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Background: Preeclampsia is a unique vascular disease during pregnancy that generally appears after 20 of weeks gestation or until 6 weeks after delivery. Left undiagnosed, preeclampsia can lead rapidly to death of both mother and fetus., Objectives: To verify the efficacy of peripheral blood inflammatory markers (BIMs)in diagnosing preeclampsia and compare them with results from other studies., Methods: Our retrospective case-control study comprised two patient groups. Pregnant women with preeclampsia and pregnant women without preeclampsia were compared for BIMs: neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and mean platelet volume (MPV). The primary endpoint of our research was to assess the predictive power of BIMs for preeclampsia diagnosis., Results: The sample size was calculated based on expected differences of BIMs between the control and study groups. Comparison of quantitative variables was conducted with independent sample t-test or alternatively by Wilcoxon rank sum test. The MPV values were slightly higher in the preeclampsia group, but not statistically significant. NLR and PLR did differentiate between study and control groups., Conclusions: The diagnostic accuracy of BIMs is unsatisfactory for preeclampsia diagnosis. Discrepancies concerning these values need to be clarified. Further large prospective studies are necessary to validate the potential factor accuracy in preeclampsia diagnosis.

Background: Information regarding the safety and efficacy of specific direct oral anticoagulants (DOAC) in the treatment of cerebral sinus and venous thrombosis (CSVT) is scarce. Apixaban is one of the most frequently prescribed DOACs. Therefore, we aimed to compare the safety and efficacy of Apixaban with those of vitamin k antagonists (VKA) in patients with CSVT., Methods: Prospective CSVT databases from seven academic medical centers were retrospectively analyzed. Patients treated with Apixaban were compared to those treated with VKA. Data on demographics, clinical presentations, risk factors, radiological and outcome parameters were studied., Results: Overall, 403 patients were included in the analysis. Of them, 48 (12%) were treated with Apixaban, and 355 (88%) were treated with VKA. Rates of coagulopathies were significantly higher in the VKA-treated patients but no other differences between the groups were found in baseline characteristics and underlying etiology. No significant differences were found between groups in efficacy or safety parameters including the rates of recanalization, favorable outcomes, one-year mortality, seizures, intracranial hemorrhage or CSVT recurrences., Conclusion: Our data suggests that Apixaban may be safe and effective for patients with CSVT. These results should be tested in prospective randomized clinical studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Simaan, Metanis, Honig, Hallevi, Filioglo, Mendel, Barnea, Naftali, Auriel, Aladdin, Orion, Dally, Leker and Molad.)

Several studies showed ethnic disparities in multiple myeloma (MM) incidence and prognosis. In order to compare prognosis and overall survival between different ethnic groups, a multicenter retrospective study was conducted in Northern Israel. A total of 145 patients suffering from MM were included (72% Jewish, and 28% Arabs) who were treated between 2008-2018. A difference was found in the stage of the disease at the time of diagnosis, patients of Arab origin were diagnosed at a more advanced stage (III), (53.7% vs. 33.7%, respectively). A mortality rate of 48.9% was found in the study, regardless of population ethnic origin. No significant differences in rates of MGUS, MM symptoms, treatments, or progression-free survival (PFS) and overall survival (OS) were observed between ethnic groups. This suggests that raising awareness of MM may result in an earlier diagnosis, especially among patients of Arab origin, preventing unnecessary suffering from these patients.

Quality of life is impaired in MDS, but the role of hemoglobin level is unclear. To study the Hb-QoL correlation at diagnosis and 1 year later, patients filled out the EQ-5D questionnaire, assessing their mobility, self care, daily activities, pain/discomfort, and anxiety/depression, using scores of 0 (normal), 1 (mild/moderate), or 2 (poor). They also evaluated their health using a visual analogue scale, scoring from 0 (poor) to 100 (excellent). The anemia subgroups were: none/normal (Hb ≥ 12.5 g/dL), mild (10 ≤ Hb < 12.5), moderate (9 ≤ Hb < 10), severe (8 ≤ Hb < 9), or very severe (Hb < 8). LR-MDS patients (n = 127) and inpatient controls (n = 141) participated. The anemic patients had a poor QoL and the MDS patients had a lower QoL with a lower Hb. The controls had no QoL difference among the various anemia subgroups. In addition, the MDS QoL sharply decreased with an Hb of < 9. The MDS patients showed a wide QoL variability, i.e., different QoL scores in the same Hb subgroup, suggesting that other factors affect QoL (e.g., age and comorbidities). After 1 year (n = 61), the QoL was still poor for most MDS patients (including 27 patients with an increased Hb). In summary: (1) a poor QoL in MDS-anemia is non-linear, suggesting other influencing factors on QoL. (2) The sharp QoL drop with Hb < 9 g/dL challenges the transfusion Hb threshold. (3) The QoL in anemic MDS patients might differ from that in non-MDS patients. (4) Raising Hb, while recommended, does not guarantee an improved QoL.

Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia. In this retrospective multicenter study, 68 SP patients were included. Compared to solitary extramedullary plasmacytoma (SEP), patients with solitary bone plasmacytoma (SBP) were younger (57.3 vs. 70.9 years, p  = 0.031), had larger plasmacytoma (median: 5.4 vs. 3 cm, p  = 0.007) and higher median involved free light chain level (61 vs. 25.8 mg/L, p  = 0.056). 92.6% of patients were treated by radiotherapy and 11.8% received systemic anti-myeloma treatment. With a median follow-up of 42 months, 45.6% of patients progressed (8.8% - recurrent SP, 36.8% - active myeloma). The median PFS was 58 months and the median OS has not been reached (10-year OS: 84.8%). Patients who received also anti-myeloma treatment had longer PFS compared to those who did not (median not reached vs. 48 months, p  = 0.056). In conclusion, SBP and SEP appear to be different diseases. Radiotherapy is the cornerstone in the SP treatment. A large prospective trial is needed to evaluate the impact of adding systemic anti-myeloma treatment to local radiotherapy.

Oral squamous cell carcinomas (OSCCs) are common cancers of cats. While papillomaviruses (PVs) are an important cause of human OSCCs, there is currently little evidence that PVs cause squamous cell carcinomas (SCCs) of the mouth or other mucosal surfaces in cats. In the present cat, in situ carcinomas developed on the gingiva and nictitating membrane. Neoplastic cells within both cancers contained prominent PV-induced cellular changes consistent with those caused by Felis catus PV3 (FcaPV3), and FcaPV3 DNA was amplified from both cancers. Neoplasms also contained intense nuclear and cytoplasmic p16 CDKN2A protein (p16) immunolabeling, suggesting PV-induced degradation of retinoblastoma protein. The molecular and histological features strongly suggested the cancers were caused by FcaPV3 infection. This is the first report of an association between PV infection and the development of an in situ carcinoma of the mucosa of cats. The identification of these lesions suggests that PVs might cause a proportion of OSCCs, and SCCs from other mucosal surfaces, in cats.

Polatuzumab (Pola)-based regimens and chimeric antigen receptor T (CAR T) cells provide superior outcome compared to conventional chemoimmunotherapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). Choosing between these strategies remains controversial. The efficacy of CAR T versus Pola-rituximab(R) /Pola-bendamustine(B)-R in R/R DLBCL patients after failing ≥2 lines of treatment was compared in a retrospective, 'real-world' study. Propensity score matching, for age, lymphoma category (de-novo/transformed), number of prior lines, Eastern Cooperative Oncology Group performance status and lactate dehydrogenase level, was applied to control for differences in patients' characteristics. Response rate, progression-free survival (PFS) and overall survival (OS) were analyzed. A total of 82 patients, treated with CAR T (n=41) or Pola-based regimens (n=41), were included. No treatment-related deaths occurred with CAR T vs. 3 (7.3%) with Pola. The overall and complete response rates were 83% and 58% with CAR T vs. 66% and 44% with Pola-based-regimens (p=0.077 and p=0.18, respectively). At a median follow-up of 9 months (range 1-19.2) and 16 months (range 0.7-25.3) for the CAR T and Pola arm respectively, the median PFS has not been reached for CAR T vs. 5.6 months for Pola (95% CI 3.6-7.6, p=0.014). Median OS has not been reached for CAR T vs. 10.8 months (95% CI 2.2-19.4) for Pola (p=0.026). To conclude, in a real-world setting, treatment with CAR T achieved superior PFS and OS compared to Pola-based regimens in patients with R/R DLBCL., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Patients with chronic lymphocytic leukemia (CLL) have a suboptimal humoral response to vaccination. Recently, BNT162b2, an mRNA COVID-19 vaccine with a high efficacy of 95% in immunocompetent individuals, was introduced. We investigated the safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with CLL from nine medical centers in Israel, Overall 400 patients were included, of whom 373 were found to be eligible for the analysis of antibody response. The vaccine appeared to be safe and only grade 1-2 adverse events were seen in 50% of the patients. Following the second dose, an antibody response was detected in 43% of the cohort. Among these CLL patients, 61% of the treatment-na ve patients responded to the vaccine, while responses developed in only 18% of those with ongoing disease, 37% of those previously treated with a BTK inhibitor and 5% of those recently given an anti-CD20 antibody. Among patients treated with BCL2 as monotherapy or in combination with anti-CD20, 62% and 14%, respectively, developed an immune response. There was a high concordance between neutralizing antibodies and positive serological response to spike protein. Based on our findings we developed a simple seven-factor score including timing of any treatment with anti-CD20, age, treatment status, and IgG, IgA, IgM and hemoglobin levels. The sum of all the above parameters can serve as a possible estimate to predict whether a given CLL patient will develop sufficient antibodies. In conclusion, the BNT162b2 mRNA COVID-19 vaccine was found to be safe in patients with CLL, but its efficacy is limited, particularly in treated patients.

