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Eliakim R.,Chaim Sheba Medical Center | Magro F.,University of Sfax
Nature Reviews Gastroenterology and Hepatology | Year: 2014

The assessment of extent and severity of IBD is crucial for directing treatment decisions. Clinical symptoms alone are neither sensitive nor specific for the assessment of lesion severity in IBD. Cross-sectional imaging techniques, as well as small-bowel capsule endoscopy (SBCE) and device-assisted enteroscopy, have a high accuracy for assessing the extent of mucosal lesions, and are reliable alternatives to ileocolonoscopy. New endoscopic techniques and devices are emerging for improved follow-up and surveillance. In this Review, we discuss different imaging techniques that are used to assess IBD activity and to survey patients with IBD, and highlight the latest developments in each area. Moreover, technical improvements and new tools that aim to measure intestinal fibrosis, postoperative recurrence, activity indices and endoscopic features are analysed. All of these imaging techniques are aimed at changing the paradigm from symptom-driven to lesion-driven treatment of IBD.


News Article | February 21, 2017
Site: www.eurekalert.org

In both groups, recreational sun exposure, black hair-dye use, a history of hospitalization for infection, and having a first-degree relative with a blood cancer were associated with B-NHL. Each group had unique risk factors too. Non-Hodgkin lymphomas (NHL), tumors which may originate from B or T lymphocytes, account for approximately 3% of the worldwide cancer burden. Most epidemiological studies of NHL have been carried out in North American and European populations, with a few focusing on East Asian populations. Very few epidemiological studies have been conducted on B-cell non-Hodgkin lymphoma (B-NHL) in Middle Eastern populations. Since Israelis and Palestinians represent genetically and culturally diverse populations living in geographic proximity, research analyzing their risk factors can enrich our understanding of genes and environment in the causation of lymphoma. Despite sharing the same ecosystem, the populations differ in terms of lifestyle, health behaviors and medical systems. Yet both populations report high incidences of NHL, which represents the fifth most common malignancy in Israel and the eighth most common malignancy among West Bank Palestinians. (As of 2012, Israel also ranked first in the world in NHL incidence rates.) Now, Israeli and Palestinian researchers have conducted a large scale epidemiological study examining risk factors for B-NHL and its subtypes in these two populations. The team was led by Prof. Ora Paltiel, Director of the Hebrew University-Hadassah Braun School of Public Health and Community Medicine, in the Hebrew University's Faculty of Medicine, and a Senior Physician in Hadassah's Hematology Department. Recruiting from both the Palestinian Arab and Israeli Jewish populations, the researchers looked at medical history, environmental and lifestyle factors among 823 people with B-cell non-Hodgkin lymphoma (B-NHL) and 808 healthy controls. Using data from questionnaires, pathology review, serology and genotyping, they uncovered some risk factors common to both populations and other factors unique to each population. The data, reported in the peer-reviewed journal PLOS ONE, showed that in both populations, overall B-NHL was associated with recreational sun exposure, black hair-dye use, a history of hospitalization for infection, and having a first-degree relative with a blood cancer. An inverse association was noted with alcohol use. Some exposures, including smoking and greater-than-monthly indoor pesticide use, were associated with specific subtypes of B-NHL. The data also pointed to differences between the populations. Among Palestinian Arabs only, risk factors included gardening and a history of herpes, mononucleosis, rubella, or blood transfusion, while these factors were not identified in the Israeli Jewish population. In contrast, risk factors that applied to Israeli Jews only included growing fruits and vegetables, and self-reported autoimmune diseases. The researchers concluded that differences in the observed risk factors by ethnicity could reflect differences in lifestyle, medical systems, and reporting patterns, while variations by lymphoma subtypes infer specific causal factors for different types of the disease. These findings require further investigation as to their mechanisms. The fact that risk factors operate differently in different ethnic groups raises the possibility of gene-environment interactions, that is, that environmental exposures act differently in individuals of different genetic backgrounds. But this divergence may reflect differences in diet, cultural habits, socioeconomic, environmental and housing conditions, medical services, exposure to infections in early life or other factors. This study reflects a unique joint scientific effort involving Israeli and Palestinian investigators, and demonstrates the importance of cooperative research even in politically uncertain climates. Cancer epidemiology will be enriched through the broadening of analytic research to include under-studied populations from a variety of ethnicities and geographic regions. "Apart from the scientific contribution that this research provides in terms of understanding risk factors for NHL, the study entails an important research cooperation among many institutions. The study provided opportunities for training Palestinian and Israeli researchers, and will provide for intellectual interaction for years to come. The data collected will also provide a research platform for the future study of lymphoma. Epidemiologic research has the potential to improve and preserve human health, and it can also serve as a bridge to dialogue among nations," said Prof. Ora Paltiel, Director of the Hebrew University-Hadassah Braun School of Public Health and Community Medicine, and a Senior Physician in Hadassah's Hematology Department. Participating institutions in this research included: Braun School of Public Health and Community Medicine, and Depts. of Hematology and Pathology, Hadassah-Hebrew University Medical Center; Dept. of Medical Laboratory Sciences and Dept. of Community Medicine, Faculty of Medicine, Al Quds University; Cancer Care Center, Augusta Victoria Hospital; Beit Jalla Hospital; Department of Statistics, Hebrew University; Department of Primary Health Care, Palestinian Ministry of Health; Tisch Cancer Institute and Institute for Translational Epidemiology, Mount Sinai School of Medicine; Rambam Medical Center and Rappaport Faculty of Medicine, Technion; Chaim Sheba Medical Center and Meir Medical Center and Tel Aviv University.


