Poorer outcome of childhood acute lymphoblastic leukemia in the Bedouin population: A report from the Berlin-Frankfurt-Muenster-based Israeli national protocols.

BACKGROUND: Therapy outcomes for childhood acute lymphoblastic leukemia (ALL) had substantially improved in the last decades, but variability across racial and ethnic groups was identified in some clinical studies. In this study, we aimed to investigate whether such a difference in outcome is found in the diverse ethnicities in Israel as well. METHODS: A retrospective study was conducted among 1154 patients (855 Jews, 195 Muslims, 52 Bedouins, 26 Druze, and 26 others) aged 1 to 21 years, who were diagnosed with ALL between 1989 and 2011 and were treated according to the same Berlin-Frankfurt-Muenster-based Israel National Study protocols. RESULTS: Bedouins had a higher incidence of t(1;19) (16% vs 3% for non-Bedouins) and a lower incidence of high-hyperdiploidy (10% vs 25% for non-Bedouins) (P = 0.01). Five-year event-free survival (EFS) and overall survival (OS) were poorer for the Bedouins (60.3% ± 7.2% and 63.1% ± 7.2%, respectively) compared with the Jews, Muslims, and Druze (80.4% ± 1.4%, 77.3% ± 3.2%, and 84% ± 7.3%, respectively, for EFS [P = 0.02], and 86.3% ± 1.2%, 82.3% ± 2.9%, and 88.3% ± 6.4%, respectively, for OS [P = 0.002]). Adherence to intensive chemotherapy was similar between the Muslims and the Bedouins. CONCLUSIONS: Our findings suggest that the Bedouins, a highly inbred ethnic Arab people, may be considered a higher risk group that may need more intensive chemotherapy and/or supportive care in order to improve their outcome.

Whole-exome sequencing identifies an α-globin cluster triplication resulting in increased clinical severity of ß-thalassemia.

Whole-exome sequencing (WES) has been increasingly useful for the diagnosis of patients with rare causes of anemia, particularly when there is an atypical clinical presentation or targeted genotyping approaches are inconclusive. Here, we describe a 20-yr-old man with a lifelong moderate-to-severe anemia with accompanying splenomegaly who lacked a definitive diagnosis. After a thorough clinical workup and targeted genetic sequencing, we identified a paternally inherited ß-globin mutation (HBB:c.93-21G>A, IVS-I-110:G>A), a known cause of ß-thalassemia minor. As this mutation alone was inconsistent with the severity of the anemia, we performed WES. Although we could not identify any relevant pathogenic single-nucleotide variants (SNVs) or small indels, copy-number variant (CNV) analyses revealed a likely triplication of the entire α-globin cluster, which was subsequently confirmed by multiplex ligation-dependent probe amplification. Treatment and follow-up was redefined according to the diagnosis of ß-thalassemia intermedia resulting from a single ß-thalassemia mutation in combination with an α-globin cluster triplication. Thus, we describe a case where the typical WES-based analysis of SNVs and small indels was unrevealing, but WES-based CNV analysis resulted in a definitive diagnosis that informed clinical decision-making. More generally, this case illustrates the value of performing CNV analysis when WES is otherwise unable to elucidate a clear genetic diagnosis.

[THE PROGNOSTIC IMPACT OF CHROMOSOMAL ABERRATIONS IN TUMOR TISSUE BIOPSIES FROM PATIENTS WITH DIFFUSE LARGE B CELL LYMPHOMA].

