Ben-Ari J.,Pediatric Intensive Care Unit |
Wolach O.,Davidoff Cancer Center |
Gavrieli R.,Tel Aviv University |
Wolach B.,Tel Aviv University
Expert Review of Anti-Infective Therapy | Year: 2012
Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency characterized by the absence or malfunction of the NADPH oxidase in phagocytic cells. As a result, there is an impaired ability to generate superoxide anions and the subsequent reactive oxygen intermediates. Consequently, CGD patients suffer from two clinical manifestations: recurrent, life-threatening bacterial and fungal infections and excessive inflammatory reactions leading to granulomatous lesions. Although the genotype of CGD was linked to the phenotypic expression of the disease, this connection is still controversial and poorly understood. Certain correlations were reported, but the clinical expression of the disease is usually unpredictable, regardless of the pattern of inheritance. CGD mainly affects the lungs, lymph nodes, skin, GI tract and liver. Patients are particularly susceptible to catalase-positive microorganisms, including Staphyloccocus aureus, Nocardia spp. and Gram-negative bacteria, such as Serratia marcescens, Burkholderia cepacea and Salmonella spp. Unusually, catalase-negative microorganisms were reported as well. New antibacterial and antimycotic agents considerably improved the prognosis of CGD. Therapy with IFN-γ is still controversial. Bone marrow stem cell transplantation is currently the only curative treatment and gene therapy needs further development. In this article, the authors discuss the genetic, functional and molecular aspects of CGD and their impact on the clinical expression, infectious complications and the hyperinflammatory state. © 2012 2012 Expert Reviews Ltd.
Spruyt O.,Peter MacCallum Cancer Center |
Westerman D.,University of Melbourne |
Milner A.,Center for Biostatistics and Clinical Trials |
Bressel M.,Center for Biostatistics and Clinical Trials |
Wein S.,Davidoff Cancer Center
BMJ Supportive and Palliative Care | Year: 2014
Context: Pain during bone marrow biopsy (BMB) under local anaesthesia (LA) is reported in 70% of patients, of whom 35% rate the pain as severe. Pain is experienced during both the biopsy and the marrow aspiration. Many medical centres use conscious sedation involving benzodiazepines and/or opioids administered orally or intravenously for BMB analgesia. Methoxyflurane (MEOF) is self-administered by a handheld device (the Penthrox inhaler), which is licensed in Australia for the relief of pain associated with short surgical procedures. Objectives: To evaluate the efficacy and safety of MEOF analgesia in patients with cancer undergoing BMB. Methods: Patients received LA plus either MEOF or placebo. The primary endpoint was worst pain intensity measured with the Numerical Rating Scale. Anxiety was assessed with the State Trait Anxiety Inventory (STAI-Y-1). Patients, operators and the research nurse rated global medication performance using a 5-point Likert scale. Results: Forty-nine of the 50 patients randomised to MEOF and 48 of the 50 patients randomised to placebo effectively received the allocated intervention. Mean±SD worst pain overall was 4.90±2.07 in MEOF group and 6.0±2.24 in placebo group (p=0.011). Worst pain during the aspiration was 3.3±2.0 in MEOF group and 5.0 ±2.4 in placebo group (p<0.001). 49% of patients treated with MEOF rated the medication as very good or excellent compared with 16.5% of the patients treated with placebo (p=0.005). 20.4% of patients treated with MEOF had an adverse event (AE) compared with 4.2% in the placebo arm (p=0.028). All AEs were grade 1. Conclusions: MEOF was safe and performed better than placebo for analgesia in BMB procedures.
