Dosimetric analysis of 3D-conformal radiotherapy and intensity modulated radiotherapy for treatment of advanced stage cervical cancer: A comparative study

Purpose: The purpose of this study is to analyze the dosimetric parameters of three dimensional conformal radiotherapy (3DCRT), intensity modulated radiotherapy (IMRT) with seven and nine fields (7F-IMRT, 9F-IMRT) in selected advanced stage cervical cancer cases.Methods: Fifteen cases of cervical cancer (IIB to IIIB) were selected for retrospective analysis. All the cases were previously treated with 3DCRT technique with prescribed dose of 50 Gy in 25 fractions.  For this study, plans with seven fields IMRT and nine fields IMRT were generated for all patients following Radiation Therapy Oncology Group (RTOG) guidelines. The plans were compared on the basis of planning target volume (PTV) coverage (dose to 1%, 5%, 95% and 99% of target), maximum dose and mean dose to organs at risk (OARs) and also doses at different volumes of OARs. Apart from this, uniformity index (UI), homogeneity index (HI), conformity index (CI) and dose spillage index (R50%) were also calculated with respect to PTV coverage.Results: The average dose value of PTV coverage for all three techniques were comparable and all the DVH indices for 7field IMRT (UI (1.04±0.01), HI (0.07 ±0.02), CI (0.75±0.03) and R50% (4.47±0.36)) were better than 3DCRT and 9F-IMRT techniques. All OAR doses were significantly reduced in 7F- IMRT compared to 3DCRT and 9F- IMRT. The target volumes ranged from 769.2 ml to 1375.6 ml with average target volume of 1071.9 ml (SD: 205.38 ml).Conclusion: This study showed that significant dose reduction to OARs could be achieved with seven field IMRT plans by maintaining the PTV coverage compared to 3DCRT or 9F- IMRT for treating cervical cancer in advanced stages particularly from IIB to IIIB

DVH Analysis of Cobalt-60 treatment plans incorporating a recently developed MLC

Purpose: The aim of this investigation was to measure the gain in DVH indices when the recently developed MLC was used for Cobalt-60 treatments.Methods: A prototype multileaf collimator (MLC) that was retrofitted to telecobalt-60 therapy machine was reported and is currently proposed for clinical trials in our institution. Ten patients’ plans that were previously planned through an ECLIPSE® treatment planning system and were treated with open beams from Cobalt-60 machine were imported into Radiation Oncology Planning System [ROPS] and the dose calculations and dose volume histogram (DVH) analysis were performed. The plans were re-planned using the Cobalt-MLC, a feature available in the ROPS planning system. The DVH analysis consisted of conformity index (CI), homogeneity index (HI) and conformation number (CN). The results of this study are presented in this paper. The analysis specifically aimed at measuring the gain in these indices when the MLC was compared with open beams.Results: DVH Comparison of ten sites using open and Cobalt MLC fields showed that the use of MLC results in reduced normal tissue dose, while maintaining the GTV dose. Lower value of CI for normal structures was observed demonstrating the sparing of critical organs when MLC was used. The index HI was studied to show the significance of hot spots outside the PTV. Hot spots were observed even with MLC beams for some cases due to less number of fields.Conclusion: It has been demonstrated through DVH analysis that the use of the recently developed MLC for Cobalt Teletherapy machine results in benefit for the treatment of patients

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Immune Dysregulation and Pathobiology Working Group Report

Immune reconstitution after hematopoietic stem cell transplantation (HCT) beyond 1 year is not completely understood. Many transplant recipients who are free of graft-versus-host disease (GVHD) and not receiving any immunosuppression more than 1 year after transplantation seem to be able to mount appropriate immune responses to common pathogens and respond adequately to immunizations. However, 2 large registry studies over the last 2 decades seem to indicate that infection is a significant cause of late mortality in some patients, even in the absence of concomitant GVHD. Research on this topic is particularly challenging for several reasons. First, there are not enough long-term follow-up clinics able to measure even basic immune parameters late after HCT. Second, the correlation between laboratory measurements of immune function and infections is not well known. Third, accurate documentation of infectious episodes is notoriously difficult. Finally, it is unclear what measures can be implemented to improve the immune response in a clinically relevant way. A combination of long-term multicenter prospective studies that collect detailed infectious data and store samples as well as a national or multinational registry of clinically significant infections (eg, vaccine-preventable severe infections, opportunistic infections) could begin to address our knowledge gaps. Obtaining samples for laboratory evaluation of the immune system should be both calendar and eventdriven. Attention to detail and standardization of practices regarding prophylaxis, diagnosis, and definitions of infections would be of paramount importance to obtain clean reliable data. Laboratory studies should specifically address the neogenesis, maturation, and exhaustion of the adaptive immune system and, in particular, how these are influenced by persistent alloreactivity, inflammation, and viral infection. Ideally, some of these long-term prospective studies would collect information on long-term changes in the gut microbiome and their influence on immunity. Regarding enhancement of immune function, prospective measurement of the response to vaccines late after HCT in a variety of clinical settings should be undertaken to better understand the benefits as well as the limitations of immunizations. The role of intravenous immunoglobulin is still not well defined, and studies to address it should be encouraged

BET Bromodomain Inhibitors Which Permit Treg Function Enable a Combinatorial Strategy to Suppress GVHD in Pre-clinical Allogeneic HSCT

