Publications by authors named "Siegal Tali"

62 Publications

Height in Adolescence as a Risk Factor for Glioma Subtypes: a Nationwide Retrospective Cohort Study of 2.2 Million Subjects.

Neuro Oncol 2021 Feb 25. Epub 2021 Feb 25.

Neuro-Oncology Unit, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.

Background: Gliomas manifest in a variety of histological phenotypes with varying aggressiveness. The etiology of glioma remains largely unknown. Taller stature in adulthood has been linked with glioma risk. The aim of this study was to discern whether this association can be detected in adolescence.

Methods: The cohort included 2,223,168 adolescents between the ages of 16-19. Anthropometric measurements were collected at baseline. Incident cases of glioma were extracted from the Israel National Cancer Registry over a follow-up period spanning 47,635,745 person-years. Cox proportional hazard models were used to estimate the hazard ratio for glioma and glioma subtypes according to height, body mass index (BMI) and sex.

Results: 1,195 patients were diagnosed with glioma during the study period. Mean(SD) age at diagnosis was 38.1 (11.7) years. Taller adolescent height (per 10cm increase) was positively associated with the risk for glioma of any type (HR 1.15; p=0.002). The association was retained in subgroup analyses for low-grade glioma (HR 1.17; p=0.031), high-grade glioma (HR 1.15; p=0.025), oligodendroglioma (HR 1.31; p=0.015), astrocytoma (HR 1.12; p=0.049), and a category of presumed IDH-mutated glioma (HR 1.17; p=0.013). There was a trend towards a positive association between height and glioblastoma, however this had borderline statistical significance (HR: 1.15; p=0.07). After stratification of the cohort by sex, height remained a risk factor for men, but not for women.

Conclusions: The previously - established association between taller stature in adulthood and glioma risk can be traced back to adolescence. The magnitude of association differs by glioma subtype.
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http://dx.doi.org/10.1093/neuonc/noab049DOI Listing
February 2021

Multicentric non-enhancing lesions in glioblastoma: A retrospective study.

J Clin Neurosci 2021 Mar 3;85:20-26. Epub 2021 Jan 3.

Neuro-oncology Unit, Davidoff Center, Rabin Medical Center, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Glioblastoma (GBM) typically presents as a single lesion. Multicentric GBM are defined as well separated lesions on MRI (enhancing and non-enhancing). Multicentric GBM with non-enhancing lesions (MNE-GBM) are rarely described in literature. We aimed at describing the radiologic characteristics, treatment, and clinical course of those patients. The institutional neuropathological database was searched for GBM patients diagnosed between 1/1/2015 and 31/05/2018. All pre-operative MRI brain scans were reviewed to identify patients with MNE-GBM. Electronic medical records and follow-up MRI scans were reviewed to assess progression-free survival (PFS) and overall survival (OS). Out of 149 adult patients with newly diagnosed GBM, 12 met the inclusion criteria of MNE-GBM, all of them presented at least one enhancing lesion. Median follow-up for the MNE-GBM patients was 16.1 months. At last follow-up, all patients had recurrence (median PFS 7.6 months) and eleven patients had deceased. Median OS was 16.2 months (95% CI, 4.1-27.5). Eleven patients received radiotherapy concomitant with temozolomide as initial treatment. Radiation field included all the disease foci (enhancing and non-enhancing lesions) in 8 patients, five of them progressed within the non-enhancing lesion. Three patients did not receive radiation for the entire non-enhancing lesions, and two of them progressed within the non-irradiated areas. In conclusion, MNE-GBM is not rare, and has high risk of aggressive progression within the separate non-enhancing lesion.
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http://dx.doi.org/10.1016/j.jocn.2020.11.050DOI Listing
March 2021

Consolidation Treatment for Primary Central Nervous System Lymphoma: Which Modality for Whom?

Acta Haematol 2020 Nov 26:1-14. Epub 2020 Nov 26.

Neuro-Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tiqva, Israel.

Primary central nervous system lymphoma is a rare aggressive disease that largely affects elderly patients and is associated with poor prognosis. The optimal treatment approach is not yet defined and it consists of induction and consolidation phases. The combination of high-dose (HD) methotrexate-based chemotherapy followed by whole-brain radiotherapy (WBRT) prolongs the median progression-free survival (PFS) and overall survival 2- to 3-fold as compared to WBRT alone but is associated with significant delayed neurotoxicity. Alternative strategies are being investigated in order to improve disease outcomes and spare patients the neurocognitive side effects. These include reduced-dose WBRT, non-myeloablative HD chemotherapy, or HD chemotherapy with autologous stem cell transplantation (HDC/ASCT). There are no randomized studies that compare all these consolidation regimens head to head but recently HDC/ASCT has been evaluated versus WBRT in prospective randomized studies. These studies proved that WBRT and HDC/ASCT yield similar 2-year PFS with preserved or improved cognitive function after HDC/ASCT. Yet, the proportion of patients treated with such intensive consolidation is low, both in real life and in specialized centers, leaving many unsettled issues. This review is appraising current dilemmas related to the choice of consolidating therapeutic modalities, their associated acute and delayed toxicity, and future prospects for alternative approaches in the elderly.
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http://dx.doi.org/10.1159/000511208DOI Listing
November 2020

Central nervous system metastases in breast cancer: the impact of age on patterns of development and outcome.

