Publications by authors named "Dina Attias"

35 Publications

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

Pediatr Blood Cancer 2020 01 8;67(1):e28024. Epub 2019 Oct 8.

Division of Pediatric Hematology/Oncology, Schneider Children's Medical Center of Israel, Petah Tiqwa, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

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.
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http://dx.doi.org/10.1002/pbc.28024DOI Listing
January 2020

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

Cold Spring Harb Mol Case Stud 2017 Nov 21;3(6). Epub 2017 Nov 21.

Departments of Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tivka 49202, Israel.

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 β-globin mutation (:c.93-21G>A, IVS-I-110:G>A), a known cause of β-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 β-thalassemia intermedia resulting from a single β-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.
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http://dx.doi.org/10.1101/mcs.a001941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701307PMC
November 2017

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

Educ Health (Abingdon) 2016 Sep-Dec;29(3):179-185

The Ruth and Bruce Rappaport Faculty of Medicine, Technion; Bnai Zion Medical Center, Haifa, Israel.

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.
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http://dx.doi.org/10.4103/1357-6283.204221DOI Listing
September 2017

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

Harefuah 2016 Jan;155(1):54-8, 65

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.
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January 2016

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

Harefuah 2016 Jan;155(1):45-9, 66

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.
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January 2016

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

Pediatr Blood Cancer 2015 Jan 4;62(1):103-8. Epub 2014 Oct 4.

Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tikva, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 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.
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http://dx.doi.org/10.1002/pbc.25251DOI Listing
January 2015

Response of cutaneous lesion of mantle cell lymphoma to lenalidomide.

Int J Hematol 2014 Jul 17;100(1):1-2. Epub 2014 May 17.

Hematology Unit, Bnai Zion Medical Center, Golomb 47 st.34108, Haifa, Israel.

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http://dx.doi.org/10.1007/s12185-014-1589-8DOI Listing
July 2014

Pegfilgrastim prophylaxis for cladribine-induced neutropenia in patients with hairy-cell leukemia.

Acta Haematol 2014 14;132(1):118-21. Epub 2014 Feb 14.

Department of Hematology, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel.

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http://dx.doi.org/10.1159/000358293DOI Listing
September 2014

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.

Haematologica 2014 Jan 9;99(1):125-30. Epub 2013 Aug 9.

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.
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http://dx.doi.org/10.3324/haematol.2013.088161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007925PMC
January 2014

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

Blood 2012 Nov 20;120(18):3670-6. Epub 2012 Aug 20.

Department of Hematology, Medical University of Lodz and Copernicus Memorial Hospital, Lodz, Poland.

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.
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http://dx.doi.org/10.1182/blood-2012-06-438804DOI Listing
November 2012

Sezary syndrome presenting with tumourous involvement of the breast detected by (18) F-fluorodeoxyglucose positron-emission tomography/computed tomography.

Br J Haematol 2012 Aug 5;158(4):432. Epub 2012 Jul 5.

Haematology-Oncology Unit, Bnai-Zion Medical Centre, Haifa, Israel.

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http://dx.doi.org/10.1111/j.1365-2141.2012.09216.xDOI Listing
August 2012

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

Hematol Oncol 2013 Jun 20;31(2):65-71. Epub 2012 Jun 20.

Hematology Unit, Bnai-Zion Medical Center, Haifa, Israel.

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.
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http://dx.doi.org/10.1002/hon.2019DOI Listing
June 2013

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

Arthritis Res Ther 2012 Jun 14;14(3):R146. Epub 2012 Jun 14.

Division of Allergy and Clinical Immunology, Bnai-Zion Medical Center, Rappaport Faculty of Medicine, Technion, Haifa-31048, Israel.

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.
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http://dx.doi.org/10.1186/ar3881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446531PMC
June 2012

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

Appl Immunohistochem Mol Morphol 2013 Mar;21(2):177-80

The Hematology Division, Bnai-Zion Medical Center, Haifa, Israel.

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.
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http://dx.doi.org/10.1097/PAI.0b013e318259852aDOI Listing
March 2013

Richter syndrome in chronic lymphocytic leukaemia manifesting only as tumorous hepatomegaly.