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma (NHL), and constitutes 30-40% of all cases in adults. DLBCL is heterogeneous in terms of its clinical course, and related molecular and genetic features. In the current era of appropriate chemo-immunotherapy, approximately 50%-60% of patients are cured after treatment. DLBCL is characterized by numerous chromosomal changes which are encountered in a high proportion of cases. OBJECTIVE: To examine whether the identification of chromosomal changes at time of diagnosis has prognostic significance in DLBCL. METHODS AND STUDY POPULATION: The study cohort included those patients with DLBCL, diagnosed and treated during 1996-2012 at the Hematology unit in Bnai-Zion Medical Center, Haifa, who had a cytogenetic study performed based on G-banding analysis from the original biopsy at the time of diagnosis. RESULTS: One hundred and twenty one patients with DLBCL were included and of these 59 also had chromosomal analysis performed from the tumor tissue at diagnosis. The average age of the cohort was 60.9 (21-87) years, and 59.3% were men. Average follow-up was 50.6 months (1-240 months). In 16 of the 59 biopsies (27.1%) lymphoma cells did not grow in vitro and analysis was not performed in these cases. Of the remaining 43 cases with chromosomal analysis: 36 (83.7%) had chromosomal aberrations, which most frequently involved chromosomes 14, 18, 1 and X. There was no difference in outcome between patients with chromosomal changes, including the presence of complex karyotype or hyperdiploidy (defined as > 50 chromosomes), and those with normal karyotype. CONCLUSIONS: Although complex changes in basic chromosomal structure and altered numbers of chromosomes were identified in patients with DLBCL, none of these features were of prognostic significance in terms of overall survival. In the light of these findings, we confirm that in common practice for DLBCL outside of clinical trials there appears to be no advantage to performing routine chromosomal studies on biopsy specimens obtained from patients with newly diagnosed DLBCL.

[EMOTIONAL INTELLIGENCE EQ--A NECESSARY SKILL FOR SUCCESS OF MEDICAL STAFF IN THE 21ST CENTURY].

During the last decade, medical organizations have undergone major changes worldwide and these continue to evolve at a rapid pace. Today the medical profession faces many new challenges that will eventually have an impact on almost every aspect of daily hospital routine. To a large extent, these issues arise from emerging new technologies, the entry of a new generation of trained workers who have different views and characteristics than previous generations, and the introduction of stricter regulations and accreditation procedures in recent years. In addition, the various hospital staff members now have different professional expectations and demands; there is also an important need to reduce costs, accompanied by a shift towards the concept of patients perceiving themselves as clients rather than only as people needing medical assistance. Facing all these challenges, undoubtedly, medical teams will need to acquire a more comprehensive set of professional skills critical for their continued success in the 21st century. These skills will have to include the ability to be more flexible, so as to be able to adapt to changing environments, to remain effective at work under stress, to develop positive personal interactive working relationships, while providing excellent service to patients, and to maintain the ability to guide and lead others in a changing medical environment. People with the above skills reflect the positive attributes of high emotional intelligence. Recent studies show that emotional intelligence plays an important role in the success of the entire medical staff and particularly for those in management roles. Hospitals will have to take into consideration all the necessary characteristics, if they wish to maintain and further consolidate their previous achievements in the 21st century. In particular, they will need to pay attention to the EQ of both new and existing staff, using it as a meaningful parameter for new recruits and for the further development of their existing medical staff. Two years ago, the Bnai-Zion Medical Center in Haifa, Israel made an important strategic decision to prepare itself to cope more successfully with the future challenges posed by the 21st century, by adopting the "language" of emotional intelligence within the different departments. This program, unique in Israel, was designed as a comprehensive in-house process for the entire hospital at all levels. It was designed as an evolving multi-stage development program with additional wards joining in at every stage, with a special design. A summary of the key points necessary for understanding the design of EQ in Bnai-Zion Medical center is described in this review. Disclosure: Ayalla Reuven-Lelong and Niva Dolev are the owners of EQ-EL--the emotional intelligence center in Israel.

Emotional intelligence: A unique group training in a hematology-oncology unit.

BACKGROUND: Emotional intelligence (EI) is increasingly viewed as one of the important skills required for a successful career and personal life. Consequently, efforts have been made to improve personal and group performance in EI, mostly in commercial organizations. However, these programs have not been widely applied in the health field. The aim of this study is to assess the impact of a unique special EI interventional process within the framework of an active hematology-oncology unit in a general hospital. METHODS: This investigation employed a pre- and post-training design using the Bar-On Emotional Quotient Inventory (EQ-i) measure of EI, both before and after completion of training 10 months later. The training included personal and group EI assessments and 10 EI workshops, each 2 weeks apart and each lasting approximately 2 h. Results were compared to a control group of medical staff who did not undergo any EI training program during the same time period. RESULTS: Average total Bar-On EQ-i level at baseline for the group was 97.9, which increased significantly after the interventional process to a score of 105.6 (P = 0.001). There were also significant increases in all five main EQ-i scales, as well as for 12 of the 15 subscales. In contrast, the control group showed no significant differences in general EI level, in any of the five main scales or 15 EI subscale areas. DISCUSSION: This pilot study demonstrated the capability of a group intervention to improve EI of medical staff working in a hematology-oncological unit. The results are encouraging and suggest that the model program could be successfully applied in a large-scale interventional program.