Breast Cancer Res Treat 2021 Jan 10;185(2):423-432. Epub 2020 Oct 10.

Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, 4941492, Petach Tikva, Israel.

Purpose: The purpose of this study is to explore differences in the pattern and outcome of central nervous system (CNS) involvement in breast cancer by age at diagnosis.

Methods: A retrospective database of a tertiary cancer center yielded 174 consecutive patients with breast cancer who were diagnosed with CNS metastases in 2006-2019. Data on histopathology, characteristics of CNS involvement, treatments, and survival (at three time points during the disease course) were compared between patients aged ≤ 45 and > 45 years. Pearson Chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses.

Results: Study population was divided according to age at diagnosis of breast cancer. 65 patients were ≤ 45 years old and 109 patients > 45 years old. The younger group was characterized by longer median overall survival (117.1 months vs 88 months, p = 0.017) and longer interval between breast cancer diagnosis to development of CNS metastases (97.4 months vs 75.9 months, p = 0.026). Median survival after development of CNS disease was not significantly different (18.7 months vs 11.1 months, p = 0.341), although it was significantly longer in younger patients within the subgroup of patients with triple-negative disease (22.5 vs 7.9 months, p = 0.033). There were no between-group differences in number, location, and clinical presentation of CNS metastases or in systemic and CNS-directed treatment approaches.

Conclusion: While the presentation of CNS involvement was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival, and for the subgroups of triple-negative patients, younger age at breast cancer diagnosis was associated with longer survival after diagnosis of CNS disease.
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http://dx.doi.org/10.1007/s10549-020-05959-xDOI Listing
January 2021

Correction to: Serum microRNA is a biomarker for post-operative monitoring in glioma.

J Neurooncol 2020 Sep;149(3):401

Department of Surgery, University of Melbourne, Parkville, VIC, Australia.

For the reference citation '[57]' in the second paragraph of the Results section of the original article there was no corresponding entry in the References section. It should have referred to the below mentioned article by Ebrahimkhani et al. (2018).
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http://dx.doi.org/10.1007/s11060-020-03630-5DOI Listing
September 2020

Tyrosine Kinase Inhibitors as a Treatment of Symptomatic CNS Metastases in Oncogene-Driven NSCLC.

J Oncol 2020 3;2020:1980891. Epub 2020 Sep 3.

Neuro-Oncology Unit, Davidoff Cancer Center, Rabin Medical Center, Beilinson Campus, Petah Tikva 49100, Israel.

Central nervous system (CNS) metastases occur frequently in oncogene-driven non-small cell lung cancer (NSCLC). Standard treatment approaches can potentially delay systemic treatment (surgical intervention) or result in neurocognitive impairment (radiotherapy). Recently, next-generation tyrosine kinase inhibitors (TKIs) have demonstrated remarkable intracranial activity. However, most clinical trials did not enroll patients suffering neurological symptoms. Our study aimed to assess the CNS activity of targeted therapies in this patient population. We present a case series of nine NSCLC patients with either mutation or rearrangement and symptomatic CNS metastases that were treated with TKIs. Clinicopathological characteristics, treatment, and outcomes were analyzed. Most patients presented with symptomatic CNS metastases at time of metastatic disease presentation (6/9). Additionally, the majority of patients had leptomeningeal disease (6/9) and multiple parenchymal metastases. Patients presented with a variety of CNS symptoms with the most common being nausea, vomiting, headache, and confusion. Most patients (6/9) responded rapidly both clinically and radiographically to the targeted treatment, with a marked correlation between systemic and intracranial radiographic response. In conclusion, upfront use of next-generation TKIs in patients with oncogene-driven NSCLC with symptomatic CNS metastases is associated with reasonable intracranial activity and represents a valuable treatment option.
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http://dx.doi.org/10.1155/2020/1980891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486631PMC
September 2020

Serum microRNA is a biomarker for post-operative monitoring in glioma.

J Neurooncol 2020 Sep 11;149(3):391-400. Epub 2020 Sep 11.

Department of Surgery, University of Melbourne, Parkville, VIC, Australia.

Purpose: A circulating biomarker has potential to provide more accurate information for glioma progression post treatment, however no such biomarker is currently available. We aimed to discover a microRNA serum biomarker for longitudinal monitoring of glioma patients.

Methods: A prospectively collected cohort of 91 glioma patients and 17 healthy controls underwent pre and post-operative serum miRNA profiling using Nanostring®. Differentially expressed miRNAs were discovered using a machine learning random forest analysis. Candidate miRNAs were then assessed by droplet digital PCR in 11 patients with multiple follow up samples and compared to tumor volume based on magnetic resonance imaging.

Results: A 9-gene miRNA signature was identified that could distinguish between glioma and healthy controls with 99.8% accuracy. Two miRNAs miR-223 and miR-320e, best demonstrated dynamic changes that correlated closely with tumor volume in LGG and GBM respectively. Importantly, miRNA levels did not increase in two cases of pseudo-progression, indicating the potential utility of this test in guiding treatment decisions.

