Blood Storage and Risk of Posttransfusion Acute Kidney Injury.

BACKGROUND: Erythrocyte transfusions are independently associated with acute kidney injury. Kidney injury may be consequent to the progressive hematologic changes that develop during storage. This study therefore tested the hypothesis that prolonged erythrocyte storage increases posttransfusion acute kidney injury. METHODS: The Informing Fresh versus Old Red Cell Management (INFORM) trial randomized 31,497 patients to receive either the freshest or oldest available matching erythrocyte units and showed comparable mortality with both. This a priori substudy compared the incidence of posttransfusion acute kidney injury in the randomized groups. Acute kidney injury was defined by the creatinine component of the Kidney Disease: Improving Global Outcomes criteria. RESULTS: The 14,461 patients included in this substudy received 40,077 erythrocyte units. For patients who received more than one unit, the mean age of the blood units was used as the exposure. The median of the mean age of blood units transfused per patient was 11 days [interquartile range, 8, 15] in the freshest available blood group and 23 days [interquartile range, 17, 30] in the oldest available blood group. In the primary analysis, posttransfusion acute kidney injury was observed in 688 of 4,777 (14.4%) patients given the freshest available blood and 1,487 of 9,684 (15.4%) patients given the oldest available blood, with an estimated relative risk (95% CI) of 0.94 (0.86 to 1.02; P = 0.132). The secondary analysis treated blood age as a continuous variable (defined as duration of storage in days), with an estimated relative risk (95% CI) of 1.00 (0.96 to 1.04; P = 0.978) for a 10-day increase in the mean age of erythrocyte units. CONCLUSIONS: In a population of patients without severely impaired baseline renal function receiving fewer than 10 erythrocyte units, duration of blood storage had no effect on the incidence of posttransfusion acute kidney injury.

Anemia in Patients With Diabetes and Prediabetes With Normal Kidney Function: Prevalence and Clinical Outcomes.

OBJECTIVE: Anemia is a known complication of diabetes mellitus (DM); however, its prevalence and prognostic relevance in patients with DM and pre-DM with normal kidney function have not been well defined. This study assessed the prevalence of anemia in patients with DM and pre-DM and evaluated its association with clinical outcomes during a 4-year follow-up period. METHODS: This retrospective analysis included patients with DM and pre-DM referred to the Meir Medical Center Endocrine Institute in 2015. Patients with an estimated glomerular filtration rate (eGFR) of <60 mL/min or any other recognized cause of anemia were excluded. The risk of developing microvascular or macrovascular complications or of death during the 4-year follow-up period was determined. RESULTS: A total of 622 patients (408 with DM and 214 with pre-DM) were included. The mean age of the patients was 64 ± 10.6 years, and 70% were women. The baseline hemoglobin A1C level was 7.1% ± 1.7% (54 mmol/mol), and the eGFR was 86.1 ± 15.3 mL/min. At the time of inclusion, 77 patients (19%) with DM and 23 (11%) with pre-DM had anemia (hemoglobin level 11.9 ± 0.8 and 11.8 ± 0.8 g/dL, respectively), compared with normal hemoglobin levels of 13.8 ± 0.9 and 13.7± 0.9 g/dL, respectively, in the others. A multivariable analysis demonstrated an inverse correlation between baseline hemoglobin (as a continuous variable) and mortality (P = .035), microvascular complications (P = .003), and eGFR decline (P < .001) but not between baseline hemoglobin and macrovascular complications (P = .567). CONCLUSION: This study found a significant prevalence of anemia unrelated to renal failure, both in patients with DM and pre-DM. Anemia in these patients is associated with the development of microvascular complications, eGFR decline, and mortality. These results underscore the need for intensive lifestyle and pharmacologic interventions in these patients.

Management and Outcome of Venous Thrombosis in Patients with Myeloproliferative Neoplasms: Data from the Israeli MPN Working Group.