Patients with chronic lymphocytic leukemia (CLL) have an impaired antibody response to coronavirus disease 2019 (COVID-19) vaccination. Here, we evaluated the antibody response to a third BNT162b2 mRNA vaccine in patients with CLL/small lymphocytic lymphoma (SLL) who failed to achieve a humoral response after standard 2-dose vaccination regimen. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies were measured 3 weeks after administration of the third dose. In 172 patients with CLL, the antibody response rate was 23.8%. Response rate among actively treated patients (12.0%; n = 12/100) was lower compared with treatment-naïve patients (40.0%; n = 16/40; OR = 4.9, 95% CI 1.9-12.9; P < .001) and patients off-therapy (40.6%; n = 13/32; OR = 5.0, 95% CI 1.8-14.1; P < .001), (P < .001). In patients actively treated with Bruton's tyrosine kinase (BTK) inhibitors or venetoclax ± anti-CD20 antibody, response rates were extremely low (15.3%, n = 9/59, and 7.7%, n = 3/39, respectively). Only 1 of the 28 patients (3.6%) treated with anti-CD20 antibodies <12 months prior to vaccination responded. In a multivariate analysis, the independent variables that were associated with response included lack of active therapy (OR = 5.6, 95% CI 2.3-13.8; P < .001) and serum immunoglobulin A levels ≥80 mg/dL (OR = 5.8, 95% CI 2.1-15.9; P < .001). In patients with CLL/SLL who failed to achieve a humoral response after standard 2-dose BNT162b2 mRNA vaccination regimen, close to a quarter responded to the third dose of vaccine. The antibody response rates were lower during active treatment and in patients with a recent exposure (<12 months prior to vaccination) to anti-CD20 therapy. This trial was registered at www.clinicaltrials.gov as #NCT04862806., (© 2022 by The American Society of Hematology.)

This national Israeli multicenter retrospective study aimed to characterize the clinical course of COVID-19 infection among patients with hematological malignancies, with special emphasis on treatment efficacy and outcome. Clinical and laboratory data from haemato-oncological patients diagnosed with COVID-19 from 16 medical centers were centrally reported. Multivariate regression analyses were used to determine variables associated with severe disease, hospitalization, and mortality. In total, 313 patients were included: 103 (35.7%) developed severe/critical respiratory infection, 178 (61.4%) were hospitalized, and 60 (20.0%) died. Age > 70 years was associated with severe/critical disease ( p  = 0.036) and mortality ( p  = 0.023), hypertension with severe/critical disease ( p  = 0.046) and hospitalization ( p  = 0.001), active haemato-oncological treatment with hospitalization ( p  = 0.009), and remdesivir treatment was associated with decreased mortality ( p  = 0.021). Convalescent plasma, enoxaparin, and corticosteroids resulted in no clinical benefit. In conclusion, COVID-19 infection seems particularly severe in patients with hematological malignancies, and of all examined therapies, remdesivir appears to be the most effective.