Conclusions: We identified a highly accurate 9-miRNA signature associated with glioma serum. Additionally, we observed dynamic changes in specific miRNAs correlating with tumor volume over long-term follow up. These results support a large prospective validation study of serum miRNA biomarkers in glioma.
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http://dx.doi.org/10.1007/s11060-020-03566-wDOI Listing
September 2020

Height as a risk factor in meningioma: a study of 2 million Israeli adolescents.

BMC Cancer 2020 Aug 20;20(1):786. Epub 2020 Aug 20.

Neuro-Oncology Unit, Davidoff Cancer Center, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel.

Background: Meningiomas are the most common primary central nervous system tumors. Potential risk factors include obesity, height, history of allergy/atopy, and autoimmune diseases, but findings are conflicting. This study sought to assess the role of the different risk factors in the development of meningioma in adolescents/young adults.

Methods: The cohort included 2,035,915 Jewish men and women who had undergone compulsory physical examination between 1967 and 2011, at age 16 to 19 years, prior to and independent of actual military enlistment. To determine the incidence of meningioma, the military database was matched with the Israel National Cancer Registry. Cox proportional hazard models were used to estimate the hazard ratios for meningioma according to sex, body mass index (BMI), height, and history of allergic or autoimmune disease.

Results: A total of 480 subjects (328 females) were diagnosed with meningioma during a follow-up of 40,304,078 person-years. Median age at diagnosis was 42.1 ± 9.4 years (range 17.4-62.6). On univariate analysis, female sex (p < 0.01) and height (p < 0.01) were associated with risk of meningioma. When the data were stratified by sex, height remained a significant factor only in men. Spline analysis of the male subjects showed that a height of 1.62 m was associated with a minimum disease risk and a height of 1.85+ meters, with a significant risk.

Conclusions: This large population study showed that sex and adolescent height in males (> 1.85 m) were associated with an increased risk of meningioma in adulthood.
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http://dx.doi.org/10.1186/s12885-020-07292-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441683PMC
August 2020

The human tumor microbiome is composed of tumor type-specific intracellular bacteria.

Science 2020 05;368(6494):973-980

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Bacteria were first detected in human tumors more than 100 years ago, but the characterization of the tumor microbiome has remained challenging because of its low biomass. We undertook a comprehensive analysis of the tumor microbiome, studying 1526 tumors and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, and brain tumors. We found that each tumor type has a distinct microbiome composition and that breast cancer has a particularly rich and diverse microbiome. The intratumor bacteria are mostly intracellular and are present in both cancer and immune cells. We also noted correlations between intratumor bacteria or their predicted functions with tumor types and subtypes, patients' smoking status, and the response to immunotherapy.
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http://dx.doi.org/10.1126/science.aay9189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757858PMC
May 2020

Echoes from the past- changing associations between brain tumors and ethnicity.

J Neurol Sci 2020 Jan 2;408:116552. Epub 2019 Nov 2.

Department of Gastroenterology, Hadassah Ein Kerem, Jerusalem 91120, Address: Kiryat Hadassah, POB 12000, Israel.

Background: cranial X radiation therapy was the standard of care for treating dermatological conditions until the 1960s, when its association to cancer and particularly high rates of brain tumors was discovered. This study examines associations found between incidence of brain tumor and ethnicity.

Methods: This study analyzed two cohorts who underwent examination at age 17 and were followed by linkage to the national cancer registry. The first cohort included 376,336 participants born in 1948-1959 (when treatment with cranial X radiation was standard care for treating tinea capitis), and the second 474,923 participants born in 1960-1971.

Results: In the first cohort, ethnicity was strongly associated with the incidence of brain tumor (BT), with higher incidence observed among patients with origins in North Africa or the Middle East. This effect was ablated in the second cohort, and a significant decrease in the rate of meningiomas was noted.

Conclusion: The association of brain tumor with ethnicity was present only during the period when treatment with cranial X radiation was the standard of care for TC in Israel, therefore it is most likely that radiation exposure was a confounding factor, and that ethnic susceptibility for brain cancer was not causative in these cohorts.
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http://dx.doi.org/10.1016/j.jns.2019.116552DOI Listing
January 2020

Primary CNS Lymphoma in the Elderly: The Challenge.

Acta Haematol 2019 15;141(3):138-145. Epub 2019 Feb 15.

Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel.

Primary central nervous system (CNS) lymphoma is an aggressive brain tumor sensitive to chemotherapy and radiotherapy. Its incidence has increased in the elderly, and they account for the majority of patients. The median survival of patients older than 70 years did not change over the last 40 years and remained in the range of 6-7 months. The definition of elderly is nonuniform, and chronological age is not the best marker of treatment tolerability or a predictor of treatment-related toxicity. Some patients who are fit can tolerate induction, consolidation, and even high-dose chemotherapy with autologous stem cell transplantation, whereas others who have multiple comorbidities with reduced renal and bone marrow function can tolerate only intermediate doses of methotrexate. The latter may benefit from maintenance treatment. The "elderly" are also susceptible to the accelerated and detrimental cognitive side effects of whole-brain irradiation which is an alternative consolidation to high-dose chemotherapy. The optimal treatment remains an unresolved matter. A comprehensive comorbidity and geriatric assessment is imperative for appraisal of treatment-induced risks for CNS and systemic toxicity. An individualized approach is required aiming to prolong survival while minimizing toxicity. Future studies should assess the potential of new agents for improving outcome and maintaining quality of life.
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http://dx.doi.org/10.1159/000495284DOI Listing
October 2019

Immune Mediated Cerebellar Ataxia: An Unknown Manifestation of Graft-versus-Host Disease.

