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ABSTRACT: The feasibility and safety of immunotherapy mediated by intentionally mismatched rIL-2 activated killer lymphocytes (IMAK) with no prior stem cell engraftment was investigated in patients with advanced chemotherapy-resistant hematological malignancies and metastatic solid tumors. Our goals were to maximize anti-cancer activity by using intentionally mismatched donor lymphocytes; amplify killing of target cancer cells by rIL-2 activation of killer cells in vitro and in vivo, and avoid the risk of graft-versus-host disease (GVHD) by anticipated rejection of alloreactive donor lymphocytes. Conditioning consisted of 5 days of fludarabine 25 mg/m(2) or a single dose of cyclophosphamide 1,000 mg/m(2), 2 subcutaneous injections of alpha interferon (IFN) 3 x 10(6) and COX2 inhibitors, followed by administration of IMAK (65 +/- 5 CD3(+)CD56(-); 17 +/- 5 CD3(-)CD56(+)) in conjunction with low dose subcutaneous rIL-2 (6 x 10(6) IU/m(2)/day) for 5 days for continuous activation of alloreactive donor lymphocytes prior to their anticipated rejection. Here, we present our phase 1 clinical study data in a cohort of 40 high-risk patients with metastatic solid tumors and hematological malignancies. Treatment was accompanied by some malaise and occasional self-limited fever but otherwise well tolerated on an outpatient basis. Transient engraftment of donor cells was documented in two patients and only one developed self-limited grade 1 GVHD. Among patients with chemotherapy-resistant disease, long-term progression-free survival was recorded in 5 of 21 evaluable patients with metastatic solid tumors and in four of five patients with hematological malignancies. We conclude that the proposed procedure is feasible, safe, and potentially effective, with some otherwise resistant cancer patients long-term disease-free, thus justifying larger Phase II studies in patients with hematological malignancies and metastatic solid tumors, preferably at a stage of minimal residual disease with the goal in mind to eradicate all malignant cells at an early stage of the disease.
Cancer Immunology and Immunotherapy 10/2010; 59(10):1511-9. · 3.70 Impact Factor
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ABSTRACT: The role of angiogenesis in the transformation of peripheral neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) in neurofibromatosis type 1 (NF1) remains elusive and forms the objective of this study.
Archival tissue from 5 children with NF1 and PNF, who developed MPNST between the ages of 8 and 15 years were analyzed for differences in microvasculature. The role of proangiogenic growth factors such as Vascular Endothelial Growth Factor (VEGF), and its receptors Flk-1 and Flt-1, and vessel maturity, defined as von Willebrand factor (vWf), α-smooth muscle actin+ (SMA+), were evaluated by immuno-histochemistry.
A qualitative evaluation of the vasculature showed predominantly α-SMA+/vWf+ more stable vessels in PNF, and an irregular meshwork of α-SMA-/vWf+ endothelial cells structures in MPNST. In NF and PNF tumor cells were VEGF-, in contrast to VEGF+ tumor cells in MPNST. If present, the VEGF stain was confined mainly to the perivascular spaces in PNF, unlike the mainly stromal VEGF stain in MPNST. VEGF receptors also manifested a tumor stage-specific pattern. Flk-1 and Flt-1 were restricted to the mature, well-formed vasculature in PNF, but exhibited a diffuse pattern in MPNST.
Our study provides a rare opportunity to document consistent and histologically detectable differences in the vascular organization of PNF and MPNST. It permits a pair-wise evaluation of the malignant conversion of benign PNF into its malignant counterpart, in the same patients. The phenotypic variations and characteristics of the vessels in these tumors are consistent with the idea that a strong proangiogenic drive contributes to the progressive growth in MPNST.