Gaucher disease (GD) is an autosomal recessive disease characterized by the buildup of glucocerebrosides in macrophages, resulting in the formation of "Gaucher cells." These cells predominantly infiltrate the liver, spleen, and bone marrow leading to hepatosplenomegaly, cytopenia, and bone pain. Anemia in GD is typically considered to result from non-hemolytic processes. Although rare, a higher rate of hemolytic anemia of the autoimmune type has been reported in GD than in the general population. The literature on non-immune hemolytic anemia in GD is scarce. We review the literature on hemolytic anemia in GD and report on a case of non-immune hemolytic anemia secondary to GD. We believe this is the first description of a patient with confirmed GD and symptomatic non-immune hemolytic anemia that responded to GD-specific treatment.

Background: One of the main obstacles of providing home-based palliative care to transfusion-dependent hematology patients is the lack of home transfusions services. While healthcare professionals are concerned with safety and cost of home transfusions, the attitude of the patients toward home transfusions are mostly unknown., Aim: To obtain quantitative data regarding the willingness and concerns of transfusion-dependent patients with hematological diseases toward the option of home transfusions., Design: A cross sectional survey including a self-administered questionnaire in one of the three main spoken languages in Israel was administered to patients in 17 hospital hematology outpatient clinics between May 2019 and March 2020., Results: About 52% of 385 patients that participated in the survey preferred home transfusions to hospital transfusions. Gender, age, education, or type of disease were not associated with preference for home transfusions, nor were hospital location or its size. The likelihood to prefer home transfusions was significantly higher among the Hebrew-speakers and those who had not experienced adverse effects previously. The most significant factor associated with preference of home transfusions was a perceived negative effect of hospital-based transfusion on quality of life. The main reason to reject home transfusions was fear of possible adverse effects and concerns over losing contact with the medical staff at the treating hospital., Conclusion: These data suggest that a significant portion of transfusion-dependent patients in Israel view home transfusions as a preferred treatment option and that its successful implementation requires maintaining ongoing contact with the treating hospital.

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.

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., (© 2020 S. Karger AG, Basel.)

The efficacy of polatuzumab vedotin in relapsed/refractory diffuse large B-cell lymphoma outside clinical study are undetermined. This retrospective study examined the efficacy and safety of polatuzumab vedotin administered in real life settings. Forty-seven patients, 31 with de-novo DLBCL and 16 with transformed lymphoma, treated with polatuzumab-based regimen in 14 Israeli centers between June 2018 and November 2019, were included. Median age was 66.1 years (60.4-78.8) and median number of prior lines was 3 (2-7). The overall response rate was 61% ( n  = 29), including 40% complete responses ( n  = 19) and 21% ( n  = 10) partial responses. The median overall survival and progression-free survival were 8.3 months and 5.6 months, respectively. An ECOG PS ≥2 predicted a decreased overall survival ( p  = 0.045). Primary refractory vs relapsed disease ( p  = 0.005) and transformed vs de-novo DLBCL ( p  = 0.039) were associated with shorter PFS ( p  = 0.027). Our data show that polatuzumab-based regimen is an effective and tolerable treatment in relapsed/refractory DLBCL.

This study tests a new comprehensive model accounting for the role of demographic, personal, and social factors in quality of life (QOL) among a sample of hematological cancer patients. We hypothesized that positive and negative affect would mediate the associations between these factors and QOL. Seventy-two patients were recruited at an outpatient hematological clinic in a midsized medical center in northern Israel. They completed measures of QOL, social support, positive and negative affect, and emotional intelligence (EI). Diagnostic and demographic information was retrieved from their files. Path analysis supported a model in which positive and negative affect mediated the association between income level, social support, EI, and QOL. This study presents a model accounting for QOL among hematological patients that for the first time pertains to demographic, personal, and interpersonal factors. This model may guide future research as well as future interventions to empower and support this fragile target population.