Acta Haematol 2019 15;141(1):19-22. Epub 2018 Nov 15.

Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petach Tikva, Israel.

Neurologic complications of allogeneic hematopoietic cell transplantation (allo-HCT) include infections, cerebrovascular events, therapy-induced neurotoxicity, recurrent malignancies, and neurologic manifestations of graft-versus-host disease (GVHD). Anti-glutamic acid decarboxylase (GAD) antibody-associated cerebellar ataxia is a well-established disorder of autoimmune origin, but there are no reports in the literature of its occurrence following allo-HCT. We describe a middle-aged woman with chronic GVHD after allo-HCT who presented with a rapidly progressive cerebellar syndrome. Thorough investigation revealed only cerebellar atrophy on brain imaging and positive anti-GAD65 antibodies in serum and cerebrospinal fluid suggesting the diagnosis of anti-GAD antibody-associated cerebellar ataxia. Despite prompt treatment with high-dose corticosteroids, intravenous immunoglobulins, and rituximab, the patient's condition rapidly deteriorated, and she died 4 months later. This case suggests that anti-GAD antibody-associated cerebellar ataxia may be a rare manifestation of chronic GVHD.
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http://dx.doi.org/10.1159/000494423DOI Listing
September 2019

The possible role of maintenance treatment for primary central nervous system lymphoma.

Blood Rev 2018 09 11;32(5):378-386. Epub 2018 Mar 11.

Neuro-Oncology Center, Davidoff Cancer Center, Rabin Medical Center - Beilinson Hospital, Petach Tikva, Israel. Electronic address:

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive brain tumor. The prognosis is poor, with high rates of relapse and disease progression after treatment. In addition, PCNSL affects a largely older population, so that a significant proportion of patients are ineligible for intensive therapies and high-dose chemotherapy. The elderly patients are also susceptible to the accelerated and detrimental cognitive side effects of whole-brain irradiation which is an alternative consolidation to high-dose chemotherapy. Maintenance therapy has been shown to be a promising strategy to prolong remission time in other hematopoietic malignancies. Herein, we discuss the place of maintenance treatment in PCNSL in view of perspective obtained from hematological malignancies and non-Hodgkin's lymphoma.
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http://dx.doi.org/10.1016/j.blre.2018.03.003DOI Listing
September 2018

Brain metastasis in gastroesophageal adenocarcinoma and HER2 status.

J Neurooncol 2018 Jun 10;138(2):315-320. Epub 2018 Feb 10.

Neuro-Oncology Center, Davidoff Center, Rabin Medical Center, Beilinson Hospital, 4941492, Petach Tikva, Israel.

The increased survival of patients with gastroesophageal adenocarcinoma (GAD) following improvements in treatment has been accompanied by a rising incidence of secondary brain metastasis. HER2 amplification/overexpression, which has been associated with an increased risk of brain metastasis in breast cancer, is found in about 20% of patients with GAD. The aim of this study was to evaluate the effect of HER2 status on brain metastasis in GAD. The database of a tertiary cancer center was searched for patients with GAD diagnosed in 2011-2015, and data were collected on clinical characteristics, brain metastasis, HER2 status, and outcome. We identified 404 patients with a confirmed diagnosis of GAD. HER2 results were available for 298: 69 (23.2%) positive and 227 negative. Brain metastasis developed in 15 patients with GAD (3.7%); HER2 results, available in 13, were positive in 6, negative in 6, and equivocal in 1. The brain metastasis rate was significantly higher in HER2-positive than HER2-negative patients with GAD (6/69, 8.7% vs. 6/227, 2.6%; RR = 3.3, 95% CI 1.1-9.9, p = 0.034). Median overall survival from diagnosis of brain metastasis was 2.3 months, with no significant difference by HER2 status. HER2 positive GAD patients may be at increased risk to develop BM. Clinicians should maintain a lower threshold for performing brain imaging in patients with HER2-positive GAD given their increased risk of brain metastasis. The role of anti-HER2 agents in the development and treatment of brain metastasis in GAD warrants further study.
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http://dx.doi.org/10.1007/s11060-018-2798-4DOI Listing
June 2018

Neurologic complications of immune checkpoint inhibitors.

J Neurooncol 2018 May 13;137(3):601-609. Epub 2018 Jan 13.

Department of Neurology, Rabin Medical Center, Beilinson Hospital, 39 Jabotinski St., Petah Tikva, Israel.

Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days-19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.
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http://dx.doi.org/10.1007/s11060-018-2752-5DOI Listing
May 2018

MicroRNAs as predictors for CNS relapse of systemic diffuse large B-cell lymphoma.

Oncotarget 2017 Oct 15;8(49):86020-86030. Epub 2017 Sep 15.

Neuro-Oncology Center, Davidoff Institute of Oncology, Rabin Medical Center, Petach Tikva, Israel.