The BCR-ABL-negative myeloproliferative neoplasms (MPN) are associated with high incidence of venous thrombosis and a significant rate of recurrent events, but there is no consensus regarding their management. In this retrospective study, we analyzed 96 patients with MPN-related venous thrombosis. The index venous thrombosis occurred at a median age of 58 years (IQR 37-71), with 58% of the events involving unusual sites. Patients who were on antiplatelet agents at the time of index thrombosis tended to be older than patients who were not receiving antiplatelets at the time of index thrombosis. The majority of index thromboses occurring after the diagnosis of MPN had uncontrolled blood counts at the time of event and were not receiving antithrombotic agents. Following the thrombotic episode, 75% of patients received long-term anticoagulation. At a median follow-up of 3.4 years, the recurrence rate was 14%. Thrombophilia was significantly more prevalent among patients with recurrent thrombosis compared to patients without recurrence (p < 0.01). Patients who developed a recurrent event early were more likely to have thrombophilia (either inherited or antiphospholipid antibodies), and controlled blood counts, and were likely to receive anticoagulation at the time of recurrence compared to patients with later recurrences. Thrombophilia may contribute to venous thrombosis recurrence, especially early after the index venous thrombosis. Suboptimal anticoagulation and blood count control are factors associated with late venous thrombosis recurrence.

MOMENTUM: momelotinib vs danazol in patients with myelofibrosis previously treated with JAKi who are symptomatic and anemic.

Hallmark features of myelofibrosis (MF) are cytopenias, constitutional symptoms and splenomegaly. Anemia and transfusion dependency are among the most important negative prognostic factors and are exacerbated by many JAK inhibitors (JAKi). Momelotinib (MMB) has been investigated in over 820 patients with MF and possesses a pharmacological and clinical profile differentiated from other JAKi by inhibition of JAK1, JAK2 and ACVR1. MMB is designed to address the complex drivers of iron-restricted anemia and chronic inflammation in MF and should improve constitutional symptoms and splenomegaly while maintaining or improving hemoglobin in JAKi-naive and previously JAKi-treated patients. The MOMENTUM Phase III study is designed to confirm and extend observations of safety and clinical activity of MMB.

Lay abstract The most important features of myelofibrosis (MF) are low blood cell counts and symptoms including tiredness, night sweats and itching, along with increased size of the spleen, which may cause a feeling of fullness and pain. Low red blood cell counts (anemia) may mean regular blood transfusions are needed and this is one of the signs MF is getting worse. Drugs called JAK inhibitors (JAKi) are available to treat MF, but can have a side effect of making blood cell counts lower. Momelotinib (MMB) is a different type of JAKi to the ones currently available, and is an experimental drug for MF. MMB is designed to treat symptoms and spleen like other JAKi, but also to improve blood cell counts. MMB has already been given to more than 820 patients with MF in other clinical studies. Some of the patients in these studies had been treated with different JAKi before, and others got MMB as their first JAKi treatment. The MOMENTUM Phase III study is designed to collect more information on the safety and effectiveness of MMB in MF.

Pregnancy and non-pregnancy related immune thrombotic thrombocytopenic purpura in women of reproductive age.

Pregnancy is a precipitating factor for immune thrombotic thrombocytopenic purpura (iTTP). We compared the clinical course and outcomes of iTTP in women of reproductive age, between those with pregnancy- and non-pregnancy-related iTTP. A review of all reproductive-aged women diagnosed with iTTP during 2010-2019 in seven university hospitals in Israel. Of 42 cases of iTTP, 12 (28.6%) were pregnancy-related. At presentation, the laboratory profiles did not differ significantly between those with pregnancy- and non-pregnancy-related iTTP, including hemoglobin (median 8.4 vs 8.0 g/dL), platelet count (12.5 vs. 11.5 X 109/L); and levels of bilirubin (1.23 vs. 1.82 mg/dL), lactate dehydrogenase (1615 vs. 1701 U/L), creatinine (0.61 vs. 0.79 mg/dL) and anti-ADAMTS13 antibodies titer (75 vs. 82 U/mL). The proportions of women with renal, neurologic, or hepatic involvement were similar between the groups. Cardiac involvement was more common among those with pregnancy-related disease (25.0% vs. 3.3%, P = 0.06). The median number of courses of plasma-exchange therapy was 11 for both groups. All the women were treated with parenteral corticosteroids and the rate of adjunctive treatments did not differ between the groups (P = 0.30). Four women (one-third) with pregnancy-related disease had preeclampsia. Two women (16.7%) with pregnancy-related iTTP died during the acute episode (P = 0.07); no deaths were observed in the non-pregnancy-related group. Among reproductive-aged women with iTTP, most clinical and laboratory profiles were similar between those with pregnancy- and non-pregnancy-related disease. However, the higher rates of cardiac involvement and mortality among women with pregnancy-related iTTP highlight its challenging management.