News Article | September 19, 2016
Site: news.mit.edu

The spread of malignant cells around the body, known as metastasis, is the leading cause of mortality in women with breast cancer. Now, a new gene therapy technique being developed by researchers at MIT is showing promise as a way to prevent breast cancer tumors from metastasizing. The treatment, described in a paper published today in the journal Nature Communications, uses microRNAs — small noncoding RNA molecules that regulate gene expression — to control metastasis. The therapy could be used alongside chemotherapy to treat early-stage breast cancer tumors before they spread, according to Natalie Artzi, a principal research scientist at MIT’s Institute for Medical Engineering and Science (IMES) and an assistant professor of medicine at Brigham and Women’s Hospital, who led the research in collaboration with Noam Shomron, an assistant professor on the faculty of medicine at Tel-Aviv University in Israel. “The idea is that if the cancer is diagnosed early enough, then in addition to treating the primary tumor [with chemotherapy], one could also treat with specific microRNAs, in order to prevent the spread of cancer cells that cause metastasis,” Artzi says. The regulation of gene expression by microRNAs is known to be important in preventing the spread of cancer cells. Recent studies by the Shomron team in Tel-Aviv have shown that disruption of this regulation, for example by genetic variants known as single nucleotide polymorphisms (SNPs), can have a significant impact on gene expression levels and lead to an increase in the risk of cancer. To identify the specific microRNAs that play a role in breast cancer progression and could therefore potentially be used to suppress metastasis, the research teams first carried out an extensive bioinformatics analysis. They compared three datasets: one for known SNPs; a second for sites at which microRNAs bind to the genome; and a third for breast cancer-related genes known to be associated with the movement of cells. This analysis revealed a variant, or SNP, known as rs1071738, which influences metastasis. They found that this SNP disrupts binding of two microRNAs, miR-96 and miR-182. This disruption in turn prevents the two microRNAs from controlling the expression of a protein called Palladin. Previous research has shown that Palladin plays a key role in the migration of breast cancer cells, and their subsequent invasion of otherwise healthy organs. When the researchers carried out in vitro experiments in cells, they found that applying miR-96 and miR-182 decreased the expression of Palladin levels, in turn reducing the ability of breast cancer cells to migrate and invade other tissue. “Previous research had discussed the role of Palladin in controlling migration and invasion (of cancer cells), but no one had tried to use microRNAs to silence those specific targets and prevent metastasis,” Artzi says. “In this way we were able to pinpoint the critical role of these microRNAs in stopping the spread of breast cancer.” The researchers then developed a method to deliver engineered microRNAs to breast cancer tumors. They embedded nanoparticles containing the microRNAs into a hydrogel scaffold, which they then implanted into mice. They found that this allowed efficient and precise delivery of the microRNAs to a target breast cancer tumor site. The treatment resulted in a dramatic reduction in breast cancer metastasis, says Artzi. “We can locally change the cells in order to prevent metastasis from occurring,” she says. To increase the effectiveness of the treatment even further, the researchers then added the chemotherapy drug cisplatin to the nanoparticles. This led to a significant reduction in both the growth of the primary tumor, and its metastasis. “We believe local delivery is much more effective (than systemic treatment), because it gives us a much higher effective dose of the cargo, in this case the two microRNAs and the cisplatin,” she says. “The research offers the potential for combined experimental therapeutics with traditional chemotherapy in cancer metastasis,” says Julie Teruya-Feldstein, a professor of pathology at Mount Sinai Hospital in New York, who was not involved in the study. The research team, which also includes MIT post doc Joao Conde and graduate student Nuria Oliva, both from IMES; graduate student Avital Gilam and postdoc Daphna Weissglas-Volkov, from Tel-Aviv University; and Eitan Friedman, an oncogeneticist from Chaim Sheba Medical Center in Israel, now hopes to move on to larger animal studies of the treatment. “We are very excited about the results so far, and the efficacy seems to be really good. So the next step will be to move on to larger models and then to clinical trials, although there is still a long way to go,” Artzi says.