Br J Haematol 2011 Oct;155(2):135

Haematology Unit, Bnai-Zion Medical Centre, Haifa, Israel.

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http://dx.doi.org/10.1111/j.1365-2141.2011.08734.xDOI Listing
October 2011

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

Pediatr Neurol 2011 Jul;45(1):42-4

Department of Pediatrics, Bnai Zion Medical Center, Rappaport School of Medicine, Haifa, Israel.

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.
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http://dx.doi.org/10.1016/j.pediatrneurol.2011.01.008DOI Listing
July 2011

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

Br J Haematol 2011 Jun 8;153(5):557-67. Epub 2011 Apr 8.

Haematology Unit, Bnai-Zion Medical Centre, Haifa, Israel.

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.
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http://dx.doi.org/10.1111/j.1365-2141.2011.08678.xDOI Listing
June 2011

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

Am J Hematol 2011 Feb;86(2):223-4

Hematology Unit, Bnai-Zion Medical Center, Haifa, Israel.

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 [2–7]. 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.
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http://dx.doi.org/10.1002/ajh.21926DOI Listing
February 2011

An unusual case of ankylosing spondylitis presenting with severe anemia.

Acta Haematol 2010 15;124(3):176-8. Epub 2010 Oct 15.

Hematology Unit, Bnai Zion Medical Center, Haifa, Israel.

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http://dx.doi.org/10.1159/000319627DOI Listing
November 2010

Frequency and natural history of inherited bone marrow failure syndromes: the Israeli Inherited Bone Marrow Failure Registry.

Haematologica 2010 Aug 30;95(8):1300-7. Epub 2010 Apr 30.

Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, 14 Kaplan Street, Petah Tiqva 49, Israel.

Background: Inherited bone marrow failure syndromes are rare genetic disorders characterized by bone marrow failure, congenital anomalies, and cancer predisposition. Available single disease registries provide reliable information regarding natural history, efficacy and side effects of treatments, and contribute to the discovery of the causative genes. However, these registries could not shed light on the true incidence of the various syndromes. We, therefore, established an Israeli national registry in order to investigate the relative frequency of each of these syndromes and their complications.

Design And Methods: Patients were registered by their hematologists in all 16 medical centers in Israel. We included patients with Fanconi anemia, severe congenital neutropenia, Diamond-Blackfan anemia, congenital amegakaryocytic thrombocytopenia, dyskeratosis congenita, Shwachman-Diamond syndrome, and thrombocytopenia with absent radii.

Results: One hundred and twenty-seven patients diagnosed between 1966 and 2007 were registered. Fifty-two percent were found to have Fanconi anemia, 17% severe congenital neutropenia, 14% Diamond-Blackfan anemia, 6% congenital amegakaryocytic thrombocytopenia, 5% dyskeratosis congenita, 2% Shwachman-Diamond syndrome, and 2% thrombocytopenia with absent radii. No specific diagnosis was made in only 2 patients. Of the thirty patients (24%) developing severe bone marrow failure, 80% had Fanconi anemia. Seven of 9 patients with leukemia had Fanconi anemia, as did all 6 with solid tumors. Thirty-four patients died from their disease; 25 (74%) had Fanconi anemia and 6 (17%) had severe congenital neutropenia.

Conclusions: This is the first comprehensive population-based study evaluating the incidence and complications of the different inherited bone marrow failure syndromes. By far the most common disease was Fanconi anemia, followed by severe congenital neutropenia and Diamond-Blackfan anemia. Fanconi anemia carried the worst prognosis, with severe bone marrow failure and cancer susceptibility. Diamond-Blackfan anemia had the best prognosis. The data presented provide a rational basis for prevention programs and longitudinal surveillance of the complications of inherited bone marrow failure syndromes.
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http://dx.doi.org/10.3324/haematol.2009.018119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2913078PMC
August 2010

2p24 Gain region harboring MYCN gene compared with MYCN amplified and nonamplified neuroblastoma: biological and clinical characteristics.

Am J Pathol 2010 Jun 15;176(6):2616-25. Epub 2010 Apr 15.

Ca-Cytogenetic Lab, Schneider Children's Medical Center of Israel, Kaplan St. 14, 49202 Petah Tikva, Israel.