A recent approach for limiting production of pro-inflammatory cytokines has been to target bromodomain and extra-terminal (BET) proteins. These epigenetic readers of histone acetylation regulate transcription of genes involved in inflammation, cardiovascular disease, and cancer. Development of BET inhibitors (BETi) has generated enormous interest for their therapeutic potential. Because inflammatory signals and donor T cells promote graft-versus-host disease (GVHD), regulating both pathways could be effective to abrogate this disorder. The objective of the present study was to identify a BETi which did not interfere in vivo with CD4+FoxP3+ regulatory T cell (Treg) expansion and function to utilize together with Tregs following allogeneic hematopoietic stem cell transplantation (aHSCT) to ameliorate GVHD. We have reported that Tregs can be markedly expanded and selectively activated with increased functional capacity by targeting TNFRSF25 and CD25 with TL1A-Ig and low dose IL-2, respectively. Here, mice were treated over 7 days (TL1A-Ig + IL-2) together with BETi. We found that the BETi EP11313 did not decrease frequency/numbers or phenotype of expanded Tregs as well as effector molecules, such as IL-10 and TGF-β. However, BETi JQ1 interfered with Treg expansion and altered subset distribution and phenotype. Notably, in Treg expanded mice, EP11313 diminished tnfa and ifng but not il-2 RNA levels. Remarkably, Treg pSTAT5 expression was not affected by EP11313 supporting the notion that Treg IL-2 signaling remained intact. MHC-mismatched aHSCT (B6 → BALB/c) was performed using in vivo expanded donor Tregs with or without EP11313 short-term treatment in the recipient. Early post-transplant, improvement in the splenic and LN CD4/CD8 ratio along with fewer effector cells and high Treg levels in aHSCT recipients treated with expanded Tregs + EP11313 was detected. Interestingly, this group exhibited a significant diminution of GVHD clinical score with less skin and ocular involvement. Finally, using low numbers of highly purified expanded Tregs, improved clinical GVHD scores were observed in EP11313 treated recipients. In total, we conclude that use of this novel combinatorial strategy can suppress pre-clinical GVHD and posit, in vivo EP11313 treatment might be useful combined with Treg expansion therapy for treatment of diseases involving inflammatory responses

2: Donor-Recipient Host-Versus-Graft Human Leukocyte Antigen Mismatches and Outcome of Cord Blood Transplants

Digitalitzat per Artypla

Prognostic factors for outcomes of patients with refractory or relapsed acute myelogenous leukemia or myelodysplastic syndromes undergoing allogeneic progenitor cell transplantation

AbstractAllogeneic progenitor cell transplantation is the only curative therapy for patients with refractory acute myelogenous leukemia or myelodysplastic syndromes. To identify prognostic factors in these patients, we performed a retrospective analysis of transplantation outcomes. Patients were selected if they had undergone an allogeneic transplantation between January 1988 and January 2002 and were not in remission or first untreated relapse at the time of transplantation. A total of 135 patients were identified. The median age was 49.5 years (range, 19-75 years). At the time of transplantation, 39.3% of patients had not responded to induction therapy, 37% had not responded to first salvage therapy, and 23.7% were beyond first salvage. Forty-one patients (30%) received unrelated donor progenitor cells. Eighty patients (59%) received either a reduced-intensity or a nonmyeloablative regimen. A total of 104 (77%) of 135 patients died, with a median survival time of 4.9 months (95% confidence interval, 3.9-6.6 months). The median progression-free survival was 2.9 months (95% confidence interval, 2.5-4.2 months). A Cox regression analysis showed that Karnofsky performance status, peripheral blood blasts, and tacrolimus exposure during the first 11 days after transplantation were predictive of survival. These data support the use of allogeneic transplantation for patients with relapsed or refractory acute myelogenous leukemia/myelodysplastic syndromes and suggest that optimal immune suppression early after transplantation is essential for long-term survival even in patients with refractory myeloid leukemias

Success of an International Learning Health Care System in Hematopoietic Cell Transplantation: The American Society of Blood and Marrow Transplantation Clinical Case Forum

The ASBMT Clinical Case Forum (CCF) was launched in 2014 as an online secure tool to enhance interaction and communication among hematopoietic cell transplantation (HCT) professionals worldwide through the discussion of challenging clinical care issues. After 14 months, we reviewed clinical and demographical data on cases posted in the CCF from 1/29/2014 to 3/18/2015. A total of 137 cases were posted during the study period. Ninety-two cases (67%) were allogeneic HCT, 29 (21%) autologous HCT and in 16 (12%) the type of transplant (auto vs. allo) was still under consideration. The diseases most frequently discussed included non-Hodgkin lymphoma (NHL; n = 30, 22%), acute myeloid leukemia (AML; n = 23, 17%) and multiple myeloma (MM; n = 20, 15%). When compared with the US transplant activity reported by the US Department of Health and Human Services, NHL and acute lymphoblastic leukemia cases were overrepresented in the CCF while myeloma was underrepresented (P < 0.001). A total of 259 topics were addressed in the CCF with a median of two topics/case (range 1-6). Particularly common topics included whether transplant was indicated (n = 57, 41%), conditioning regimen choice (n = 44, 32%), and post-HCT complications after day 100 (n = 43, 31%). The ASBMT CCF is a successful tool for collaborative discussion of complex cases in the HCT community worldwide and may allow identification of areas of controversy or unmet need from clinical, educational and research perspectives