News Article | September 19, 2016
Site: www.biosciencetechnology.com

The spread of malignant cells around the body, known as metastasis, is the leading cause of mortality in women with breast cancer. Now, a new gene therapy technique being developed by researchers at MIT is showing promise as a way to prevent breast cancer tumors from metastasizing. The treatment, described in a paper published today in the journal Nature Communications, uses microRNAs — small noncoding RNA molecules that regulate gene expression — to control metastasis. The therapy could be used alongside chemotherapy to treat early-stage breast cancer tumors before they spread, according to Natalie Artzi, a principal research scientist at MIT’s Institute for Medical Engineering and Science (IMES) and an assistant professor of medicine at Brigham and Women’s Hospital, who led the research in collaboration with Noam Shomron, an assistant professor on the faculty of medicine at Tel-Aviv University in Israel. “The idea is that if the cancer is diagnosed early enough, then in addition to treating the primary tumor [with chemotherapy], one could also treat with specific microRNAs, in order to prevent the spread of cancer cells that cause metastasis,” Artzi said. The regulation of gene expression by microRNAs is known to be important in preventing the spread of cancer cells. Recent studies by the Shomron team in Tel-Aviv have shown that disruption of this regulation, for example by genetic variants known as single nucleotide polymorphisms (SNPs), can have a significant impact on gene expression levels and lead to an increase in the risk of cancer. To identify the specific microRNAs that play a role in breast cancer progression and could therefore potentially be used to suppress metastasis, the research teams first carried out an extensive bioinformatics analysis. They compared three datasets: one for known SNPs; a second for sites at which microRNAs bind to the genome; and a third for breast cancer-related genes known to be associated with the movement of cells. This analysis revealed a variant, or SNP, known as rs1071738, which influences metastasis. They found that this SNP disrupts binding of two microRNAs, miR-96 and miR-182. This disruption in turn prevents the two microRNAs from controlling the expression of a protein called Palladin. Previous research has shown that Palladin plays a key role in the migration of breast cancer cells, and their subsequent invasion of otherwise healthy organs. When the researchers carried out in vitro experiments in cells, they found that applying miR-96 and miR-182 decreased the expression of Palladin levels, in turn reducing the ability of breast cancer cells to migrate and invade other tissue. “Previous research had discussed the role of Palladin in controlling migration and invasion (of cancer cells), but no one had tried to use microRNAs to silence those specific targets and prevent metastasis,” Artzi said. “In this way we were able to pinpoint the critical role of these microRNAs in stopping the spread of breast cancer.” The researchers then developed a method to deliver engineered microRNAs to breast cancer tumors. They embedded nanoparticles containing the microRNAs into a hydrogel scaffold, which they then implanted into mice. They found that this allowed efficient and precise delivery of the microRNAs to a target breast cancer tumor site. The treatment resulted in a dramatic reduction in breast cancer metastasis, said Artzi. “We can locally change the cells in order to prevent metastasis from occurring,” she said. To increase the effectiveness of the treatment even further, the researchers then added the chemotherapy drug cisplatin to the nanoparticles. This led to a significant reduction in both the growth of the primary tumor, and its metastasis. “We believe local delivery is much more effective (than systemic treatment), because it gives us a much higher effective dose of the cargo, in this case the two microRNAs and the cisplatin,” she said. “The research offers the potential for combined experimental therapeutics with traditional chemotherapy in cancer metastasis,” said Julie Teruya-Feldstein, a professor of pathology at Mount Sinai Hospital in New York, who was not involved in the study. The research team, which also includes MIT post doc Joao Conde and graduate student Nuria Oliva, both from IMES; graduate student Avital Gilam and postdoc Daphna Weissglas-Volkov, from Tel-Aviv University; and Eitan Friedman, an oncogeneticist from Chaim Sheba Medical Center in Israel, now hopes to move on to larger animal studies of the treatment. “We are very excited about the results so far, and the efficacy seems to be really good. So the next step will be to move on to larger models and then to clinical trials, although there is still a long way to go,” Artzi said.