Systemic diffuse large B-cell lymphoma (DLBCL) is a potentially curable disease using current regimen of immunochemotherapy. Central nervous system (CNS) relapse is a complication that occurs in approximately 5% of DLBCL patients and is associated with a high fatality rate. Early identification of molecular markers for CNS involvement may serve for the highly needed accurate stratification of patients into risk groups regarding CNS relapse. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level and are known to be involved in DLBCL pathophysiology. In this study, we utilized miRNA multiplex reading of systemic newly diagnosed DLBCL samples obtained from patients with clinical risk factors for CNS involvement whose disease course was distinguished by the presence or absence of subsequent CNS relapse. The analysis detected two differentially expressed miRNAs, miR-20a and miR-30d, that predict for CNS involvement. Replication of these results in different samples was used for validation. We performed bioinformatics miRNA-target enrichment analysis to reveal a number of putative mechanisms for these miRNAs regulation of CNS relapse, including neuronal plasticity and WNT signaling pathway. Altogether, we show that the expression level of two miRNAs may have valuable information that may refine stratification for patients-at-risk for relapse with CNS involvement in DLBCL. Further larger scale studies are needed to shed light on the pathways involved in this disease.
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http://dx.doi.org/10.18632/oncotarget.20902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689664PMC
October 2017

[NEURO-ONCOLOGY A NEW FIELD IN DAVIDOFF CANCER CENTER AT RABIN MEDICAL CENTER].

Harefuah 2017 Aug;156(8):512-516

Neuro-Oncology Center at Davidoff Cancer Center.

Introduction: Neuro-oncology is a subspecialty attracting physicians from medical disciplines such as neurology, neurosurgery, pediatrics, oncology, and radiotherapy. It deals with diagnosis and management of primary brain tumors, as well as metastatic and non-metastatic neurological manifestations that frequently affect cancer patients including brain metastases, paraneoplastic syndromes and neurological complications of cancer treatment. A neuro-oncology unit was established in Davidoff Cancer Center at Rabin Medical Center. It provides a multidisciplinary team approach for management of brain tumors and services, such as expert outpatient clinics and inpatient consultations for the departments of oncology, hematology, bone marrow transplantation and other departments in the Rabin Medical Center. In addition, expert consultation is frequently provided to other hospitals that treat cancer patients with neurological manifestations. The medical disciplines that closely collaborate for the daily management of neuro-oncology patients include radiotherapy, hematology, oncology, neuro-surgery, neuro-radiology and neuro-pathology. The neuro-oncology center is also involved in clinical and laboratory research conducted in collaboration with researchers in Israel and abroad. The new service contributes substantially to the improved care of cancer patients and to the advance of research topics in the field of neuro-oncology.
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August 2017

Aberrant paramagnetic signals outside the tumor volume on routine surveillance MRI of brain tumor patients.

J Neurooncol 2017 Sep 10;134(2):371-376. Epub 2017 Jul 10.

Neuro-Oncology Center, Davidoff Cancer Center, Rabin Medical Center, Campus Beilinson, Petach Tikva, Israel.

Late complications of cerebral radiation therapy (RT) involve vascular injury with acquired cavernous malformation, telangiectasias and damage to vascular walls which are well recognized in children. Its incidence in adults is unknown. Blood products and iron deposition that accompany vascular injury create paramagnetic effects on MRI. This study retrospectively investigated the frequency of paramagnetic lesions on routine surveillance MRI of adult brain tumor patients. MRI studies of 115 brain tumor patients were reviewed. Only studies containing sequences of either susceptibility weighted images or gradient echo or blood oxygenation level dependent imaging were included. Lesions inside the tumor volume were not considered. 68 studies fulfilled the above criteria and included 48 patients with previous RT (35 followed for >2 years and 13 for 1 year) and 20 patients who were not treated with RT. The median age at time of irradiation was 47 years. Aberrant paramagnetic lesions were found in 23/35 (65%) patients followed for >2 years after RT and in only 1/13 (8%) patients followed for 1-year after radiation (p = 0.03). The 1-year follow-up group did not differ from the control group [2/20 (9%)]. Most lesions were within the radiation field and none of the patients had related symptomatology. The number and incidence of these lesions increased with time and amounted to 75% over 3 years post RT. MRI paramagnetic signal aberrations are common findings in adult brain tumor patients that evolve over time after RT. The clinical significance of these lesions needs further investigation.
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http://dx.doi.org/10.1007/s11060-017-2536-3DOI Listing
September 2017

Expression level of miRNAs on chromosome 14q32.31 region correlates with tumor aggressiveness and survival of glioblastoma patients.

J Neurooncol 2016 12 29;130(3):413-422. Epub 2016 Aug 29.