Enhanced expression of αVß3 integrin in villus and extravillous trophoblasts of placenta accreta.

BACKGROUND: Placenta accreta is one of the most serious complications in obstetrics and gynecology. Villous trophoblasts (VT) and extravillous trophoblasts (EVT) play a central role in normal placentation. Placenta accreta is characterized by abnormal invasion of EVT cells through the uterine layers, due to changes in several parameters, including adhesion proteins. Although αvß3 integrin is a central adhesion molecule, participating in multiple invasive pathological conditions including cancer, data on placenta accreta are lacking. OBJECTIVE: To study the expression pattern of αvß3 integrin in placenta accreta in comparison with normal placentas. STUDY DESIGN: We collected tissue samples from placentas defined as percreta, the most severe presentation of placenta accreta and from normal control placentas (n = 10 each). The samples underwent protein extractions for analyses of αvß3 expression by Western blots (WB) and a parallel tissue assessment by immunohistochemistry (IHC). RESULTS: WB results indicated significantly elevated αvß3 integrin expression in the percreta samples compared to normal placentas. These elevated levels were mainly contributed by EVT cells, as demonstrated by IHC. αvß3 integrin demonstrated a classical membranal expression in the VT cells, whereas a uniformly distributed expression was documented in the EVT cells. These patterns of the αvß3 integrin localization were similar in both accreta and normal placental samples. CONCLUSIONS: Enhanced αvß3 integrin expression, mainly in extra villous trophoblasts of placenta percreta, implies for a role of this adhesion molecule in pathological placentation.

Splanchnic vein thromboses associated with myeloproliferative neoplasms: An international, retrospective study on 518 cases.

Myeloproliferative Neoplasms (MPN) course can be complicated by thrombosis involving unusual sites as the splanchnic veins (SVT). Their management is challenging, given their composite vascular risk. We performed a retrospective, cohort study in the framework of the International Working Group for MPN Research and Treatment (IWG-MRT), and AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM). A total of 518 MPN-SVT cases were collected and compared with 1628 unselected, control MPN population, matched for disease subtype. Those with MPN-SVT were younger (median 44 years) and enriched in females compared to controls; PV (37.1%) and ET (34.4%) were the most frequent diagnoses. JAK2V617F mutation was highly prevalent (90.2%), and 38.6% of cases had an additional hypercoagulable disorder. SVT recurrence rate was 1.6 per 100 patient-years. Vitamin K-antagonists (VKA) halved the incidence of recurrence (OR 0.48), unlike cytoreduction (OR 0.96), and were not associated with overall or gastrointestinal bleeding in multivariable analysis. Esophageal varices were the only independent predictor for major bleeding (OR 17.4). Among MPN-SVT, risk of subsequent vascular events was skewed towards venous thromboses compared to controls. However, MPN-SVT clinical course was overall benign: SVT were enriched in PMF with lower IPSS, resulting in significantly longer survival than controls; survival was not affected in PV and slightly reduced in ET. MPN-U with SVT (n = 55) showed a particularly indolent phenotype, with no signs of disease evolution. In the to-date largest, contemporary cohort of MPN-SVT, VKA were confirmed effective in preventing recurrence, unlike cytoreduction, and safe; the major risk factor for bleeding was esophageal varices that therefore represent a major therapeutic target.

Effect of Short-Term vs. Long-Term Blood Storage on Mortality after Transfusion.