Zbar A.P.,Chaim Sheba Medical Center | Khaikin M.,Chaim Sheba Medical Center
Diseases of the Colon and Rectum | Year: 2012

The internal anal sphincter is currently regarded as a significant contributor to continence function. Four physiological and morphological aspects of the internal anal sphincter are presented as part of the current evidence base for its preservation in anal surgery. 1) The incidence of continence disturbance following deliberate internal anal sphincterotomy is underestimated, although there is presently no prospective imaging or physiologic data supporting the selective use of sphincter-sparing surgical alternatives. 2) Given that the resting pressure is a measure of internal anal sphincter function, its physiologic representation (the rectoanal inhibitory reflex) shows inherent differences between incontinent and normal cohorts which suggest that internal anal sphincter properties act as a continence defense mechanism. 3) Anatomical differences in distal external anal sphincter overlap at the point of internal anal sphincter termination may preclude internal anal sphincter division in some patients where the distal anal canal will be unsupported following deliberate internal anal sphincterotomy. 4) internal anal sphincter-preservation techniques in fistula surgery may potentially safeguard postoperative function. Prospective, randomized trials using preoperative sphincter imaging and physiologic parameters of the rectoanal inhibitory reflex are required to shape surgical decision making in minor anorectal surgery in an effort to define whether alternatives to internal anal sphincter division lead to better functional outcomes. ©The ASCRS 2012.


Multiple Myeloma (MM) is a lymphatic neoplasm characterized by clonal proliferation of malignant plasma cell that eventually develops resistance to chemotherapy. Drug resistance, differentiation block and increased survival of the MM tumor cells result from high genomic instability. Chromosomal translocations, the most common genomic alterations in MM, lead to dysregulation of cyclin D, a regulatory protein that governs the activation of key cell cycle regulator--cyclin dependent kinase (CDK). Genomic instability was reported to be affected by over expression of another CDK regulator--cyclin E (CCNE). This occurs early in tumorigenesis in various lymphatic malignancies including CLL, NHL and HL. We therefore sought to investigate the role of cyclin E in MM. CCNE1 expression was found to be heterogeneous in various MM cell lines (hMMCLs). Incubation of hMMCLs with seliciclib, a selective CDK-inhibitor, results in apoptosis which is accompanied by down regulation of MCL1 and p27. Ectopic over expression of CCNE1 resulted in reduced sensitivity of the MM tumor cells in comparison to the paternal cell line, whereas CCNE1 silencing with siRNA increased the cell sensitivity to seliciclib. Adhesion to FN of hMMCLs was prevented by seliciclib, eliminating adhesion-mediated drug resistance of MM cells. Combination of seliciclib with flavopiridol effectively reduced CCNE1 and CCND1 protein levels, increased subG1 apoptotic fraction and promoted MM cell death in BMSCs co-culture conditions, therefore over-coming stroma-mediated protection. We suggest that seliciclib may be considered as essential component of modern anti MM drug combination therapy.


