Oncolytic virotherapy for metastatic breast cancer - a case report.

Background: Breast cancer is one of the most common malignancies worldwide and remains incurable after metastasis, with a 3-year overall survival rate of <40%. Case presentation: A 40-year-old, Caucasian patient with a grade-3 estrogen receptor-, progesterone receptor-, Her2-positive breast tumor and two lung nodules was treated with intramuscular targeted immunotherapy with trastuzumab and oral tamoxifen hormone therapy, together with customized intra-tumoral oncolytic virotherapy (IT-OV) over a 17-month period. PET/CT imaging at 3 and 6 months showed increased primary tumor size and metabolic glucose uptake in the primary tumor, axillary lymph nodes and lung nodules, which were paralleled by a hyperimmune reaction in the bones, liver, and spleen. Thereafter, there was a steady decline in both tumor size and metabolic activity until no radiographic evidence of disease was observed. The treatment regimen was well tolerated and good quality of life was maintained throughout. Conclusion: Integration of IT-OV immunotherapy in standard treatment protocols presents an attractive modality for late-stage primary tumors with an abscopal effect on metastases.

Effective Treatment of Glioblastoma Multiforme With Oncolytic Virotherapy: A Case-Series.

Glioblastoma multiforme (GBM) remains an incurable condition, associated with a median survival time of 15 months with best standard of care and 5-year survival rate of <10%. We report on four GBM patients on combination treatment regimens that included oncolytic virus (OV) immunotherapy, who achieved clinical and radiological responses with long-term survival, thus far, of up to 14 years, and good quality of life. We discuss the radiological findings that provide new insights into this treatment, the scientific rationale of this innovative and promising therapy, and considerations for future research.

Therapeutic properties of mesenchymal stem cells for autism spectrum disorders.

Recent studies of autism spectrum disorders (ASD) highlight hyperactivity of the immune system, irregular neuronal growth and increased size and number of microglia. Though the small sample size in many of these studies limits extrapolation to all individuals with ASD, there is mounting evidence of both immune and nervous system related pathogenesis in at least a subset of patients with ASD. Given the disturbing rise in incidence rates for ASD, and the fact that no pharmacological therapy for ASD has been approved by the Food and Drug Administration (FDA), there is an urgent need for new therapeutic options. Research in the therapeutic effects of mesenchymal stem cells (MSC) for other immunological and neurological conditions has shown promising results in preclinical and even clinical studies. MSC have demonstrated the ability to suppress the immune system and to promote neurogenesis with a promising safety profile. The working hypothesis of this paper is that the potentially synergistic ability of MSC to modulate a hyperactive immune system and its ability to promote neurogenesis make it an attractive potential therapeutic option specifically for ASD. Theoretical mechanisms of action will be suggested, but further research is necessary to support these hypothetical pathways. The choice of tissue source, type of cell, and most appropriate ages for therapeutic intervention remain open questions for further consideration. Concern over poor regulatory control of stem cell studies or treatment, and the unique ethical challenges that each child with ASD presents, demands that future research be conducted with particular caution before widespread use of the proposed therapeutic intervention is implemented.

The role of angiogenesis in the transformation of plexiform neurofibroma into malignant peripheral nerve sheath tumors in children with neurofibromatosis type 1.

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Immunotherapy in high-risk chemotherapy-resistant patients with metastatic solid tumors and hematological malignancies using intentionally mismatched donor lymphocytes activated with rIL-2: a phase I study.

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.

Post-autologous stem cell transplantation administration of rituximab improves the outcome of patients with aggressive B cell non-Hodgkin's lymphoma.

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.

A retrospective review of the outcome after second or subsequent allogeneic transplantation.

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.

Successful cell-mediated cytokine-activated immunotherapy for relapsed acute myeloid leukemia after hematopoietic stem cell transplantation.

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.

Post-hematopoietic stem cell transplantion immune-mediated cytopenias.

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.

Neuroblastoma cell death is induced by inorganic arsenic trioxide (As(2)O(3)) and inhibited by a normal human bone marrow cell-derived factor.

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.

Induction of late graft-versus-host disease in a patient post-allogeneic stem cell transplantation by progesterone in conjunction with donor lymphocyte infusion.