Genetic analysis and clinical picture of severe congenital neutropenia in Israel.

BACKGROUND: The relative frequency of mutated genes among patients with severe congenital neutropenia (SCN) may differ between various ethnic groups. To date, few population-based genetic studies have been reported. This study describes the genetic analysis of 32 Israeli patients with SCN. PROCEDURES: Clinical data were retrieved from the prospective Israeli Inherited Bone Marrow Failure Registry. Recruitment included living and deceased patients who were diagnosed between 1982 and 2012, for whom molecular diagnosis was performed. ELANE, HAX1 and G6PC3 genes were sequenced in all patients, and GFI-1 and WAS genes were sequenced if other genes were wildtype. RESULTS: Eleven patients (34%) had heterozygous mutations in ELANE (10 kindreds), eight (25%) had homozygous mutations in G6PC3 (5 kindreds) and 13 (41%) had no detected mutations. No patients had mutations in HAX1 or WAS. Four of the eight patients with G6PC3 mutations had congenital anomalies. The probability of survival for all patients was 50% at age of 18. Deaths were mainly due to sepsis (5 patients, 4/5 not responding to G-CSF, none with G6PC3 mutation). Two patients developed acute myelogenous leukemia (AML) and one myelodysplastic syndrome (MDS), none with G6PC3 mutation. CONCLUSIONS: We found a unique pattern of SCN mutations in Israel with homozygous G6PC3 mutations in eight (25%) patients, the highest frequency described so far. HAX1 mutations, reported mainly in Sweden and Iran, were absent. Patients with G6PC3 mutations had congenital anomalies, appeared to have a better response to G-CSF, and so far have not developed AML or MDS.

Monocyte count at diagnosis is a prognostic parameter in diffuse large B-cell lymphoma: results from a large multicenter study involving 1191 patients in the pre- and post-rituximab era.

In this study we assessed the prognostic significance of absolute monocyte count and selected the best cut-off value at diagnosis in a large cohort of patients with diffuse large B-cell lymphoma. Data were retrieved for therapy-naïve patients with diffuse large B-cell lymphoma followed in Israel and Italy during 1993-2010. A final cohort of 1017 patients was analyzed with a median follow up of 48 months and a 5-year overall survival rate of 68%. The best absolute monocyte count cut-off level was 630/mm(3) and the 5-year overall survival for patients with counts below this cut-off was 71%, whereas it was 59% for those with a count >630 mm(3) (P=0.0002). Of the 1017 patients, 521 (51%) were treated with chemo-immunotherapy, and in this cohort, using multivariate analysis, elevated monocyte count retained a negative prognostic value even when adjusted for International Prognostic Index (HR1.54, P=0.009). This large study shows that a simple parameter such as absolute monocyte count (>630/mm(3)) can easily be used routinely in the evaluation of newly diagnosed diffuse large B-cell lymphoma to identify high-risk patients with a worse survival in the rituximab era.

Wilms' tumor gene 1: a possible new proangiogenic factor in Hodgkin lymphoma.