News Article | November 17, 2016
DENVER - The use of hybrid capture-based (HC-based) next-generation sequencing (NGS) to identify targetable oncogenic drivers in patients with lung adenocarcinoma results in the detection of genomic alterations (GAs) not identified in routine screening, and impacts treatment decisions and clinical outcomes. Lung cancer is the most common type of cancer with the highest cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for roughly 85% with about 40% being adenocarcinoma. Targeted therapy that targets driver genomic alterations (GAs) significantly prolongs survival in lung adenocarcinoma patients, and tumor genotyping allows for the detection of GAs in approximately 60% of patients. Currently, the technologies (polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybridization) used for the detection of GAs cannon identify all alterations in EGFR exons and introns or all variants of ALK rearrangements. HC-based NGS is a technology that offers broad gene sequencing, extensive genetic information regarding GAs and exon/intron mutations, gene rearrangements and amplifications. However, the utility of HC-based NGS in clinical practice is yet to be extensively reviewed. A group of Israeli researchers, led by Dr. Nir Peled, conducted a retrospective study on a cohort of 101 patients with advanced lung cancer that were treated at the Davidoff Cancer Center, Rabin Medical Center, Israel between 11/2011 and 10/2015, who underwent HC-based NGS using broad gene panels. Demographic and clinic-pathologic characteristics, treatments, and outcome data were collected. The results of the study published in the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer (IASLC), show that of the 101 patients with advanced lung cancer included in the study, the median age at diagnosis was 63 years, 94% of the patients were diagnosed at stage III-IV, 53% were women, 45% were never smokers, and 85% had adenocarcinoma. HC-based NGS was performed before standard EGFR/ALK testing (15% of patients due to lack of tissue) or after testing revealed negative or inconclusive (85% of patients) results. HC-based NGS was performed before treatment with 1st-line therapy in 51.5% patients and after treatment failure in 48.5% of patients. HC-NGS identified clinically actionable GAs in 50% of patients (EGFR 18%, RET 9%, ALK 8%, MET 6%, and ERBB2 5%) and identified EGFR/ALK aberrations not detected via standard screening in 15 patients. HC-based NGS results caused deviations to treatment strategy in 43 patients (42.6%). The overall response rate to targeted therapies in these patients was 65% (complete, 14.7%; partial 50%). Median survival was not reached. Immunotherapy was administered in 33 patients, mostly without an actionable driver, presenting disease control rate of 32% and an association to tumor mutation burden. The authors comment that, "This study draws attention to the rate of high false negative results in clinical routine practice and may not allow patients to have access to therapy targeting driver mutations. It also can expose patients to immunotherapy as 2nd-line treatment that may not work in this population of patients. Our study is restricted by its retrospective nature, its relatively small sample size, and by being a single-center study. In addition, the high percentage of never smokers, female preponderance, and the relatively young median age of our patient group represent a selection bias with a high pre-test probability for the existence of driver mutation. The results of large future prospective trials such as the National Lung Matrix Trial (NLMT) in the UK, and the Molecular Analysis for Therapy Choice (MATCH) Program, led by the US National Cancer Institute, are thus eagerly anticipated. Nevertheless, the high impact of HC-based NGS on treatment strategy, and the high overall response rate observed in this study, highlight the need for identifying molecular drivers and support the implementation of HC-based NGS in lung cancer." Co-authors Anna Belilovski Rozenblum and Nir Peled are members of IASLC. The International Association for the Study of Lung Cancer (IASLC) is the only global organization dedicated to the study of lung cancer. Founded in 1974, the association's membership includes more than 5,000 lung cancer specialists in over 100 countries. Visit http://www. for more information.
Kovjazin R.,Vaxil BioTherapeutics Ltd. |
Volovitz I.,The Tel Aviv Sourasky Medical Center |
Kundel Y.,Davidoff Cancer Center |
Rosenbaum E.,Davidoff Cancer Center |
And 6 more authors.
Vaccine | Year: 2011
An optimal cancer vaccine should be able to induce highly potent, long-lasting, tumor-specific responses in the majority of the cancer patient population. One approach for achieving this is to use synthetic peptide vaccines derived from widely expressed tumor-associated antigens, that promiscuously bind multiple MHC class I and class II alleles. MUC1-SP-L (ImMucin, VXL100) is a 21mer peptide encoding the complete signal peptide domain of MUC1, a tumor-associated antigen expressed by over 90% of solid and non-solid tumors. MUC1-SP-L was predicted in silico to bind various MHC class I and MHC class II alleles, covering the majority of the Caucasian population. PBLs obtained from 13 naïve donors all proliferated, with a Stimulation Index (SI = 2), to the MUC1-SP-L peptide, producing mixed CD4 + and CD8 + responses. Similar results were manifested by MUC1-SP-L in PBLs derived from 9 of 10 cancer patients with MUC1 positive tumors. CD4 + and CD8 + T cell populations exhibited CD45RO memory markers and secreted IFN-gamma and IL-2 following stimulation with MUC1-SP-L. These T cells also exhibited proliferation to the MUC1-SP-L inner 9mer epitopes and cytotoxicity against tumor cell lines expressing MUC1 and a concordant MHC class I allele. Cytotoxicity to MUC1-expressing human and murine tumors was shown also in T cells obtained from HLA-A2 transgenic mice and BALB/c syngeneic mice immunized with the MUC1-SP-L and GM-CSF. In an immunotherapy model, BALB/c mice inoculated with metastatic MUC1 transfected murine DA3 mammary tumor cells, exhibited significantly prolonged survival following vaccination with MUC1-SP-L. Our results indicate superior immunological and anti-tumor properties of MUC1-SP-L compared to previously published MUC1-derived epitopes. © 2011 Elsevier Ltd. All rights reserved.
