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עמוד בית
Sun, 23.06.24

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December 2014
Nira Varda-Bloom PhD, Avraham J. Treves PhD, Tatiana Kroupnik MSc, Dan Spiegelstein MD, Ehud Raanani MD and Arnon Nagler MD

Background: Non-mobilized peripheral blood contains mostly committed cells with limited numbers of early progenitors. Objectives: To enrich functional progenitor cells from healthy donors and ischemic heart disease patients by short-term culture of mononuclear cells with defined culture conditions.

Methods: Mononuclear cells obtained from healthy donors and ischemic heart disease patients were cultured for 7 days in a cytokine cocktail. We tested the multilineage differentiation capacities and phenotype of cultured cells.

Results: The short-term culture (7 days) of all study groups with a defined cytokine cocktail resulted in two distinct cell populations (adherent and non-adherent) that differed in their differentiation capacities as well as their cell surface markers. Cultured adherent cells showed higher differentiation potential and expressed endothelial and mesenchymal fibroblast-like surface markers as compared to fresh non-cultured mononuclear cells. The non-adherent cell fraction demonstrated high numbers of colony-forming units, indicating a higher differentiation potential of hematopoietic lineage.

Conclusions: This study proved the feasibility of increasing limited numbers of multipotent progenitor cells obtained from the non-mobilized peripheral blood of healthy donors and ischemic patients. Moreover, we found that each of the two enriched subpopulations (adherent and non-adherent) has a different differentiation potential (mesenchymal, endothelial and hematopoietic).

April 2014
Arie Apel MD, Meirav Kedmi MD, Etai Levi MD, Miriam Berkowicz MD, Yaron Davidovitz MD, Abraham Kneller MD, Elena Ribakovsky MD, Avichai Shimoni MD, Arnon Nagler MD MSc and Abraham Avigdor MD
 Background: Acute lymphocytic leukemia (ALL) is a rare disease with a poor outcome in adults. Over the years different protocols have been developed with the aim of improving the outcome. The German study group protocols (GMALL), which are the most frequently used in our institutions, changed significantly between the periods 1989–93 and 1999–2003.

Objectives: To investigate whether the change in protocols over the years resulted in an outcome difference at two hospitals in Israel.

Methods: We thoroughly reviewed the records of 153 patients from Sheba Medical Center and Soroka Medical Center, of whom 106 comprised the study group. The patients were divided into two groups according to the treatment protocol used: 40 patients with the 1989/93 protocol and 66 with the 1999/2003 protocol. Outcome was analyzed for the two groups.

Results: We found a significant difference in disease-free survival (DFS) between the two groups for B cell-ALL (B-ALL) patients who achieved complete remission after induction. There was no difference in overall survival. We did not find any difference in outcome for T cell-ALL patients or for CD20-positive patients.

Conclusions: In our retrospective analysis, GMALL 99/2003 led to a better DFS for B-ALL patients who were in complete remission after induction. This is possibly related to the differences in medications between the protocols, but may also be due to better supportive care. Despite the proven advantage of the newer protocols regarding overall survival, in our experience there was no other significant difference between the two regimens. 

January 2013
M. Michael, A. Shimoni and A. Nagler
 Acute graft-versus-host disease (GVHD) is a major source of morbidity and mortality after allogeneic stem cell transplantation. Therapy of established acute GVHD depends heavily on corticosteroids, which have limited efficacy and are considerably toxic. It is still a matter of debate whether there is an alternative therapy to corticosteroids. Second-line treatment for acute GVHD after failure of steroids is not well substantiated due to the lack of controlled studies. This review examines the current treatment for acute GVHD, as well as novel therapeutics, such as cellular approaches (e.g., adoptive transfer of mesenchymal stem cells) and enhancement of regulatory T cells (e.g., photopheresis). These approaches avoid the toxicity of generalized immunosuppression and are likely to play a prominent future role in acute GVHD therapy.

August 2012
T. Tohami, A. Nagler and N. Amariglio

Chronic myeloid leukemia (CML) is a clonal hematological disease that represents 15–20% of all adult leukemia cases. The study and treatment of CML has contributed pivotal advances to translational medicine and cancer therapy. The discovery that a single chromosomal abnormality, the Philadelphia (Ph) chromosome, is responsible for the etiology of this disease was a milestone for treating and understanding CML. Subsequently, CML became the first disease for which allogeneic bone marrow transplantation is the treatment of choice. Currently, CML is one of the few diseases where treatment targeted against the chromosomal abnormality is the sole frontline therapy for newly diagnosed patients. The use of directed therapy for CML challenged disease monitoring during treatment and led to the development of definitions that document response and predict relapse sooner than the former routine methods. These methods relied on classical cytogenetics through molecular cytogenetics (FISH) and, finally, on molecular monitoring assays. This review discusses the laboratory tools used for diagnosing CML, for monitoring during treatment, and for assessing remission or relapse. The advantages and disadvantages of each test, the common definition of response levels, and the efforts to standardize molecular monitoring for CML patient management are discussed.

March 2006
M.I. Besser. A.J. Treves. O. Itzhaki, I. Hardan, A. Nagler, M.Z. Papa, R. Catane, E. Winkler, B. Shalmon-Sifroni and J. Schachter

Background: Metastatic melanoma is an aggressive and highly malignant cancer. The 5 year survival rate of patients with metastatic disease is less than 5% with a median survival of only 6–10 months. Drugs like dacarbazin (DTIC) as a single agent or in combination with other chemotherapy agents have a response rate of 15–30%, but the duration of response is usually short with no impact on survival. Interleukin-2-based immunotherapy has shown more promising results. The National Institutes of Health recently reported that lymphodepleting chemotherapy, followed by an adoptive transfer of large numbers of anti-tumor specific tumor-infiltrating lymphocytes, resulted in an objective regression in 51% of patients.