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.

Sparing effect by montelukast treatment for chronic graft versus host disease: a pilot study.

BACKGROUND: Chronic graft versus host disease (GvHD) is a major complication after allogeneic stem cell transplantation (SCT), which is usually progression from acute GvHD. Chronic GvHD is the main cause of severe morbidity and mortality in long-term survivors after SCT. The cysteinyl leukotrienes (cysLTs) and eosinophils play an important role in the pathogenesis of GvHD, which is the rationale for the combined use of montelukast (Mk) in the treatment of this illness. METHODS: Mk was administrated to 19 eligible patients with refractory chronic GvHD, in addition to their standard immunosuppressive regimens. Mk was given orally (10 mg once daily) for a mean period of 10 months (range, 2-21 months). Organ-specific response was determined by the new scoring criteria established by the National Institutes of Health consensus project. RESULTS: Based on organ involvements endpoints, overall response to the combined therapy with Mk was observed in 15 of 19 (79%) patients. Significant improvement of skin liver and gastrointestinal was observed in 53%, 62%, and 46%, respectively. Generally, Mk was notably beneficial in milder stages of GvHD, which lead to earlier withdrawal of other immunosuppressive agents. Side effects of Mk administration were not documented, nor were cases of relapse of the basic disease. CONCLUSIONS: Our preliminary prospective investigation supports the potential efficacy of Mk as a safe and toxicity-sparing supplement to standard therapy for patients with chronic GvHD. Future clinical studies are necessary to establish the optimal dose of Mk and its role in the symptomatic and prophylactic treatment of acute and chronic GvHD.

Complete remission of multiple myeloma after autoimmune hemolytic anemia: possible association with interferon-alpha.

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.

Euthanasia: an overview and the jewish perspective.

BACKGROUND: End-of-life care poses fundamental ethical problems to clinicians. Defining euthanasia is a difficult and complex task, which causes confusion in its practical clinical application. Over the course of history, abuse of the term has led to medical atrocities. Familiarity with the relevant bioethical issues and the development of practical guidelines might improve clinical performance. OBJECTIVE: To define philosophical concepts, to present historical events, to discuss the relevant attitudes in modern bioethics and law that may be helpful in elaborating practical guidelines for clinicians regarding euthanasia and end-of-life care. Concepts found in the classic sources of Jewish tradition might shed additional light on the issue and help clinicians in their decision-making process. METHODS: An historical overview defines the concepts of active versus passive euthanasia, physician-assisted suicide and related terms. Positions found in classical Jewish literature are presented and analyzed with their later interpretations. The relevance and application in modern clinical medicine of both the general and Jewish approaches are discussed. RESULTS: The overview of current bioethical concepts demonstrates the variety of approaches in western culture and legal systems. Philosophically and conceptually, there is a crucial distinction between active and passive euthanasia. The legitimacy of active euthanasia has been the subject of major controversy in recent times in various countries and religious traditions. CONCLUSION: The historical overview and the literature review demonstrate the need to provide clearer definitions of the concepts relating to euthanasia, for in the past the term has led to major confusion and uncontrolled abuse. Bioethical topics should, therefore, be included in medical training and continuing education. There are major debates and controversies regarding the current clinical and legal approaches. We trust that classical Jewish sources might contribute to the establishment of clinical definitions, meaningful approaches and practical guidelines for clinicians.

A non-myeloablative conditioning regimen in allogeneic stem cell transplantation from related and unrelated donors in elderly patients.

We describe our experience with the use of a single non-myeloablative preparative regimen in stem-cell transplantation (NST) in 37 heavily pretreated patients > or =55 years. The conditioning regimen consisted of fludarabine, low-dose busulfan, and antithymocyte globulin. Acute graft-versus-host disease (GVHD) grade III-IV and chronic GVHD developed in 15.6% and 44.4% of cases, respectively. With a median follow-up period of 22 (range 3-113) months, the 1-year overall survival and disease-free-survival were 55% and 53%, respectively, while the overall non-relapse mortality was 35%. In conclusion, reduced intensity stem cell transplantation is feasible and effective in patients > or =55 years. Age per se, should no longer be considered as a contra-indication to stem cell transplantation.