Although the role of MYCN amplification in neuroblastoma is well established, the biological and clinical characteristics of the 2p gain region harboring the MYCN gene remain unclear. The aim of this study was to compare the biological and clinical characteristics of these tumors with MYCN amplified and nonamplified neuroblastoma and to determine their impact on disease outcome. Samples from 177 patients were analyzed by fluorescence in situ hybridization, including MYCN, 1p, 17q, and 11q regions; 2p gain was identified in 25 patients, MYCN amplification in 31, and no amplification in 121 patients. Patients with 2p gain had a significantly worse 5-year event-free survival rate than patients with no MYCN amplified (P < 0.001), and an intermediate 5-year overall survival rate difference existed between the MYCN amplified tumors (P = 0.025) and nonamplified (P = 0.003) groups. All of the 2p gain samples were associated with segmental and/or numerical alterations in the other tested regions. The presence of segmental alterations with or without MYCN amplification was recently found to be the strongest predictor of relapse in a multivariate analysis. The results of the present study suggest that the determination of MYCN gene copy number relative to chromosome 2, when evaluating MYCN status at diagnosis, may help to reveal the underlying genetic pattern of these tumors and better understand their clinical behavior.
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http://dx.doi.org/10.2353/ajpath.2010.090624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877825PMC
June 2010

Extended triple intrathecal therapy in children with T-cell acute lymphoblastic leukaemia: a report from the Israeli National ALL-Studies.

Br J Haematol 2009 Oct 19;147(1):113-24. Epub 2009 Aug 19.

Centre of Paediatric Haematology/Oncology, Schneider Children's Medical Centre of Israel, Petah Tiqwa, Israel.

Owing to the increased central nervous system (CNS) relapse risk in T-cell acute lymphoblastic leukaemia (ALL), it is unclear whether preventive cranial radiation (pCRT) can be safely omitted. In this study, pCRT was replaced by extended triple intrathecal therapy (TIT) in prednisone good early responders - medium-risk (MR) group, accounting for 76% of T-ALL patients. From 1989 to 2003, 143 T-ALL patients aged 1-18 years were enrolled in the Israel National Studies (INS) 89 (n = 84) and INS 98 (n = 59) trials, based on ALL-Berlin-Frankfurt-Munster (BFM) 86/90 and ALL-BFM 95 protocols, respectively. Five-year event-free survival (EFS) of the MR group in the INS 89 (n = 60) was 70 +/- 5.9% and the INS 98 (n = 43), 83.7 +/- 5.6% (P = 0.12); the cumulative incidence (CI) of any CNS relapse was 5.0 +/- 2.8% and 2.3 +/- 2.3% (P = 0.50), respectively. There was no difference in outcome between MR patients with a white blood cell count (WBC) >or=100 x 10(9)/l treated with extended TIT (n = 17) or pCRT (n = 10). For all T-ALL patients, 5-year EFS was 61.9 +/- 5.3% in INS 89 and 72.9 +/- 5.8% in INS 98, (P = 0.21); the CI of any CNS relapse was 7.1 +/- 2.8% and 1.7 +/- 1.7% (P = 0.142), respectively. Outcome of T-ALL MR patients given extended TIT in the context of BFM-based protocols with long-term follow-up appeared to be comparable to studies in which a larger proportion of patients was irradiated, and was associated with low risk of CNS relapse, regardless of the WBC.
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http://dx.doi.org/10.1111/j.1365-2141.2009.07853.xDOI Listing
October 2009

Burkitt lymphoma in children: the Israeli experience.

J Pediatr Hematol Oncol 2009 Jun;31(6):428-36

Department of Pediatric Hematology-Oncology, Rambam Health Care Campus, Technion-Israel Institute of Technology, Haifa, Israel.

Background: We analyzed the results of the French-American-British-LMB 96 protocol performed in 9 centers in Israel on 88 patients with B-cell non-Hodgkin lymphoma treated from 2000 to 2005.