Dotan Z.A.,Chaim Sheba Medical Center
Prostate cancer and prostatic diseases | Year: 2013

The aim of radical prostatectomy (RP) is the complete removal of the prostate gland with negative surgical margins. The presence of cancer at the surgical margin is associated with higher probability of disease progression. Current methods of intraoperative margin assessment are inaccurate or time-consuming.The study goal was to evaluate the ability of a novel device (Dune Medical Devices) to differentiate between cancer and BPH. A total of 49 patients undergoing RP in four medical centers between November 2007 and May 2008 were enrolled in this study.The device was applied to numerous intra- and extra-capsular sites of freshly excised RP specimens. Measurement sites were accurately marked and analyzed histologically. The ability of the device to differentiate between malignant and nonmalignant sites was assessed. A total of 15,156 measurements from 45 patients were analyzed. Differentiation of the intra-capsular malignant sites from extra-capsular nonmalignant sites (bladder neck and apex regions) depends on the cancer feature size. Differentiation was achieved with sensitivity and specificity of 93.6 (95% confidence interval (CI): 88-98) and 94.1 (95% CI: 93-95), respectively, at feature sizes at or >0.8 mm in diameter. The device was able to discriminate between all intra-capsular malignant (with feature sizes down to a few cells) and nonmalignant measurement sites, with sensitivity and specificity of 80.8 (95% CI: 73-87) and 68.4 (95% CI: 67-69), respectively. First results from a radio-frequency near-field spectroscopy sensor look promising for differentiation between cancer and benign prostate tissue. The sensor's dimensions (radius of ~ 1 mm) and design enable use in open, laparoscopic and robotic RP to evaluate the surgical margins intraoperatively.


Shimoni A.,Chaim Sheba Medical Center | Nagler A.,Chaim Sheba Medical Center
Best Practice and Research: Clinical Haematology | Year: 2011

Allogeneic stem-cell transplantation (SCT) is potentially curative therapy in AML by providing both dose-intensive chemo-radiotherapy and induction of graft-versus-leukemia (GvL) effect. Historically, more emphasis was given to the intensity of conditioning. Over the last decade the pendulum turned more towards induction of GvL as the primary goal. A plethora of non-myeloablative (NMA) and reduced-intensity conditioning regimens (RIC) were introduced trying to reduce transplant-related toxicities and allow SCT in elderly and medically infirm patients. In addition, reduced-toxicity myeloablative regimens (RTC) based on fludarabine and myeloablative alkylating-agent doses were designed to allow safer administration of dose-intensive therapy. Conditioning dose-intensity is highly correlated with outcome after SCT. Increased dose-intensity is associated with reduced relapse risk, but also with higher non-relapse mortality. Overall outcome is determined by the net effect of these opposing effects as may be predicted by patient age, comorbidities and disease status at transplantation. Retrospective comparative trials showed that while outcome may be similar with the various regimens in patients given SCT in remission, NMA/RIC are inferior when SCT is given in advanced disease, due to high relapse risk. RTC regimens may be more effective in this setting yet better tolerated by patients not eligible for myeloablative conditioning. Randomized studies are needed to define the role of different regimens. Future studies will also focus on the design of more accurate models to select the best regimen in each setting. A search for novel regimens or post-transplant approaches with more intensive anti-leukemic activity, but limited toxicity will also be of marked benefit. © 2011 Elsevier Ltd. All rights reserved.