Background: Major advances in the treatment of patients with hairy cell leukemia (HCL) have been made following the introduction of purine analogues. The major significant short-term toxicity of cladribine therapy are neutropenia and neutropenic fever (NF) which may be life-threatening., Aim: In this retrospective study, we compared the incidence and duration of neutropenia and hospitalization in patients with HCL treated with cladribine followed by peg-filgrastim as primary prophylaxis versus daily filgrastim given "on demand" according to absolute neutrophil count (ANC)., Methods: Medical records of patients with HCL diagnosed and followed in 12 medical centers in Israel during 1985-2015 were examined for details of disease at diagnosis. The efficacy of peg-filgrastim and filgrastim was assessed by evaluating the incidence of neutropenia (ANC < 1.0 × 10 [9]/L), number and length of hospitalizations, and number of days from the last day of therapy to recovery of ANC to >1.0 × 10 [9]/L., Results: The study population included 202 patients with HCL, 159 of whom (80.7%) were treated with cladribine; 78 patients (49%) required hospitalization for the administration of broad-spectrum antibiotics due to NF. Twenty-eight (19%) patients were treated with peg-filgrastim as primary prophylaxis, while 74 (64%) received filgrastim "on demand" due to neutropenia. Median length of hospitalization, and nadir duration were 8 and 18 days respectively (p = 0.71, p = 0.44)., Conclusions: Infectious complications post-cladribine treatment remain high. No difference was found in terms of incidence of NF, number of febrile days, and nadir duration in patients receiving primary peg-filgrastim prophylaxis compared to filgrastim given on demand. Both approaches are justifiable, and the choice remains at the physician's discretion., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Acquired hemophilia A is a rare disease. The incidence has been estimated to be 1.3-1.5 cases per 1 million persons per year. The etiology of acquired hemophilia A varies. It may develop in patients with autoimmune disorders, hematologic and solid cancers or in women during pregnancy or following childbirth. In about half of the cases no underlying disease can be found. The clinical picture is dominated by severe soft tissue hematomas especially in the cases of pregnancy-related acquired hemophilia A. Unlike congenital hemophilia A, bleeding into joints is rare. Pregnancy-related acquired hemophilia A may develop following any pregnancy but is observed more often in primigravidas. In most cases it arises in the postpartum period, most commonly 1-4 months after delivery. If factor VIII inhibitors develop during pregnancy or labor, they are frequently associated with severe uterine bleeding. The prognosis of pregnancy-related acquired hemophilia A is good with a high percentage of spontaneous remissions especially if the inhibitor was detected postpartum. Patients with acquired inhibitors do not usually have personal or family history of bleeding tendency, thus it is the presence of bleeding at multiple sites with prolonged activated partial thromboplastin time not corrected by incubation with normal plasma (mixing study) that raises the suspicion of inhibitor. Prompt diagnosis and treatment achieved by close collaboration among gynecologists and hematologists may improve the prognosis and prevent severe bleeding.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. The therapeutic approach to CLL includes chemotherapeutic regimens and immunotherapy. Complement-mediated cytotoxicity, which is one of the mechanisms activated by the therapeutic monoclonal antibodies, depends on the availability and activity of the complement (C) system. The aim was to study the structure of circulating C components and evaluate the importance of C5 structural integrity for C activity in CLL patients. Blood samples were collected from 40 naïve CLL patients and 15 normal controls (NC). The Western blot analysis showed abnormal C5 pattern in some CLL patients, while patterns of C3 and C4 were similar in all subjects. Levels of the C activation markers sC5b-9 and C5a were quantified before and after activation via the classical (CP) and alternative (AP) pathways. In patients with abnormal C5, basal levels of sC5b-9 and C5a were increased while activities of the CP and of the CP C5-convertase, the immediate C5-upstream complex, were decreased compared to NC and to patients with normal C5. The data indicate a link between CP activation and apparent C5 alterations in CLL. This provides a potential prognostic tool that may personalize therapy by identifying a sub-group of CLL patients who display an abnormal C5 pattern, high basal levels of sC5b-9 and C5a, and impaired CP activity, and are likely to be less responsive to immunotherapy due to compromised CP activity., Competing Interests: The authors have declared that no competing interests exist.