Leslie and Michael Gaffin Center for Neuro-Oncology, Neurology Department, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

The 54 microRNAs (miRNAs) within the DLK-DIO3 genomic region on chromosome 14q32.31 (cluster-14-miRNAs) are organized into sub-clusters 14A and 14B. These miRNAs are downregulated in glioblastomas and might have a tumor suppressive role. Any association between the expression levels of cluster-14-miRNAs with overall survival (OS) is undetermined. We randomly selected miR-433, belonging to sub-cluster 14A and miR-323a-3p and miR-369-3p, belonging to sub-cluster 14B, and assessed their role in glioblastomas in vitro and in vivo. We also determined the expression level of cluster-14-miRNAs in 27 patients with newly diagnosed glioblastoma, and analyzed the association between their level of expression and OS. Overexpression of miR-323a-3p and miR-369-3p, but not miR-433, in glioblastoma cells inhibited their proliferation and migration in vitro. Mice implanted with glioblastoma cells overexpressing miR323a-3p and miR369-3p, but not miR433, exhibited prolonged survival compared to controls (P = .003). Bioinformatics analysis identified 13 putative target genes of cluster-14-miRNAs, and real-time RT-PCR validated these findings. Pathway analysis of the putative target genes identified neuregulin as the most enriched pathway. The expression level of cluster-14-miRNAs correlated with patients' OS. The median OS was 8.5 months for patients with low expression levels and 52.7 months for patients with high expression levels (HR 0.34; 95 % CI 0.12-0.59, P = .003). The expression level of cluster-14-miRNAs correlates directly with OS, suggesting a role for this cluster in promoting aggressive behavior of glioblastoma, possibly through ErBb/neuregulin signaling.
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http://dx.doi.org/10.1007/s11060-016-2248-0DOI Listing
December 2016

Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases.

Lung Cancer 2016 08 31;98:114-117. Epub 2016 May 31.

Thoracic Cancer Unit, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.

Central nervous system (CNS) metastases occur in 30% of patients with advanced non-small cell lung cancer (NSCLC). Localized treatments targeting CNS metastases result in delays in systemic therapy administration and are associated with neurocognitive impairment. Nivolumab is an immune check-point inhibitor that is approved as a second-line treatment of NSCLC. Data regarding the intracranial activity of nivolumab is lacking. We retrospectively reviewed the efficacy and safety of nivolumab in five patients with advanced NSCLC and new/progressing intracranial metastases. Intracranial response was assessed by magnetic resonance imaging (MRI) using mRECIST v. 1.1 criteria. All patients had parenchymal brain metastases; two patients had leptomeningeal carcinomatosis diagnosed according to radiological criteria. All patients were asymptomatic and did not require corticosteroids or immediate local therapy. We observed one complete and one partial response in the brain. Stabilization of leptomeningeal carcinomatosis for 10 weeks was achieved in one additional patient. Two patients progressed in the CNS. Time-to-response comprised 5 weeks and 9 weeks; both responses are still ongoing at the time of the report (24+ and 28+ weeks since start of treatment). Systemic responses and intracranial responses were largely concordant. No treatment-related or CNS metastases-related grade≥3 adverse events were observed. Nivolumab might have intracranial activity and favorable safety profile in patients with CNS metastases secondary to NSCLC. Nivolumab CNS activity warrants further evaluation.
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http://dx.doi.org/10.1016/j.lungcan.2016.05.031DOI Listing
August 2016

Progressive diffuse meningioangiomatosis: Response to bevacizumab treatment.

Neurology 2016 04 30;86(17):1643-4. Epub 2016 Mar 30.

From Davidoff Cancer Center (S.Y.-K., D.L., T.S.), Rabin Medical Center (S.F.-H., N.M., E.I., J.L., I.S.), Petah Tikva; Tel-Aviv University (S.Y.-K., D.L., T.S.), Israel; and MD Anderson Cancer Center (G.F.), Houston, TX.

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http://dx.doi.org/10.1212/WNL.0000000000002610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844238PMC
April 2016

Dynamics of circulating hypoxia-mediated miRNAs and tumor response in patients with high-grade glioma treated with bevacizumab.

J Neurosurg 2016 10 22;125(4):1008-1015. Epub 2016 Jan 22.

Leslie and Michael Gaffin Center for Neuro-Oncology and Department of Neurology, The Agnes Ginges Center for Human Neurogenetics.

OBJECTIVE Bevacizumab is an antiangiogenic agent under investigation for use in patients with high-grade glioma. It produces a high rate of radiological response; however, this response should be interpreted with caution because it may reflect normalization of the tumor vasculature and not necessarily a true antitumor effect. The authors previously demonstrated that 4 hypoxia-mediated microRNAs (miRNA)-miR-210, miR-21, miR-10b, and miR-196b-are upregulated in glioma as compared with normal brain tissue. The authors hypothesized that the regulation and expression of these miRNAs would be altered in response to bevacizumab treatment. The object of this study was to perform longitudinal monitoring of circulating miRNA levels in patients undergoing bevacizumab treatment and to correlate it with tumor response. METHODS A total of 120 serum samples from 28 patients with high-grade glioma were prospectively collected prior to bevacizumab (n = 15) or temozolomide (TMZ; n = 13) treatment and then longitudinally during treatment. Quantification of the 4 miRNAs was evaluated by real-time polymerase chain reaction using total RNA extracted from the serum. At each time point, tumor response was assessed by Response Assessment in Neuro-Oncology criteria and by performing MRI using fluid attenuated inversion recovery (FLAIR) and contrast-enhanced images. RESULTS As compared with pretreatment levels, high levels of miR-10b and miR-21 were observed in the majority of patients throughout the bevacizumab treatment period. miR-10b and miR-21 levels correlated negatively and significantly with changes in enhancing tumor diameters (r = -0.648, p < 0.0001) in the bevacizumab group but not in the TMZ group. FLAIR images and the RANO assessment did not correlate with the sum quantification of these miRNAs in either group. CONCLUSIONS Circulating levels of miR-10b and miR-21 probably reflect the antiangiogenic effect of therapy, but their role as biomarkers for tumor response remains uncertain and requires further investigation.
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http://dx.doi.org/10.3171/2015.8.JNS15437DOI Listing
October 2016

Durable brain response with pulse-dose crizotinib and ceritinib in ALK-positive non-small cell lung cancer compared with brain radiotherapy.