INTRODUCTION: Wilms' tumor gene 1 (WT1) was recently found to play a role in solid and hematologic malignancies and serves as a marker of prognosis and minimal residual disease in acute leukemia. WT1 was also found to be involved in tumor angiogenesis. There are no data concerning the involvement of WT1 in angiogenesis in lymphoproliferative tumors. The aim of this study was to explore the involvement of WT1 in Hodgkin lymphoma. METHODS: The expression of WT1, neuropilin 1, and VEGF was tested by immunohistochemistry in lymph nodes biopsies of 20 Hodgkin patients and 7 reactive lymph nodes. RESULTS: WT1 was expressed in endothelial cells, in 95% of the malignant lymph nodes. The average of WT1 expression scale was higher in the malignant lymph nodes than in reactive lymph nodes. We found a positive correlation between WT1 expression scale and the angiogenesis scale (0.53) that was statistically significant (P<0.05). As the number of vessels increases, the expression of WT1 is more intense. CONCLUSIONS: We found, for the first time, that WT1 is expressed in endothelial cells in Hodgkin lymphoma. The clinical implications of these findings should be tested in a future study.

Absolute monocytosis at diagnosis correlates with survival in diffuse large B-cell lymphoma-possible link with monocytic myeloid-derived suppressor cells.

Some patients with lymphoma have monocytosis at diagnosis, but its significance is unclear. The recently recognized subpopulation, monocytic myeloid-derived suppressor cells (M-MDSCs), has immunoregulatory function, suppresses host anti-tumour immunity and plays a role in cancer tolerance. Data from 91 untreated patients with diffuse large B-cell lymphoma (DLBCL) were evaluated for monocytosis >1000/mm(3) at diagnosis and its significance compared with a number of well-established prognostic factors for DLBCL including age, stage, gender, B symptoms, extranodal sites, LDH and CRP levels, bone marrow involvement and International Prognostic Index (IPI) score. In 23 of these patients with DLBCL and 15 healthy controls, the proportion of M-MDSCs in the peripheral blood was determined by flow cytometry. Monocytosis was found in 17.6% of the patient cohort examined. In the multivariate analysis, bone marrow involvement, IPI score and monocytosis were the only independent prognostic factors seen to be associated with decreased progression free and overall survival. Patients with DLBCL had on average increased M-MDSCs counts at diagnosis compared with controls, which returned to normal after achieving remission. In conclusion, monocytosis was identified as an independent prognostic factor in DLBCL and correlated with worse overall survival. The significant increases in the M-MDSCs pool observed in some of the cases examined may possibly help to explain why monocytosis is associated with poor outcome in these patients.

Rozrolimupab, a mixture of 25 recombinant human monoclonal RhD antibodies, in the treatment of primary immune thrombocytopenia.

Rozrolimupab, a recombinant mixture of 25 fully human RhD-specific monoclonal antibodies, represents a new class of recombinant human antibody mixtures. In a phase 1 or 2 dose escalation study, RhD(+) patients (61 subjects) with primary immune thrombocytopenia received a single intravenous dose of rozrolimupab ranging from 75 to 300 µg/kg. The primary outcome was the occurrence of adverse events. The principal secondary outcome was the effect on platelet levels 7 days after the treatment. The most common adverse events were headache and pyrexia, mostly mild, and reported in 20% and 13% of the patients, respectively, without dose relationship. Rozrolimupab caused an expected transient reduction of hemoglobin concentration in the majority of the patients. At the dose of 300 µg/kg platelet responses, defined as platelet count ≥ 30 × 10(9)/L and an increase in platelet count by > 20 × 10(9)/L from baseline were observed after 72 hours and persisted for at least 7 days in 8 of 13 patients (62%). Platelet responses were observed within 24 hours in 23% of patients and lasted for a median of 14 days. Rozrolimupab was well tolerated and elicited rapid platelet responses in patients with immune thrombocytopenia and may be a useful alternative to plasma-derived products. This trial is registered at www.clinicaltrials.gov as #NCT00718692.

Semaphorin 3A is a marker for disease activity and a potential immunoregulator in systemic lupus erythematosus.