Lega I.C.,University of Toronto |
Shah P.S.,University of Toronto |
Shah P.S.,Mount Sinai Hospital |
Margel D.,Davidoff Cancer Center |
And 3 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2014
Diabetes may be a risk factor for cancer and is associated with worse cancer outcomes. Metformin may reduce cancer risk; however, its effect on mortality following cancer remains less clear. EMBASE and Medline were searched through February 10, 2014, for studies reporting an adjusted risk estimate for the effect of metformin therapy on mortality following cancer among diabetic patients. Random-effects models were used to obtain summary HR for the association between metformin and all-cause and cancer-specific mortality. Twenty-one observational studies were meta-analyzed in the primary analysis. Metformin was associated with a reduction in all-cause mortality [HR, 0.73; 95% confidence intervals (CI), 0.64-0.83] and cancer-specific mortality (HR, 0.74; 95% CI, 0.62-0.88). Subgroup analyses by cancer site showed a significant reduction in mortality for colon cancer (four studies, HR, 0.65; 95% CI, 0.56-0.76) but not for breast and prostate cancers. Observational studies indicate that metformin exposure at cancer diagnosis may be associated with a reduction in mortality. However, these findings need to be interpreted with caution as methodologic limitations of individual studies may have introduced biases in these findings. Our results emphasize the need for well-designed studies to further understand the relationship between metformin and survival following cancer.
Shavit R.,Thoracic Cancer Research and Detection Center |
Ilouze M.,Thoracic Cancer Research and Detection Center |
Ilouze M.,Davidoff Cancer Center |
Feinberg T.,Thoracic Cancer Research and Detection Center |
And 4 more authors.
Cellular Oncology | Year: 2015
Introduction: Lung cancer is the leading cause of cancer death. Radiation therapy plays a key role in its treatment. Ionizing radiation induces cell death through chromosomal aberrations, which trigger mitotic catastrophe and apoptosis. However, many lung cancer patients show resistance to radiation. Dichloroacetate (DCA) is a small molecule that can promote mitochondrial activation by increasing the influx of pyruvate. Here, we tested whether DCA may increase the sensitivity of non-small cell lung cancer (NSCLC) cells to radiation through this mechanism. Methods: Two representative NSCLC cell lines (A549 and H1299) were tested for their sensitivity to radiation with and without pre-exposure to DCA. The treatment efficacy was evaluated using a clonogenic survival assay. An extracellular flux analyzer was used to assess the effect of DCA on cellular oxygen consumption as a surrogate marker for mitochondrial activity. Results: We found that DCA increases the oxygen consumption rate in both A549 and H1299 cells by 60 % (p = 0.0037) and 20 % (p = 0.0039), respectively. Pre-exposure to DCA one hour before radiation increased the cytotoxic death rate 4-fold in A549 cells (55 to 13 %, p = 0.004) and 2-fold in H1299 cells (35 to 17 %, p = 0.28) respectively, compared to radiation alone. Conclusion: Mitochondrial induction by DCA may serve as a radio-sensitizer in non-small cell lung cancer. © 2015, International Society for Cellular Oncology.
PubMed | Tel Aviv University, Davidoff Cancer Center and University of Houston
Type: Journal Article | Journal: Leukemia & lymphoma | Year: 2016
Alterations in chronic lymphocytic leukemia (CLL) cell metabolism have been studied by several investigators. Unlike normal B lymphocytes or other leukemia cells, CLL cells, like adipocytes, store lipids and utilize free fatty acids (FFA) to produce chemical energy. None of the recently identified mutations in CLL directly affects metabolic pathways, suggesting that genetic alterations do not directly contribute to CLL cells metabolic reprogramming. Conversely, recent data suggest that activation of STAT3 or downregulation of microRNA-125 levels plays a crucial role in the utilization of FFA to meet the CLL cells metabolic needs. STAT3, known to be constitutively activated in CLL, increases the levels of lipoprotein lipase (LPL) that mediates lipoprotein uptake and shifts the CLL cells metabolism towards utilization of FFA. Herein, we review the evidence for altered lipid metabolism, increased mitochondrial activity and formation of reactive oxygen species (ROS) in CLL cells, and discuss the possible therapeutic strategies to inhibit lipid metabolism pathways in patient with CLL.