J Clin Neurosci 2016 Apr 8;26:46-9. Epub 2015 Dec 8.

Thoracic Cancer Unit, Davidoff Cancer Center, Rabin Medical Center, Kaplan Street, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel. Electronic address:

Crizotinib achieves excellent systemic control in anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC); however, central nervous system (CNS) metastases frequently occur as an early event. Whole brain irradiation, the standard treatment, results in neurocognitive impairment. We present a case series of three ALK+ NSCLC patients with progressing CNS metastases who were treated with pulse-dose crizotinib followed by ceritinib. Three ALK+ NSCLC patients treated between 2011 and 2014 (two males, two never smokers, age range 20-54years, all echinoderm microtubule-associated protein-like 4/ALK rearrangement), were diagnosed with progressing cerebral disease while receiving crizotinib. Clinico-pathological characteristics, treatments, and outcomes were analyzed. In two patients the progression was limited to the CNS, and radiological evidence of leptomeningeal spread was present in one patient. Sequential use of crizotinib 500mg administered once daily (pulse-dose) followed by ceritinib on progression achieved control of the disease in the CNS for over 18 months and over 7 months in Patient 1 and Patient 2, respectively. This strategy provided durable CNS control after whole-brain radiotherapy failure in Patient 1, and allowed the whole-brain radiotherapy to be deferred in Patient 2. Limited CNS progression was documented in Patient 3 while he was on standard-dose/pulse-dose crizotinib for 15months; durable (over 7 months) complete remission was achieved with stereotactic radiotherapy and ceritinib. Manipulating the crizotinib schedule in ALK+ NSCLC patients with CNS metastases and using a novel ALK-inhibitor at the time of further progression may provide durable CNS control and allow brain radiotherapy to be deferred.
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http://dx.doi.org/10.1016/j.jocn.2015.05.068DOI Listing
April 2016

Clinical Relevance of Prognostic and Predictive Molecular Markers in Gliomas.

Authors:
Tali Siegal

Adv Tech Stand Neurosurg 2016 (43):91-108

Center for Neuro-Oncology, Davidoff Institute of Oncology, Rabin Medical Center, Campus Beilinson, Petach Tikva, 49100, Israel.

Sorting and grading of glial tumors by the WHO classification provide clinicians with guidance as to the predicted course of the disease and choice of treatment. Nonetheless, histologically identical tumors may have very different outcome and response to treatment. Molecular markers that carry both diagnostic and prognostic information add useful tools to traditional classification by redefining tumor subtypes within each WHO category. Therefore, molecular markers have become an integral part of tumor assessment in modern neuro-oncology and biomarker status now guides clinical decisions in some subtypes of gliomas. The routine assessment of IDH status improves histological diagnostic accuracy by differentiating diffuse glioma from reactive gliosis. It carries a favorable prognostic implication for all glial tumors and it is predictive for chemotherapeutic response in anaplastic oligodendrogliomas with codeletion of 1p/19q chromosomes. Glial tumors that contain chromosomal codeletion of 1p/19q are defined as tumors of oligodendroglial lineage and have favorable prognosis. MGMT promoter methylation is a favorable prognostic marker in astrocytic high-grade gliomas and it is predictive for chemotherapeutic response in anaplastic gliomas with wild-type IDH1/2 and in glioblastoma of the elderly. The clinical implication of other molecular markers of gliomas like mutations of EGFR and ATRX genes and BRAF fusion or point mutation is highlighted. The potential of molecular biomarker-based classification to guide future therapeutic approach is discussed and accentuated.
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http://dx.doi.org/10.1007/978-3-319-21359-0_4DOI Listing
February 2016

MicroRNA as potential biomarkers in Glioblastoma.

J Neurooncol 2015 Nov 21;125(2):237-48. Epub 2015 Sep 21.

Clinical Sciences Building, Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia.

Glioblastoma is the most aggressive and lethal tumour of the central nervous system and as such the identification of reliable prognostic and predictive biomarkers for patient survival and tumour recurrence is paramount. MicroRNA detection has rapidly emerged as potential biomarkers, in patients with glioblastoma. Over the last decade, analysis of miRNA in laboratory based studies have yielded several candidates as potential biomarkers however, the accepted use of these candidates in the clinic is yet to be validated. Here we will examine the use of miRNA signatures to improve glioblastoma stratification into subgroups and summarise recent advances made in miRNA examination as potential biomarkers for glioblastoma progression and recurrence.
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http://dx.doi.org/10.1007/s11060-015-1912-0DOI Listing
November 2015

Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology.