INTRODUCTION: Semaphorin 3A (sema3A) and neuropilin-1 (NP-1) play a regulatory role in immune responses and have a demonstrated effect on the course of collagen induced arthritis. This study was undertaken to evaluate the role of sema3A and NP-1 in the pathogenesis of systemic lupus erythematosus (SLE) and the specific effect of sema3A on the auto-reactive properties of B cells in SLE patients. METHODS: Thirty two SLE and 24 rheumatoid arthritis (RA) patients were assessed and compared with 40 normal individuals. Sema3A serum levels were measured and correlated with SLE disease activity. The in vitro effect of sema3A in reducing Toll-like receptor 9 (TLR-9) expression in B cells of SLE patients was evaluated. RESULTS: Sema3A serum levels in SLE patients were found to be significantly lower than in RA patients (55.04 ± 16.30 ng/ml versus 65.54 ± 14.82 ng/ml, P = 0.018) and lower yet than in normal individuals (55.04 ± 16.30 ng/ml versus 74.41 ± 17.60 ng/ml, P < 0.0001). Altered serum sema3A levels were found to be in inverse correlation with SLE disease activity, mainly with renal damage. The expression of both sema3A and NP-1 on B cells from SLE patients was significantly different in comparison with normal healthy individuals. Finally, when sema3A was co-cultured with cytosine-phosphodiester-guanine oligodeoxynucleotides (CpG-ODN)-stimulated B cells of SLE patients, their TLR-9 expression was significantly reduced, by almost 50% (P = 0.001). CONCLUSIONS: This is the first study in which a reduced serum level of sema3A was found in association with SLE disease activity. It also raises the possibility that sema3A may have a regulatory function in SLE.

Giant pediatric aneurysmal bone cysts of the occipital bone: case report and review of the literature.

Cranial aneurysmal bone cysts are uncommon. Cranial aneurysmal bone cysts of the occipital bone are exceedingly rare. A 2-year-old toddler with this rare cyst presented with a large space-occupying lesion of the posterior fossa, with cerebellar tonsillar herniation. The patient experienced complete recovery after total excision of the lesion. We review the literature regarding this rare presentation, and discuss the origin, pathogenesis, pathologic features, imaging characteristics, and treatment of cranial aneurysmal bone cysts.

Myeloid-derived suppressor cells--their role in haemato-oncological malignancies and other cancers and possible implications for therapy.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells at different stages of maturation that play a role in cancer tolerance and function as an immune-suppressive cell subpopulation. They utilize different mechanisms to block both innate and adaptive arms of anti-tumour immunity, mostly through inhibition of T cell activation and expansion. Further advances in our understanding of this cell population in both murine models and humans has enabled more accurate characterization of their phenotype and the recognition of two major classes of MDSCs: granulocytic and monocytic. Recently, the mechanism of action and clinical importance of MDSCs has been more clearly defined and their interactions with cancer cells have been shown to be among the factors influencing tumour development and induction of tolerance. Most of the earlier studies were performed using murine models, but recent clinical investigations have shown their potential role in human cancers. Here, we review the origin of MDSCs, their mechanisms of action, the factors influencing their production and related signalling pathways. We focus on their role in human solid tumours and haemato-oncological malignancies, and relate to possible novel therapeutic approaches targeting MDSCs which could be considered together with other anticancer strategies in the not too distant future.

Hypereosinophilia, JAK2V617F, and Budd-Chiari syndrome: who is responsible for what?

Budd-Chiari syndrome (BCS) is characterized by hepatic venous outflow obstruction, which sometimes may be life threatening, with the development of fulminant hepatic failure. In cases of this kind, the most frequent underlying cause of BCS, myeloproliferative neoplasms (MPN), should always be excluded first, and molecular analysis of the Janus Kinase 2 (JAK2) mutation must always be performed [1]. While the association of BCS with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis is well documented, hypereosinophilia has only been described in sporadic cases [2­7]. Furthermore, Jak2 mutation in association with hypereosinophilia has been reported very rarely and its prevalence in this disorder still requires further investigation [8,9]. To the best of our knowledge, cases with the above association occurring together with BCS have not been reported until now. Here, we describe a young woman presenting with idiopathic eosinophilia, JAK2 mutation, and BCS. We also elaborate briefly on the biological mechanism and clinical features of this rare entity. In our opinion, this case supports the formal inclusion of hypereosinophilic syndrome (HES) in the WHO MPN category and also raises the possible pathogenetic contribution of eosinophils, or their products, in MPN-associated splanchnic vein thrombosis.