Journal of Pediatric Hematology/Oncology 10/2010; 32(7):548-53. · 1.16 Impact Factor
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The American journal of bioethics: AJOB 10/2009; 9(10):W3-4. · 4.00 Impact Factor
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ABSTRACT: With the escalation of terrorism worldwide in recent years, situations arise in which the perpetration of violence and the defense of human rights come into conflict, creating serious ethical problems. The Geneva Convention provides guidelines for the medical treatment of enemy wounded and sick, as well as prisoners of war. However, there are no comparable provisions for the treatment of terrorists, who can be termed unlawful combatants or unprivileged belligerents. Two cases of severely injured terrorists are presented here to illustrate the dilemmas facing the medical staff that treated them. It is suggested that international legal and bioethical guidelines are required to define the role of the physician and auxiliary medical staff vis a vis injured terrorists. There are extreme situations where the perpetration of violence and the defense of human rights come into conflict, leading to serious ethical and psychological discord. Terrorists, using violence to create fear in order to further their political objectives, might require life-saving medical care if injured during the course of their terror activities.
The American journal of bioethics: AJOB 10/2009; 9(10):40-2. · 4.00 Impact Factor
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ABSTRACT: The major cause of treatment failure following high-dose therapy with autologous stem cell transplantation (ASCT) for aggressive B cell non-Hodgkin's lymphoma (NHL) is persistent disease or recurrence. We describe our experience with the administration of rituximab post-ASCT, either as maintenance therapy or for the treatment of relapsed disease in patients with aggressive B cell NHL. Fifty-six patients achieved complete remission post-transplant, and 19 of them received maintenance with rituximab. Maintenance with rituximab resulted in statistically significant superior outcome in terms of progression free (PFS; p = 0.002) and overall survival (OS; p = 0.011). The median PFS and OS of patients in the maintenance arm has not been reached yet, while the median PFS and OS of patients in the control arm were 29 and 42 months, respectively. Fifty-four patients had disease progression or relapsed post-ASCT, and 15 of them received rituximab in combination with chemo- and/or radiotherapy in order to achieve disease remission. Therapeutic administration of rituximab resulted in statistically significant prolongation of OS (p = 0.021). The median OS of patients treated with rituximab was 17 months, while median OS of patients in the control group was 10 months. We consider that the results of our study are promising but need to be verified within large randomized trials.
Annals of Hematology 09/2009; 89(3):263-72. · 2.62 Impact Factor
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ABSTRACT: The failure of allogeneic stem cell transplant (allo-SCT) is cumbersome. We analyzed our experience in a second allo-SCT. Between the years 1981 and 2007, 144 patients underwent 2 or more allo-SCT. The first to second transplant interval ranged from 18 days to 13.25 years (median 98 days). The most frequent indications for the second SCT were activity of the basic disease (78), rejection (37), and engraftment failure (25). Twenty-nine of the 144 (20%) patients transplanted survived more then a year with treatment-related mortality of 45.5% as the leading cause of death. Interestingly, despite the low rate of graft-versus-host disease (GVHD) prophylaxis used, only 51 and 16 of the patients developed acute and chronic GVHD (aGVHD, cGVHD), respectively. Factors indicating higher likelihood for survival were nonmalignant disease, a nonrelapse indication for the second SCT, full HLA-matching, and the use of reduced-intensity conditioning (RIC). Age at transplantation, time interval between transplants, the development of GVHD, conditioning regimen, GVHD prophylaxis, or graft source were not shown to influence the prognosis. With a median follow-up of 4.5 years, 25 patients (17.2%) are alive, and 18 are disease-free. We conclude that although toxic, a second allo-SCT can lead to long-term survival.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2009; 15(4):483-9. · 3.15 Impact Factor
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ABSTRACT: Despite significant advances in neonatology, there will always be newborns with serious life-threatening conditions creating most difficult bioethical dilemmas. Active euthanasia for adult patients is one of the most controversial bioethical questions; for severely ill neonates, the issue is even more complex, due to their inability to take part in any decision concerning their future. The Groningen Protocol introduced in 2005 by P.J. Sauer proposes criteria allowing active euthanasia for severely ill, not necessarily terminal, newborns with incurable conditions and poor quality of life in order to spare them unbearable suffering. We discuss the ethical dilemma and ideological foundations of the protocol, the opinions of its defenders and critics, and the dangers involved. The Jewish perspective relating to the subject is presented based on classical Jewish sources, which we trust may enrich modern bioethical debates. In Jewish law, the fetus acquires full legal status only after birth. However, while the lives of terminally ill neonates must in no way be actively destroyed or shortened, there is no obligation to make extraordinary efforts to prolong their lives. Accurate preimplantation or prenatal diagnosis might significantly reduce the incidence of nonviable births, but active killing of infants violates the basic foundations of Jewish law, and opens the 'slippery slope' for uncontrolled abuse. Therefore, we call upon the international medical and bioethical community to reject the Groningen Protocol that permits euthanization and to develop ethical guidelines for the optimal care of severely compromised neonates.