Lancet Oncol 2015 Jul;16(7):e322-32

Department of Neurology, University Hospital Zürich, Zürich, Switzerland.

The management of primary CNS lymphoma is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very few controlled studies available. In 2013, the European Association of Neuro-Oncology created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adults with primary CNS lymphoma. In this Review, we present these guidelines, which provide consensus considerations and recommendations for diagnosis, assessment, staging, and treatment of primary CNS lymphoma. Specifically, we address aspects of care related to surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stem-cell transplantation, radiotherapy, intraocular manifestations, and management of elderly patients. The guidelines should aid clinicians in their daily practice and decision making, and serve as a basis for future investigations in neuro-oncology.
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http://dx.doi.org/10.1016/S1470-2045(15)00076-5DOI Listing
July 2015

A 66-year-old patient with progressive left hemiparesis: question.

J Clin Neurosci 2014 Nov;21(11):1966, 2031

Department of Neurology, Center Rabin Medical Center, Campus Beilinson, 49100 Petach Tikva, Israel.

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http://dx.doi.org/10.1016/j.jocn.2014.03.024DOI Listing
November 2014

Clinical impact of molecular biomarkers in gliomas.

Authors:
Tali Siegal

J Clin Neurosci 2015 Mar 18;22(3):437-44. Epub 2014 Dec 18.

Center for Neuro-Oncology, Davidoff Institute of Oncology, Rabin Medical Center, Campus Beilinson, 49100 Petach Tikva, Israel. Electronic address:

The World Health Organization (WHO) classification system for glial tumors provides guidance as to the predicted course of the disease and choice of treatment. However, histologically identical tumors may have a very different outcome and response to treatment. Molecular markers that carry both diagnostic and prognostic information add valuable tools by redefining tumor subtypes within each WHO category. Therefore, molecular biomarkers have become an integral part of tumor assessment in modern neuro-oncology and biomarker status now guides clinical decisions in some subtypes of gliomas, including anaplastic oligodendroglioma and glioblastoma in the elderly. This review discusses the prognostic and predictive impact of molecular markers that have undergone extensive study in recent years. The clinical relevance of contemporary molecular classification of gliomas using the routine assessment of IDH mutations, promoter methylation of MGMT, chromosomal deletion of 1p/19q, mutations of EGFR and ATRX genes, and BRAF fusion or point mutation is highlighted. The potential of molecular biomarker-based classification to guide future therapeutic approach is discussed and accentuated.
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http://dx.doi.org/10.1016/j.jocn.2014.10.004DOI Listing
March 2015

Antineoplastic effect of decoy oligonucleotide derived from MGMT enhancer.

PLoS One 2014 2;9(12):e113854. Epub 2014 Dec 2.

Leslie and Michael Gaffin Center for Neuro-Oncology and Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Silencing of O(6)-methylguanine-DNA-methyltransferase (MGMT) in tumors, mainly through promoter methylation, correlates with a better therapeutic response and with increased survival. Therefore, it is conceivable to consider MGMT as a potential therapeutic target for the treatment of cancers. Our previous results demonstrated the pivotal role of NF-kappaB in MGMT expression, mediated mainly through p65/NF-kappaB homodimers. Here we show that the non-canonical NF-KappaB motif (MGMT-kappaB1) within MGMT enhancer is probably the major inducer of MGMT expression following NF-kappaB activation. Thus, in an attempt to attenuate the transcription activity of MGMT in tumors we designed locked nucleic acids (LNA) modified decoy oligonucleotides corresponding to the specific sequence of MGMT-kappaB1 (MGMT-kB1-LODN). Following confirmation of the ability of MGMT-kB1-LODN to interfere with the binding of p65/NF-kappaB to the NF-KappaB motif within MGMT enhancer, the efficacy of the decoy was studied in-vitro and in-vivo. The results of these experiments show that the decoy MGMT-kB1-LODN have a substantial antineoplastic effect when used either in combination with temozolomide or as monotherapy. Our results suggest that MGMT-kB1-LODN may provide a novel strategy for cancer therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0113854PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252043PMC
July 2015

Conflicting pathology reports: a diagnostic dilemma.

J Neurosurg 2015 Feb 28;122(2):276-9. Epub 2014 Nov 28.

Departments of 1 Neurosurgery.

The differential diagnosis of a brain lesion with two discordant pathology reports includes the presence of collision tumor, metaplastic changes, and labeling errors that occurred during the processing of the specimen. The authors present a case in which the first brain biopsy from a 47-year-old patient with a history of heavy smoking was compatible with metastatic small cell carcinoma, and the second biopsy taken during decompression craniotomy 3 weeks later was compatible with WHO Grade IV glioblastoma. Using short tandem repeat (STR) analysis of the two specimens and nontumor-derived patient DNA, the authors found that the two specimens did not belong to the same individual. The authors conclude that allele imbalance or loss of heterozygosity detected by STR analysis is a reliable and valuable diagnostic tool for clarifying discrepancies in discordant pathology reports.
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http://dx.doi.org/10.3171/2014.10.JNS131518DOI Listing
February 2015