Breeding vegetative crops (e.g. beets, cabbage, forage grasses) is challenged by two conflicting aims. For field production, flowering must be avoided while flowering and seed set is necessary for breeding and seed production. The biennial species sugar beet makes shoot elongation ('bolting') followed by flowering after a long period of cold temperatures. Field production in northern geographical regions starts in spring. A thickened storage root is formed only during vegetative growth. It is expected that winter beets, which are sown before winter would have a much higher yield potential. However, field production was not possible so far due to bolting after winter. We propose a strategy to breed winter beets exploiting haplotype variation at two major bolting time loci, B and B2. Both genes encode transcription factors controlling the expression of two orthologs of the Arabidopsis gene FLOWERING LOCUS T (FT). We detected an epistatic interaction between both genes because F 2 plants homozygous for two B/B2 mutant alleles did not bolt even after vernalization. Fluorescence complementation studies revealed that both proteins form a heterodimer in vivo. In non-bolting plants, the bolting activator BvFT2 was completely downregulated whereas the repressor BvFT1 was upregulated which suggests that both genes acquire a CONSTANS (CO) like function in beet. Like CO, B and B2 proteins house CCT and BBX domains which, in contrast to CO are split between the two beet genes. We propose an alternative regulation of FT orthologs in beet that can be exploited to breed winter beets.

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. Patients with stage I disease are usually treated with radiotherapy (RT). In previous studies, mostly from the pre positron emission tomography-computed tomography (PET-CT) era, the 5 year progression-free survival (PFS) and overall survival (OS) rates of stage I disease were 60-80% and 80-93%, respectively. This study retrospectively evaluated the outcome of stage I FL which was treated with involved field RT in the PET-CT era between 2002 and 2015. Ninety-one patients were enrolled. Five year PFS and OS rates were 73% and 97%, respectively. Relapse occurred in 19 (21%) patients, 74% occurring outside the radiation field. In conclusion, PET-CT staging of clinical stage I FL may contribute to the improved prognosis in patients treated with RT compared to historical cohorts, possibly due to better identification of "genuine" stage I disease.

The species Beta vulgaris encompasses wild and cultivated members with a broad range of phenological development. The annual life cycle is commonly found in sea beets (ssp. maritima ) from Mediterranean environments which germinate, bolt, and flower within one season under long day conditions. Biennials such as the cultivated sugar beet ( B. vulgaris ssp. vulgaris ) as well as sea beets from northern latitudes require prolonged exposure to cold temperature over winter to acquire floral competence. Sugar beet is mainly cultivated for sugar production in Europe and is likely to have originated from sea beet. Flowering time strongly affects seed yield and yield potential and is thus a trait of high agronomic relevance. Besides environmental cues, there are complex genetic networks known to impact life cycle switch in flowering plants. In sugar beet, BTC1, BvBBX19, BvFT1 , and BvFT2 are major flowering time regulators. In this study, we phenotyped plants from a diversity Beta panel encompassing cultivated and wild species from different geographical origin. Plants were grown under different day length regimes with and without vernalization. Haplotype analysis of BTC1, BvBBX19, BvFT1 , and BvFT2 was performed to identify natural diversity of these genes and their impact on flowering. We found that accessions from northern latitudes flowered significantly later than those from southern latitudes. Some plants did not flower at all, indicating a strong impact of latitude of origin on life cycle. Haplotype analysis revealed a high conservation of the CCT-, REC-, BBX-, and PEBP-domains with regard to SNP occurrence. We identified sequence variation which may impact life cycle adaptation in beet. Our data endorse the importance of BTC1 in the domestication process of cultivated beets and contribute to the understanding of distribution and adaption of Beta species to different life cycle regimes in response to different environments. Moreover, our data provide a resource for haplotypes identified for the major floral regulators in beet.

Philadelphia chromosome-positive (Ph+) leukemia is characterized by reciprocal translocation between chromosomes 9 and 22. The resultant BCR/ABL fusion protein displays constitutive tyrosine kinase activity, leading to the induction of aberrant proliferation and neoplastic transformation. The bone marrow (BM) microenvironment is tumor-promoting, and contributes to disease recurrence in Ph+ leukemia. Activity in the BM microenvironment is mediated by several cellular compartments, extracellular matrix, various soluble factors including transforming growth factor beta 1 (TGF-β1), and the hypoxic conditions in the BM niche. TGF-β1 is released during bone remodeling and plays a role in maintaining leukemic stem cells, as well as being implicated in the epithelial-mesenchymal transition (EMT) process in most solid tumors. Although EMT is largely implicated in epithelial tumors, recent findings argue for an EMT-like process in leukemia as well. The surface receptor CD44 is involved in cell adhesion, cell migration, and homing of normal and malignant hematopoietic stem cells. Elevation of CD44 expression is considered a marker for a worse prognosis in most hematological malignancies. We explored the functions of Snail and Twist1 in Ph+ leukemia. We showed that ectopic expression of Snail and, to a lesser extent, Twist1, upregulates CD44 expression that is β-catenin-dependent. Moreover, the presence of Snail or Twist1 partially blocked phorbol 12-myristate 13-acetate-induced megakaryocyte differentiation, while that of Twist significantly altered imatinib-induced erythroid differentiation. Thus EMT modulators affected proliferation, CD44 gene expression and differentiation ability of Ph+ leukemia cells., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

This corrects the article DOI: 10.1038/nature21370.