Pessach I.,Chaim Sheba Medical Center | Shimoni A.,Chaim Sheba Medical Center | Nagler A.,Chaim Sheba Medical Center
Human Reproduction Update | Year: 2013

Background: Hematopoietic growth factors (HGFs) are mostly used as supportive measures to reduce infectious complications associated with neutropenia. Over the past decade, the use of HGFs became a common method for mobilizing human CD34+ stem cells, either for autologous or allogeneic transplantation. However, since their introduction the long-term safety of the procedure has become a major focus of discussion and research. Most information refers to healthy normal donors and data concerning pregnant and lactating women are scarce. The clinical question, which is the core of this review, is whether stem cell donation, preceded by administration of granulocytecolony stimulating factor (G-CSF) for mobilization, is a safe procedure for pregnant donors. Methods: Literature searches were performed in Pubmed for English language articles published before the end of May 2012, focusing on G-CSF administration during pregnancy, lactation and hematopoietic stem cell donation. Searches included animal and human studies. Results: Data from animals (n = 15 studies) and women (n = 46 studies) indicate that G-CSF crosses the placenta, stimulates fetal granulopoiesis, improves neonatal survival mostly for very immature infants, promotes trophoblast growth and placental metabolism and has an anti-abortive role. Granulocyte macrophage-CSF is a key cytokine in the maternal immune tolerance towards the implanted embryo and exerts protective long-term programming effects to preimplantation embryos. The available data suggest that probably CSFs should notbe administered during the time of most active organogenesis (first trimester), except perhaps for the first week during which implantation takes place. Provided CSF is administered during the second and third trimesters, it appears to be safe, and pregnant women receiving the CSF treatment can become hematopoietic stem cell donors. There are also risks related to the anesthesia, which is required for the bone marrow aspiration. During lactation, there should be a period of at least 3 days to allow for clearance of CSF from milk before resuming breast feeding. With regard to teratogenicity or leukaemogenity, in non-pregnant or non-lactating women reports show that CSF administration is associated with a risk for leukemia; however, this risk is not higher compared with the control population. Conclusions: The information available to date indicates that administration of CSF in general, and G-CSF in particular, is safe and healthy pregnant women can serve as donors of either bone marrow or peripheral blood stem cells. However, the clinical experience is rather limited and therefore until more data become available, G-CSF should not be used during pregnancy and lactation when other therapeutic options, instead of stem cell transplantation, are available. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.


Cyclophosphamide (Cy) combined with total-body irradiation (TBI) or with busulfan (Bu) are currently the most common myeloablative regimens used in allogeneic stem-cell transplantation (alloSCT) in adults with acute myelogenous leukemia (AML). Intravenous (IV) Bu has more predictable bioavailability and a safer toxicity profile than the oral formulation. Comparative studies of outcomes have been performed between oral Bu/Cy and Cy/TBI, but there have been no comparative trials in the era of IV Bu. We performed a retrospective registry-based study comparing outcomes of patients with AML in first or second remission after alloSCT from sibling donors who underwent IV Bu/Cy (n = 795) or Cy/TBI (n = 864) conditioning. Engraftment rate was 98% and 99% after IV Bu/Cy and Cy/TBI, respectively. Grade 2 to 4 acute graft-versus-host disease (GVHD) was significantly lower in the IV Bu/Cy compared with Cy/TBI group (P < .001). Similarly, chronic GVHD was significantly lower in the IV Bu/Cy compared with Cy/TBI group (P = .003). Cumulative incidence of 2-year nonrelapse mortality (NRM; ± standard deviation [SD]) was 12% ± 1% in the IV Bu/Cy group and 15% ± 2% in the Cy/TBI group (P = .14), and 2-year relapse incidence (RI; ± SD) was 26% ± 3% and 21% ± 1%, respectively (P = .012). Leukemia-free survival (LFS) rate (± SD) was 61% ± 2% after IV Bu/Cy and 64% ± 2% after Cy/TBI (P = .27). In multivariable analysis, adjusting for differences between both groups, patients who received IV Bu/Cy had lower acute and chronic GVHD, higher RI, and a trend toward lower NRM. LFS was not statistically different between the two conditioning regimens. This retrospective study shows that final outcomes after myeloablative conditioning using IV Bu/Cy were not statistically different from those after Cy/TBI.

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