Dreifuss T.,Bar - Ilan University |
Betzer O.,Bar - Ilan University |
Shilo M.,Bar - Ilan University |
Popovtzer A.,Davidoff Cancer Center |
And 2 more authors.
Nanoscale | Year: 2015
Theranostics is defined as the combination of therapeutic and diagnostic capabilities in the same agent. Nanotechnology is emerging as an efficient platform for theranostics, since nanoparticle-based contrast agents are powerful tools for enhancing in vivo imaging, while therapeutic nanoparticles may overcome several limitations of conventional drug delivery systems. Theranostic nanoparticles have drawn particular interest in cancer treatment, as they offer significant advantages over both common imaging contrast agents and chemotherapeutic drugs. However, the development of platforms for theranostic applications raises critical questions; is the optimal particle for therapy also the optimal particle for diagnostics? Are the specific characteristics needed to optimize diagnostic imaging parallel to those required for treatment applications? This issue is examined in the present study, by investigating the effect of the gold nanoparticle (GNP) size on tumor uptake and tumor imaging. A series of anti-epidermal growth factor receptor conjugated GNPs of different sizes (diameter range: 20-120 nm) was synthesized, and then their uptake by human squamous cell carcinoma head and neck cancer cells, in vitro and in vivo, as well as their tumor visualization capabilities were evaluated using CT. The results showed that the size of the nanoparticle plays an instrumental role in determining its potential activity in vivo. Interestingly, we found that although the highest tumor uptake was obtained with 20 nm C225-GNPs, the highest contrast enhancement in the tumor was obtained with 50 nm C225-GNPs, thus leading to the conclusion that the optimal particle size for drug delivery is not necessarily optimal for imaging. These findings stress the importance of the investigation and design of optimal nanoparticles for theranostic applications. © 2015 The Royal Society of Chemistry.
Caspi O.,Davidoff Cancer Center
Harefuah | Year: 2013
Although the origin of many common modern medicines that are routinely being used nowadays in healthcare is in medicinal plants and fungi, herbal medicine as a standalone profession is no longer included in the curricula of most Western medical schools. The medicinal plant Lei Gong Teng [also known as Thunder God Vine, Tripterygium Wilfordii Hook f., that is core to traditional Chinese herbal medicine, was praised for its possible anti-inflammatory properties in ancient traditional scripts that date back thousands of years. Yet, modern interest in its proven immune-modulatory properties serves as a vivid example to the bridge that is being built, gradually but constantly, between the tradition of healing arts and the world of modern therapeutics. In this review we summarize the main findings from an increasing number of clinical and laboratory studies published in top peer-reviewed medical journals that verify the traditional indications for which Lei Gong Teng was used medicinally. Based on these findings, and the risk-benefit profile of the plant's debarked root, we conclude that Lei Gong Teng and its active metabolites should be included in the Israeli herbal pharmacopeia.
Wein S.,Davidoff Cancer Center |
Pery S.,Davidoff Cancer Center |
Zer A.,Davidoff Cancer Center
Journal of Clinical Oncology | Year: 2010
Adolescents and young adults (AYAs) with cancer are a heterogeneous group. Nevertheless, there are sufficient unifying characteristics to form a distinct clinical entity. Management of this special group requires a broad-based interdisciplinary clinical team, which should include palliative care (PC), psychology, social work, oncology, and nursing representatives. The function of PC is to provide impeccable pain and other symptom control and to coordinate care as the disease progresses. Features unique to AYAs with cancer include the psychosocial developmental phases, a young person facing death, grief, and bereavement. Pharmacologic and medical interventions by PC in AYAs are broadly similar to adults. Developing trust and being flexible are key skills that PC must use with AYAs. There is a paucity of high-quality controlled studies in the PC literature in general and AYA-PC in particular. Therefore, the methodology of this article is largely based on the narrative and clinical experience. The experience is based on clinicians' work with AYAs with cancer in Israel and Australia. Clinical lessons will be drawn by comparing and contrasting the cultures. Nevertheless, most PC clinical interventions, both pharmacologic and psychosocial, are derived from literature where there is a good evidence base. Future development of PC within AYAs should be coordinated at a national level via appropriate palliative and oncology professional organizations. © 2010 by American Society of Clinical Oncology.