BACKGROUND: Randomized, controlled trials have suggested that the transfusion of blood after prolonged storage does not increase the risk of adverse outcomes among patients, although most of these trials were restricted to high-risk populations and were not powered to detect small but clinically important differences in mortality. We sought to find out whether the duration of blood storage would have an effect on mortality after transfusion in a general population of hospitalized patients. METHODS: In this pragmatic, randomized, controlled trial conducted at six hospitals in four countries, we randomly assigned patients who required a red-cell transfusion to receive blood that had been stored for the shortest duration (short-term storage group) or the longest duration (long-term storage group) in a 1:2 ratio. Only patients with type A or O blood were included in the primary analysis, since pilot data suggested that our goal of achieving a difference in the mean duration of blood storage of at least 10 days would not be possible with other blood types. Written informed consent was waived because all the patients received treatment consistent with the current standard of care. The primary outcome was in-hospital mortality, which was estimated by means of a logistic-regression model after adjustment for study center and patient blood type. RESULTS: From April 2012 through October 2015, a total of 31,497 patients underwent randomization. Of these patients, 6761 who did not meet all the enrollment criteria were excluded after randomization. The primary analysis included 20,858 patients with type A or O blood. Of these patients, 6936 were assigned to the short-term storage group and 13,922 to the long-term storage group. The mean storage duration was 13.0 days in the short-term storage group and 23.6 days in the long-term storage group. There were 634 deaths (9.1%) in the short-term storage group and 1213 (8.7%) in the long-term storage group (odds ratio, 1.05; 95% confidence interval [CI], 0.95 to 1.16; P=0.34). When the analysis was expanded to include the 24,736 patients with any blood type, the results were similar, with rates of death of 9.1% and 8.8%, respectively (odds ratio, 1.04; 95% CI, 0.95 to 1.14; P=0.38). Additional results were consistent in three prespecified high-risk subgroups (patients undergoing cardiovascular surgery, those admitted to intensive care, and those with cancer). CONCLUSIONS: Among patients in a general hospital population, there was no significant difference in the rate of death among those who underwent transfusion with the freshest available blood and those who underwent transfusion according to the standard practice of transfusing the oldest available blood. (Funded by the Canadian Institutes of Health Research and others; INFORM Current Controlled Trials number, ISRCTN08118744 .).

Electronic patient identification for sample labeling reduces wrong blood in tube errors.

BACKGROUND: Wrong blood in tube (WBIT) errors are a preventable cause of ABO-mismatched RBC transfusions. Electronic patient identification systems (e.g., scanning a patient's wristband barcode before pretransfusion sample collection) are thought to reduce WBIT errors, but the effectiveness of these systems is unclear. STUDY DESIGN AND METHODS: Part 1: Using retrospective data, we compared pretransfusion sample WBIT rates at hospitals using manual patient identification (n = 16 sites; >1.6 million samples) with WBIT rates at hospitals using electronic patient identification for some or all sample collections (n = 4 sites; >0.5 million samples). Also, we compared WBIT rates after implementation of electronic patient identification with preimplementation WBIT rates. Causes and frequencies of WBIT errors were evaluated at each site. Part 2: Transfusion service laboratories (n = 18) prospectively typed mislabeled (rejected) samples (n = 2844) to determine WBIT rates among samples with minor labeling errors. RESULTS: Part 1: The overall unadjusted WBIT rate at sites using manual patient identification was 1:10,110 versus 1:35,806 for sites using electronic identification (p < 0.0001). Correcting for repeat samples and silent WBIT errors yielded overall adjusted WBIT rates of 1:3046 for sites using manual identification and 1:14,606 for sites using electronic identification (p < 0.0001), with wide variation among individual sites. Part 2: The unadjusted WBIT rate among mislabeled (rejected) samples was 1:71 (adjusted WBIT rate, 1:28). CONCLUSION: In this study, using electronic patient identification at the time of pretransfusion sample collection was associated with approximately fivefold fewer WBIT errors compared with using manual patient identification. WBIT rates were high among mislabeled (rejected) samples, confirming that rejecting samples with even minor labeling errors helps mitigate the risk of ABO-incompatible transfusions.

Characteristics and outcomes of young adults with Philadelphia-negative myeloproliferative neoplasms.

OBJECTIVE: Approximately 10% of Philadelphia (Ph)-negative myeloproliferative neoplasms (NPM) are diagnosed at young adulthood. We aim to define the features of this group. METHODS: A multicenter retrospective study, including patients 18-45 years of age, diagnosed with Ph-negative MPN between 1985 and 2017. RESULTS: One hundred nine patients were included, 37 with polycythemia vera (34%), 54 with essential thrombocytosis (50%), 15 with primary myelofibrosis (PMF) (14%), and 3 with MPN unclassifiable (3%). Median age was 33 years and 62 (57%) were females. During a median follow-up of 8 years, 39 patients (37%) had at least one thrombotic event. 30/39 of events were venous (77%), 23/30 of which were splanchnic (77%). In 14/39 (36%), thrombosis preceded MPN diagnosis. In a multivariable analysis, only splenomegaly predicted for thrombosis (HR 5.6, CI: 1.4-22). The 10-year risk for secondary myelofibrosis was similar for ET and PV (0.13 vs 0.19, P = 0.51). The 10-year risk for leukemic transformation or mortality was significantly higher for PMF (0.3, P = 0.04). CONCLUSIONS: The risks of mortality and of progression to MF/leukemia in young adults are similar to older population. Thrombotic events are frequently a presenting sign with a high incidence of venous, in particular splanchnic, events.