Neonatology 02/2009; 96(1):6-10. · 2.66 Impact Factor
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ABSTRACT: Three phenotypically distinct cell types are present in human neuroblastomas (NB) and NB cell lines: I-type stem cells, N-type neuroblastic precursors, and S-type Schwannian/melanoblastic precursors. The stimulation of human N-type neuroblastoma cell proliferation by normal human bone marrow monocytic cell conditioned medium (BMCM) has been demonstrated in vitro, a finding consistent with the high frequency of bone marrow (BM) metastases in patients with advanced NB. Inorganic arsenic trioxide (As(2)O(3)), already clinically approved for the treatment of several hematological malignancies, is currently under investigation for NB. Recent studies show that As(2)O(3) induces apoptosis in NB cells. We examined the impact of BMCM on growth and survival of As(2)O(3)-treated NB cell lines, to evaluate the response of cultured NB cell variants to regulatory agents. We studied the effect of BMCM on survival and clonogenic growth of eleven As(2)O(3)-treated NB cell lines grown in sparsely seeded, non-adherent, semi-solid cultures. As(2)O(3) had a strong inhibitory effect on survival of all tested NB cell lines. BMCM augmented cell growth and survival and reversed the inhibitory action of As(2)O(3) in all tested cell lines, but most strongly in N-type cells(.) While As(2)O(3) effectively reduced survival of all tested NB cell lines, BMCM effectively impacted its inhibitory action. Better understanding of micro-environmental regulators affecting human NB tumor cell growth and survival may be seminal to the development of therapeutic strategies and clinically effective agents for this condition.
Cancer Microenvironment 01/2009; 1(1):153-7.
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ABSTRACT: Acute myeloid leukemia (AML) is an extremely aggressive disease with a high relapse rate even after allogeneic hematopoietic stem cell transplantation (HSCT). We report the successful outcome of cell-mediated cytokine-activated immunotherapy in a high-risk pediatric AML patient who relapsed shortly after allogeneic HSCT. Donor lymphocyte infusion along with interferon induced a graft-versus-leukemia effect, presenting as a reversible episode of graft-versus-host disease, which led to stable complete donor chimerism and total eradication of AML for over 24 months, at the time of this report. The curative potential of immunotherapy in hematological malignancies is discussed.
American Journal of Hematology 01/2009; 84(3):188-90. · 4.67 Impact Factor
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Panagiotis D Tsirigotis,
Igor B Resnick,
Reuven Or,
Sharon Elad,
Irina Zilberman,
Luba Yoffe,
Alexander Levovic,
Svetlana Miron, Benjamin Gesundheit,
Shimon Slavin,
Michael-Yechiel Shapira
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ABSTRACT: Immune-mediated cytopenias after allogeneic stem cell transplantation can be categorized as either alloimmune when host or donor immunity reacts against donor or host elements, respectively, or autoimmune when donor immunity reacts against donor hematopoietic tissue, owing to poorly understood mechanisms that result in severe impairment of central and peripheral tolerance. Immune cytopenias are manifested as monolineage or more rarely as bilineage cytopenias, and are usually mediated through humoral immune mechanisms. On the contrary, immune-mediated pancytopenia is a rare event with only few cases reported in the literature. The exact pathogenesis of immune pancytopenia is not well known although it is possible that cellular immunity may play a significant role. The importance of these syndromes lies in the fact that they can cause severe morbidity and mortality. Differential diagnosis from other causes of post-transplant pancytopenia is of extreme value because these disorders can respond to various treatment modalities.