Procedure: The majority of the patients was male (63/88, 72%), with a median age of 8.9 years (range, 2.5 to 20 y). Ethnic origin was Jewish in 73% (64/88), and Arabic in 27%. Fifty (57%) patients were classified as Burkitt lymphoma, 5 (5.7%) as Burkitt-like lymphoma, 22 (25%) as diffuse large B cell (DLBC), and 9 (10.2%) as Burkitt leukemia with over 25% of their bone marrow (BM) involved. Initial disease sites included the abdomen in 43%, head and neck in 45%, and mediastinum in 7%. Stage I: 9.1%; stage II: 28.4%; stage III: 45.5%, stage IV: 17%. Two patients had BM involvement alone, 5 patients had central nervous system (CNS) involvement alone, and 4 had both CNS and BM. The children were divided into 3 groups according to risk factors, with 5 in group A, 69 in group B, and 14 in group C.

Results: With a median follow-up of 3 years (12 mo to 7.6 y), the Kaplan-Meier for event-free survival (EFS) and overall survival (OS) according to whole group treatment was 88.6% and 90.9%, group A was 100% and 100%; group B was 89.9% and 92.8%; and group C was 78.6% and 78.6%. There were no untoward events or deaths in group A, whereas 6 patients relapsed in group B, 4 of whom died (all relapsed during the first year), with tumor lysis syndrome in 3 patients and death of toxicity in 1 patient who had multiorgan failure 2 days after initiation of COP. Three patients in group C relapsed and died (all patients relapsed during the first 6 months), with tumor lysis syndrome in 4 patients but no deaths from toxicity. EFS for LDH less than twice was 96.4%, EFS for LDH more than twice was 73.3% (P=0.002). OS according to primary site: bone and ovary: 100%; head and neck: 95%; abdomen: 92%; mediastinum: 50%. The difference between the mediastinal primary site to all other primary sites was statistically significant with P=0.003. All the mediastinal tumors were of DLBC origin but no significant differences in outcome were found when DLBC was compared with other histologies (DLBC: 81.8%, other B line: 90.9%). OS for patients of Arabic ethnic origin was 79.2%, for Jewish patients was 95.3%, P=0.02. We could not determine any prognostic factors that were different between the groups, which raises the question of a genetic influence.

Conclusions: In nonresected mature B-cell lymphoma of childhood and adolescence with no BM or CNS involvement, a 93% cure rate can be achieved, similar to the French-American-British/LMB 96 trial. Patients with primary DLBC mediastinal mass had a significantly reduced OS, indicating the need for a different therapeutic approach.
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http://dx.doi.org/10.1097/MPH.0b013e31819a5d58DOI Listing
June 2009

Primary mediastinal B-cell lymphoma in the pediatric patient: Can a rational approach to therapy be based on adult studies?

Pediatr Blood Cancer 2009 May;52(5):566-70

Division of Pediatric Hematology/Oncology, Bnai Zion, Medical Center, Bruce Rappoport Faculty of Medicine, Technion Institute, Haifa, Israel.

The literature on adult and pediatric primary mediastinal B-cell lymphoma (PMBCL) was reviewed and compared. Biologically, adult PMBCL has more similarities to Hodgkin Lymphoma (HL) than diffuse large B-cell lymphoma (DLBCL). Pediatric studies suggest that the biology is similar to that in adults. Median age of children is 14.3 years and the overall survival (OS) is reported as 78.6% and event-free survival (EFS) as 67.4%. Adverse prognostic factors included LDH >500 and mass size over 10 cm, with a trend towards better survival in younger patients. Studies in adults show better survival with intensified chemotherapy and the addition of rituximab. Data on the use of radiation therapy show improved CR rates and survival with addition of involved field radiation therapy (IFRT). Positron emission tomography (PET) with computerized tomography (CT) imaging response-assessment after two courses and at therapy-end may allow for the rational use of IFRT in pediatric/adolescent patients who are more susceptible to development of adverse late effects.
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http://dx.doi.org/10.1002/pbc.21821DOI Listing
May 2009

The efficacy of rituximab in high-grade pediatric B-cell lymphoma/leukemia: a review of available evidence.

Curr Opin Pediatr 2008 Feb;20(1):17-22

Division of Pediatric Hematology/Oncology, Bnai Zion Medical Center, Bruce Rappoport Faculty of Medicine, Technion Institute, Haifa, Israel.