Objectives: To introduce the TIL[1] technology to advanced metastatic melanoma patients in Israel.

Methods: We generated TIL cultures from tumor tissue, choosing those with specific activity against melanoma and expanding them to large numbers.

Results: TIL cultures from nine patients were established and examined for their specific activity against the patients' autologous tumor cells. Twelve TIL cultures derived from 5 different patients showed the desired anti-tumor activity, making those 5 patients potential candidates for the therapy.

Conclusions: Pre-clinical studies of the TIL technology in a clinical laboratory set-up were performed successfully and this modality is ready for treating metastatic melanoma patients at the Sheba Medical Center's Ella Institute.

[1] TIL = tumor-infiltrating lymphocytes 

March 2004
R.M. Nagler and A. Nagler

Patients with graft-versus-host disease suffer from xerostomia, oral infections and mucosal pathologies. The continuous increase in the number of patients treated worldwide with bone marrow transplants, combined with improved survival statistics result in a concomitant increase in the number of GVHD[1] patients. the pathogenesis of GVHD is based on donor graft T lymphocytes that recognize antigenic disparities between donor and recipient, and on the disregulation of a broad panel of cytokines. Consequently, various tissues and organs, including the mucosa of the oral and gastrointestinal tract, are damaged via cytotoxicity caused by infiltrating T cells. Since the salivary glands are a known major target of GVHD and their secretions significantly contribute to preserving mucosal integrity, this mucosal insult is further enhanced by the reduced quantity and altered quality of saliva. GVHD occurs in 40–70% of patients treated by bone marrow and peripheral blood stem cell transplantation. limited studies suggest that a large percentage of GVHD patients are affected and that the induced salivary dysfunction occurs rapidly following transplantation, affecting both major and minor salivary glands and reflecting the severity of the disease. Moreover, profound sialochemical alterations may be diagnostic of GVHD. an additional reason for the vast amount of research is that GVHD, as an autoimmune-like disease, seems to be an appropriate model for studying a much more prevalent, well-known and studied autoimmune disease involving salivary glands, namely, sjögren’s syndrome. The present review describes the GVHD-related sialometric and sialochemical data available in the literature for both major and minor salivary glands in both human and rodent models, and discusses a possible mechanism.

[1] GVHD = Graft-Versus-Host Disease

January 2004
Y. Cohen and A. Nagler

In recent years, umbilical cord blood has emerged as an alternative source of hematopoietic progenitors (CD34+) for allogeneic stem cell transplantation, mainly in patients who lack an human leukocyte antigen-matched marrow donor. Since 1998, about 2,500 patients have received UCB[1] transplants for a variety of malignant and non-malignant diseases. The vast majority of recipients were children with an average weight of 20 kg, however more than 500 UCB transplantations have already been performed in adults. The “naive” nature of UCB lymphocytes may explain the lower incidence and severity of graft versus host disease encountered in UCBT[2] compared to the allogeneic transplant setting. Furthermore, UCB is rich in primitive CD16-CD56++ natural killer cells, which possess significant proliferative and cytotoxic capacities and can be expanded using interleukin-12 or 15, so as to mount a substantial graft versus leukemia effect. The major disadvantage of UCB is the low yield of stem cells, resulting in higher graft failure rates and slower time to engraftment compared to bone marrow transplantation. A rational approach thus involves ex vivo expansion of UCB-derived hematopoietic precursors.

[1] UCB = umbilical cord blood

[2] UCBT = UCB transplantations

May 2003
A. Leibovitz, G. Plotnikov, B. Habot, M. Rosenberg, A. Wolf, R. Nagler, E. Graf and R. Segal

Objective: To reexamine the impact of prolonged nasogastric tube feeding on the oral microbiota and to explore the salivary flow and composition in elderly patients in long-term care.

Methods: We compared a group of elderly patients fed by nasogastric tube with a control group of elderly patients in long-term care who are fed orally. Bacteriologic studies were performed by culturing samples from the oropharynx. Saliva studies included quantitative and biochemical analysis of basal and stimulated salivary flow.

Results: Bacteriologic studies performed in 90 patients revealed a significantly higher prevalence of gram-negative bacteria in nasogastric tube-fed patients (73% vs. 13%, P < 0.001). It is emphasized that Pseudomonas aeruginosa and Klebsiella pneumoniae were commonly and exclusively isolated from the oral flora of the nasogastric tube-fed patients (P < 0.001, P < 0.05). In the saliva studies performed on 23 nasogastric tube-fed and 21 control patients, basal and stimulated salivary flow was not significantly different in the two groups, however the ratio of stimulated to basal flow was reduced in the nasogastric tube-fed group (P < 0.05). Significant differences were also found in the concentrations of sodium, amylase, phosphor and magnesium. Noteworthy was the concentration of uric acid, the main non-enzymatic antioxidant of saliva, which was significantly lower in nasogastric-tube fed patients (P < 0.002).

Conclusions: These findings suggest that prolonged nasogastric tube feeding is associated with pathologic colonization of the oropharynx and with alterations in the saliva that are related to the risk of aspiration pneumonia. Further research is called for, as well as a thorough revision of the existing oral cleansing procedures in these patients.

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