[PRACTICAL ADVICE FOR THE APPROPRIATE USE OF DIRECT ORAL ANTICOAGULANTS].

INTRODUCTION: The direct oral anticoagulants (DOACs) are a class of drugs used for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and for prevention and treatment of venous thrombo-embolism. They are as effective and are safer than the vitamin K antagonists that were the oral drugs previously used for this purpose. The DOACs are convenient to use because of their fixed dose-response relationship which makes routine monitoring of drug levels unnecessary. Further, they have no food interactions and relatively few drug interactions. A number of practical considerations related to the routine clinical use of the DOACs have become apparent. These include choosing the appropriate drug and importantly dose-based on patient characteristics, managing the use of DOACs peri-operatively and the appropriate management of the acutely bleeding DOAC-treated patient. Recent controlled and observational studies provide guidance for dealing with these clinical situations thus enhancing the efficacy and safety of DOAC treatment in routine clinical practice.

Molecular insights into the transcriptional regulatory role of thyroid hormones in ovarian cancer.

The regulation of cancer-relevant genes by the thyroid hormones, 3, 5, 3'-Triiodo-L-thyronine (T3) and L-thyroxine (T4), was recently acknowledged. However, limited data exists on the hormonal effects on gene expression in ovarian cancer, a gynecological malignancy associated with a low cure rate. The expression of fifteen genes involved in DNA repair, cell cycle, apoptosis, and tumor suppression was evaluated in OVCAR-3 and A2780 cell lines, using real-time PCR following short incubation with T3 (1 nM) or T4 (100 nM). The thyroid hormones downregulated the expression of the majority of genes examined. Support for the involvement of the MAPK and PI3K in thyroid hormone-mediated gene expression was shown for a set of genes. FAS expression was inhibited in A2780 cells, while an unexpected induction was demonstrated in OVCAR-3 cells. An analogous effect on the protein levels of FAS receptor and its soluble form was demonstrated by Western blotting. We further established, using primer sets that discriminate between the different RNA isoforms, that the hormones increase the mRNA levels of both coding and non-coding FAS mRNAs. The prevalence of these isoforms, using The Cancer Genome Atlas (TCGA) analysis, was significantly more abundant in 17 cancer types, including ovarian cancer, compared to normal tissues. Our results highlight the role of thyroid hormones in the expression of cancer-relevant-genes in ovarian cancer and provide an important insight into the pathways by which mitogenic and anti-apoptotic effects are exerted.

Chemical and thyroid hormone profile of the bone marrow interstitial fluid in hematologic disorders and patients without primary hematologic disorders.

Bone marrow interstitial fluid (BMIF) has not been well characterized. BMIF was isolated from 60 patients including plasma cell dyscrasias (PCD, n = 33), other primary hematologic disorders (OHD, n = 15), and patients with secondary or nonhemtologic disorders (NHD, n = 12) and analyzed for an array of chemical constituents. These included total cholesterol, glucose, phosphate, creatinine, urea, total protein, albumin, globulins, total bilirubin, aspartate aminotransferase, lactate dehydrogenase, sodium, osmolarity, free triiodothyronine (free T3), total triiodothyronine (total T3), and free tetraiodothyronine (free T4). Levels of BMIF components were compared between patient groups and to plasma levels. Compared with plasma, total cholesterol, total protein, total bilirubin, sodium, and calculated osmolarity were lower in BMIF in all groups (P < 0.05). Calculated globulins and aspartate aminotransferase were lower in BMIF of PCD patients and patients with NHD. Albumin was lower in BMIF of patients with PCD and patients with OHD. Lastly, free T4 was significantly higher in BMIF of patients with PCD and patients with OHD. Similar results were demonstrated in a separate analysis performed in patients with multiple myeloma. To conclude, the chemical and thyroid hormone composition of BMIF differs significantly from plasma in several key constituents.