Immunotherapy 01/2009; 1(1):39-47. · 1.85 Impact Factor
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Journal of Clinical Oncology 10/2008; 26(26):4353-5. · 18.37 Impact Factor
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ABSTRACT: Since the beginning of medical history, ethics has interested medical practitioners. The subject has become particularly important in recent years due to the huge advancements in medicine and medical technology and has elicited much public interest. While international ethical principles and guidelines have been established, classical Jewish tradition has always placed great emphasis on bioethics. Prof. Avraham Steinberg's monumental Encyclopedia of Jewish Medical Ethics presents the subject comprehensively and in depth. We propose a bioethics syllabus, to be integrated into the medical curriculum in three stages: i) preclinical - covering basic ethical concepts and principles, relevant history, and ethical codes; ii) clinical - covering bioethical topics relating to the human life cycle; iii) prior to students' final examinations and further specialization - covering bioethical topics relating to their personal interests. Steinberg's Encyclopedia is an ideal basis for the development of a professional course, including Jewish traditional aspects. Such a course would provide future physicians with a varied cultural and intercultural background, help shape their image, and improve the quality of medical care.
The Israel Medical Association journal: IMAJ 06/2008; 10(5):397-400. · 1.02 Impact Factor
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American Journal of Psychiatry 05/2008; 165(4):425-8. · 12.54 Impact Factor
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ABSTRACT: Patients after stem cell transplantation (SCT), often develop graft-versus-host disease (GVHD) which, although potentially dangerous, is associated with the beneficial graft-versus-leukemia (GVL) effect. Where there is high risk of disease recurrence, donor lymphocyte infusions (DLI) are given to provide long-term disease control. We present a patient treated with DLI 4 years post-SCT, who developed acute GVHD after administration of progesterone to induce menstruation. This rare allergic reaction warrants further investigation.
Leukemia Research 04/2008; 32(3):501-3. · 2.92 Impact Factor
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ABSTRACT: Three phenotypically distinct cell types are present in human neuroblastomas (NB) and NB cell lines: I-type stem cells, N-type
neuroblastic precursors, and S-type Schwannian/melanoblastic precursors. The stimulation of human N-type neuroblastoma cell
proliferation by normal human bone marrow monocytic cell conditioned medium (BMCM) has been demonstrated in vitro, a finding consistent with the high frequency of bone marrow (BM) metastases in patients with advanced NB. Inorganic arsenic
trioxide (As2O3), already clinically approved for the treatment of several hematological malignancies, is currently under investigation for
NB. Recent studies show that As2O3 induces apoptosis in NB cells. We examined the impact of BMCM on growth and survival of As2O3-treated NB cell lines, to evaluate the response of cultured NB cell variants to regulatory agents. We studied the effect
of BMCM on survival and clonogenic growth of eleven As2O3-treated NB cell lines grown in sparsely seeded, non-adherent, semi-solid cultures. As2O3 had a strong inhibitory effect on survival of all tested NB cell lines. BMCM augmented cell growth and survival and reversed
the inhibitory action of As2O3 in all tested cell lines, but most strongly in N-type cells. While As2O3 effectively reduced survival of all tested NB cell lines, BMCM effectively impacted its inhibitory action. Better understanding
of micro-environmental regulators affecting human NB tumor cell growth and survival may be seminal to the development of therapeutic
strategies and clinically effective agents for this condition.
Cancer Microenvironment 01/2008; 1(1):153-157.
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Journal of Clinical Oncology 12/2007; 25(33):5321-4. · 18.37 Impact Factor
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09/2007: pages 353-363;
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Mayo Clinic Proceedings 09/2007; 82(8):907. · 5.70 Impact Factor
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ABSTRACT: A patient with multiple myeloma (MM) was being maintained on human recombinant interferon-alpha (INF-alpha) after VAD and autologous bone marrow transplantation (pretreated with melphalan). An episode of immune thrombocytopenia and (Coombs positive) autoimmune hemolytic anemia (AIHA) was noted while on maintenance INF-alpha, which remitted when it was withdrawn. Following this event, he achieved a state of stable disease that persists (more than 3 years) with no specific myeloma treatment. This sequence of events suggests a relationship between an immunological reaction induced by INF-alpha and the prolonged phase of stable disease.
American Journal of Hematology 07/2007; 82(6):489-92. · 4.67 Impact Factor
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American Journal of Hematology 05/2007; 82(4):332-3. · 4.67 Impact Factor