Purpose Of Review: This review evaluates whether rituximab has efficacy in high-grade pediatric B-cell lymphoma/leukemia. Current pediatric protocols for CD20+ B-cell lymphoma/leukemia significantly improve survival, but with major morbidity. To assess whether rituximab has efficacy in very high-grade pediatric disease, all published data on rituximab therapy for Burkitt's lymphoma/B acute lymphoblastic leukaemia (B-ALL) and pediatric patients with relapsed/refractory large B-cell lymphoma were reviewed.

Recent Findings: Three trials in adult Burkitt's/B-ALL showed a significant survival advantage when rituximab was added to standard chemotherapy. Minimal pediatric data have been published, but 19 children with mature B-cell lymphoma/B-ALL received rituximab, alone or in combination with chemotherapy, as salvage therapy, after failure of intensive chemotherapy. Fifteen of 19 (79%) responded, 12 (63%) remained alive in continuous complete remission at 5+ to 48+ months of follow-up. Two patients were alive in partial remission. Five patients died, four of progressive disease. Only one patient had no response to rituximab.

Summary: Rituximab has demonstrated efficacy in Burkitt's disease in adults. Although positive reporting bias is suspected, it appears that rituximab, even as monotherapy, has efficacy in heavily pretreated pediatric patients with high-grade B-lymphoma/B-ALL. Rituximab use can be justified in a prospective controlled chemotherapy dose-reduction study.
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http://dx.doi.org/10.1097/MOP.0b013e3282f424b0DOI Listing
February 2008

Primary duodenal mucosa-associated lymphoid tissue (MALT) lymphoma--a rare presentation of gastric outlet obstruction.

Can J Gastroenterol 2007 Jun;21(6):393-5

Gastroenterology Unit, Bnai-Zion Medical Center, Haifa, Israel.

Malignant lymphoma of mucosa-associated lymphoid tissue (MALT) can arise in a variety of anatomical sites. The majority of these tumors arise in the stomach, with fewer than 30% arising in the small intestine. Primary duodenal MALT lymphoma is a very rare neoplasm. There are very few cases of duodenal MALT lymphoma reported in the literature. This is the third published case presenting clinically as a gastric outlet obstruction. The patient was successfully treated with a combination of chemotherapy and rituximab.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658124PMC
http://dx.doi.org/10.1155/2007/768149DOI Listing
June 2007

Safe and efficacious allogeneic bone marrow transplantation for nonmalignant disorders using partial T cell depletion and no posttransplantation graft-versus-host-disease prophylaxis.

Biol Blood Marrow Transplant 2007 Mar;13(3):329-38

Department of Pediatric Hemato-Oncology, Meyer Children Hospital, Haifa, Israel.

In an attempt to abrogate the deleterious effects of graft-versus-host disease (GVHD), allogeneic transplantation for nonmalignant diseases was performed using high-dose CD34-cell infusion, partial T cell depletion, and no posttransplantation GVHD prophylaxis. Between 1998 and 2004, 16 patients with matched related donors were treated. Median age was 1.5 years (range, 5 months-18 years). The conditioning regimen consisted of busulphan 16 mg/kg, cyclophosphamide 200 mg/kg, antithymocyte globulin (ATG) 25 mg/kg, and fludarabine 200 mg/m(2). No GVHD prophylaxis was given. High doses of CD34 cells, positively selected by immunomagnetic beads, were infused at a median dose of 10.7 x 10(6) CD34/kg (range, 7.4-50 x 10(6)). A total of 1 x 10(5)/kg T cells were given. All patients engrafted, with no graft rejections. All were alive and well at a median of 37 months posttransplantation (range, 18-89 months). Only 1 patient developed chronic GVHD. No episodes of severe infection occurred during or after transplantation. Immunologic reconstitution with CD3/CD4 T cells > 200/microL was observed at a median of 117 days and that with naive T cells (CD4/CD45RA) at a median of 188 days posttransplantation. Our findings suggest that allogeneic transplantation from a matched family donor for nonmalignant disorders can be successfully performed using high doses of CD34 cells, moderate T cell depletion, and no posttransplantation immunosuppression.
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http://dx.doi.org/10.1016/j.bbmt.2006.10.028DOI Listing
March 2007