Targeted next generation sequencing for the diagnosis of patients with rare congenital anemias.

BACKGROUND: Most patients with anemia are diagnosed through clinical phenotype and basic laboratory testing. Nonetheless, in cases of rare congenital anemias, some patients remain undiagnosed despite undergoing an exhaustive workup. Genetic testing is complicated by the large number of genes involved in rare anemias and the similarities in the clinical presentation of the different syndromes. OBJECTIVE: We aimed to enhance the diagnosis of patients with congenital anemias by using targeted next-generation sequencing. METHODS: Genetic diagnosis was performed by gene capture followed by next-generation sequencing of 76 genes known to cause anemia syndromes. RESULTS: Genetic diagnosis was achieved in 13 out of 21 patients (62%). Six patients were diagnosed with pyruvate kinase deficiency, 4 with dehydrated hereditary stomatocytosis, 2 with sideroblastic anemia, and 1 with CDA type IV. Eight novel mutations were found. In 7 patients, the genetic diagnosis differed from the pretest presumed diagnosis. The mean lag time from presentation to diagnosis was over 13 years. CONCLUSIONS: Targeted next-generation sequencing led to an accurate diagnosis in over 60% of patients with rare anemias. These patients do not need further diagnostic workup. Earlier incorporation of this method into the workup of patients with congenital anemia may improve patients' care and enable genetic counseling.

Management of extreme thrombocytosis in myeloproliferative neoplasms: an international physician survey.

Extreme thrombocytosis (ExT) has been associated with an increased bleeding risk in myeloproliferative neoplasm (MPN) patients and is included in the high risk category in treatment guidelines. Treatment of patients with ExT has not been studied in prospective trials. To study physicians' approaches to ExT, we distributed a web based questionnaire with clinical case scenarios to 202 members of MPN working groups. Cases included low thrombotic risk essential thrombocythemia (ET) with either JAK2V617F or CALR mutation, polycythemia vera with ExT either with or without leukocytosis, an ET patient needing urgent orthopedic surgery, and a poorly controlled ET patient with acute cerebral venous sinus thrombosis. Responses were received from 90 physicians (45 %) and were variable in most case scenarios. Country of practice had the most significant influence on physician response. The USA and Israel physicians responded similarly in most cases and differently to the Europe physicians. Treatment of asymptomatic JAK2V617F positive ET and target platelet count on cytoreduction were significantly influenced by physician years of experience. Responses were not influenced by the volume of MPN practice or by whether MPN was considered a major interest by the physician. Our results show a lack of consensus on how to manage MPN patients with ExT. Randomized controlled trials properly designed to address these questions are needed.

[INR LEVELS DURING HOSPITALIZATION AT THE DEPARTMENT OF MEDICINE].

BACKGROUND: Warfarin has a narrow therapeutic index with INR values between 2.0 - 3.0. According to our clinical experience, control of INR levels during hospitalization is poor. OBJECTIVES: The study aimed to evaluate control of INR levels during hospitalization in the departments of internal medicine, to determine the factors that influence INR levels during hospitalization, and the association between the control of INR levels before and during hospitalization. METHODS: This is a retrospective study, including the data of patients who were admitted to the internal medicine wards at Meir and Rabin Medical Centers, Israel, between May 2011 and May 2013. Inclusion criteria: patients who were treated with warfarin prior and during the index hospitalization and at least 3 INR tests were taken during the hospitalization and the 3 months before it. The collected data included: demographic parameters (age, gender), medical background, cause of admission, relevant medications for INR control, duration of hospitalization and INR values. The INR control during hospitalization and the previous 3 months, the parameters that affect INR levels and the association between control before and during hospitalization were evaluated. RESULTS: Of 1861 screened patients, only 299 filled the inclusion criteria. Among those patients, 93 (31%) were considered to have well controlled INR rates during the hospitalization. No significant differences were found between the controlled and uncontrolled groups. The risk of a well-controlled patient before admission to be uncontrolled during admission was 63%, whereas the risk of an uncontrolled patient before admission to remain uncontrolled during hospitalization was 73%. CONCLUSIONS: By using a larger study group it might be possible to achieve significant results and to set guidelines for INR control during admission. DISCUSSION: Most patients are not monitored well enough to estimate their degree of INR control. Most of the patients, who could be evaluated, were uncontrolled.