Chenopodium quinoa (quinoa) is a highly nutritious grain identified as an important crop to improve world food security. Unfortunately, few resources are available to facilitate its genetic improvement. Here we report the assembly of a high-quality, chromosome-scale reference genome sequence for quinoa, which was produced using single-molecule real-time sequencing in combination with optical, chromosome-contact and genetic maps. We also report the sequencing of two diploids from the ancestral gene pools of quinoa, which enables the identification of sub-genomes in quinoa, and reduced-coverage genome sequences for 22 other samples of the allotetraploid goosefoot complex. The genome sequence facilitated the identification of the transcription factor likely to control the production of anti-nutritional triterpenoid saponins found in quinoa seeds, including a mutation that appears to cause alternative splicing and a premature stop codon in sweet quinoa strains. These genomic resources are an important first step towards the genetic improvement of quinoa.

Objectives: We reviewed the clinical presentation and approach for the treatment of symptomatic seminal vesicle cyst associated with ipsilateral renal agenesis while presenting our experience with a series of 5 patients treated with minimally invasive surgery for Zinner syndrome., Materials and Methods: Between the years 2008 and 2016, we operated on 5 patients who presented with symptomatic seminal vesicle cyst and ipsilateral renal agenesis. Patients' charts and medical records were reviewed and compared with past published minimally invasive series., Results: Four patients were treated in a laparoscopic approach and one was treated with robotic-assisted seminal vesicle cyst excision. In all cases, the cystic complex was drained and excised with marsupialization of the remaining cyst walls to prevent cystic recurrence. The mean operating time was 3:47 h and mean hospitalization time was 7 days (4-14). The mean follow-up period was 3.2 years (range 1.7-4.8 years). All patients reported a resolution of symptoms during postoperative follow-up., Conclusions: Seminal vesicle cyst with ipsilateral renal agenesis should be suspected in young male patients presenting with pelvic cystic masses. Treatment is reserved for symptomatic patients and the preferred approach is minimally invasive surgery. This approach is feasible and effective while providing advantages both for the patient and the surgeon., (© 2017 S. Karger AG, Basel.)

Metastatic adenocarcinoma presenting as microangiopathic hemolytic anemia (MAHA) is a rare finding. We report the case of a young patient who presented with MAHA as the initial symptom of metastatic gastric adenocarcinoma. Cancer-related microangiopathic hemolytic anemia is a paraneoplastic syndrome characterized by Coombs-negative hemolytic anemia with schistocytes and thrombocytopenia. A high index of suspicion and prompt diagnosis can prevent ulterior deterioration, especially when chemotherapy is the optimal treatment in these cases, which can stop the hemolysis.

Light-chain amyloidosis (AL) is associated with low survival rates, particularly in patients with cardiac involvement. We evaluated the outcome of 73 consecutive, non-selected 'real-world' AL patients, treated with first-line bortezomib-based induction, focusing on the benefit of concurrent administration of alkylating agents. Most patients had renal (77%), cardiac (66%), or multiorgan (74%) involvement. Sixty-eight per cent (n = 50) received alkylating agent (mostly cyclophosphamide). Severe adverse events were seen in 45%, most evident in patients with cardiac involvement, with no increased toxicity in patients receiving an alkylator agent. Hematological response (HemR) was obtained in 77% of patients, including 33% very good partial responses and 19% complete responses. Age <70 yr, lack of cardiac and peripheral neurologic involvement, and co-administration of an alkylating agent were associated with significantly improved HemR. NYHA cardiac failure staging was the only independent factor affecting overall survival. Administration of an alkylating agent and the achievement of both HemR and organ response were associated with a statistically significant improved survival in those surviving the first 6 months of induction. First-line bortezomib-based regimen resulted in favorable response and survival in newly diagnosed patients. Co-administration of an alkylating agent improved outcome without increasing treatment-related toxicity., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)