Human T cells express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor function

<p>Abstract</p> <p>Background</p> <p>Foxp3 has been suggested to be a standard marker for murine Tregs whereas its role as marker for human Tregs is controversial. While some reports have shown that human Foxp3+ T cells had no regulatory function others have shown their role in the inhibition of T cell proliferation.</p> <p>Methods</p> <p>T cell activation was performed by means of brayostatin-1/ionomycin (B/I), mixed lymphocyte reaction (MLR), and CD3/CD28 activation. T cell proliferation was performed using BrdU and CFSE staining. Flow cytometry was performed to determine Foxp3 expression, cell proliferation, viabilities and phenotype analyses of T cells.</p> <p>Results</p> <p>Both CD4+ and CD8+ T cells expressed Foxp3 upon activation <it>in vitro</it>. Expression of Foxp3 remained more stable in CD4+CD25+ T cells compared to that in CD8+CD25+ T cells. The CD4+CD25+Foxp3+ T cells expressed CD44 and CD62L, showing their effector and memory phenotypes. Both FoxP3- responder T cells and CD4+FoxP3+ T cells underwent proliferation upon CD3/CD28 activation.</p> <p>Conclusion</p> <p>Expression of Foxp3 does not necessarily convey regulatory function in human CD4+CD25+ T cells. Increased FoxP3 on CD44+ effector and CD44+CD62L+ memory T cells upon stimulation suggest the activation-induced regulation of FoxP3 expression.</p

Patterns of fatigue in adolescents receiving chemotherapy

Abstract: Purpose/Objectives: To describe patterns of fatigue in adolescents and the impact of fatigue during one month of chemotherapy, to explore variables that affect fatigue, and to explore the feasibility of collecting daily selfreport data in this population. Design: Longitudinal, descriptive. Setting: Two pediatric oncology centers in central Virginia. Sample: 20 adolescents with a variety of cancer diagnoses receiving chemotherapy. Methods: Adolescents described daily fatigue for one month using rating scales and qualitative diaries Main Research Variables: Fatigue severity. Finding: Adolescents commonly reported a peak in fatigue in the days immediately following chemotherapy administration. The most common pattern for adolescents who received chemotherapy on a schedule every three to four weeks was a &quot;declining rollercoaster&quot; pattern, with fatigue severity alternating on a daily basis but gradually declining until chemotherapy was scheduled again. Adolescents who received chemotherapy weekly showed more frequent peaks and troughs (the &quot;yo-yo&quot; pattern) that did not diminish in severity over the weeks of the study. Adolescents associated fatigue with other symptoms, particularly sleep-wake disturbances, pain, and nausea, and frequently reported that fatigue interfered with daily activities. Conclusions: Fatigue commonly bothers adolescents receiving chemotherapy, particularly in the days following chemotherapy administration and when other symptoms are present. Although fatigue interfered with the adolescents&apos; abilities to maintain their usual lifestyles, many still participated in the typical activities of adolescence. Implications for Nursing: Fatigue is a complex and dynamic symptom. Oncology clinicians and researchers should frequently assess fatigue in adolescents receiving chemotherapy and apply timely and tailored interventions to match the factors that contribute to fatigue and influence fatigue severity. Management of fatigue during treatment will help adolescents stay involved in age-related activities and meet developmental milestones. Article: Adolescents diagnosed with cancer represent a group of patients with a unique cancer epidemiology, development profile, and research needs. The population&apos;s most common cancers include lymphoma, leukemia, central nervous system cancers, endocrine and germ cell tumors, and sarcomas--a spectrum of cancers different than that seen in adults or in younger childre

Distinct signatures of the immune responses in low risk versus high risk neuroblastoma

<p>Abstract</p> <p>Background</p> <p>Over 90% of low risk (LR) neuroblastoma patients survive whereas less than 30% of high risk (HR) patients are long term survivors. Age (children younger than 18 months old) is associated with LR disease. Considering that adaptive immune system is well developed in older children, and that T cells were shown to be involved in tumor escape and progression of cancers, we sought to determine whether HR patients may tend to show a signature of adaptive immune responses compared to LR patients who tend to have diminished T-cell responses but an intact innate immune response.</p> <p>Methods</p> <p>We performed microarray analysis of RNA extracted from the tumor specimens of HR and LR patients. Flow cytometry was performed to determine the cellular constituents in the blood while multiplex cytokine array was used to detect the cytokine profile in patients' sera. A HR tumor cell line, SK-N-SH, was also used for detecting the response to IL-1β, a cytokines which is involved in the innate immune responses.</p> <p>Results</p> <p>Distinct patterns of gene expression were detected in HR and LR patients indicating an active T-cell response and a diminished adaptive immune response, respectively. A diminished adaptive immune response in LR patients was evident by higher levels of IL-10 in the sera. In addition, HR patients had lower levels of circulating myeloid derived suppressor cells (MDSC) compared with a control LR patient. LR patients showed slightly higher levels of cytokines of the innate immune responses. Treatment of the HR tumor line with IL-1β induced expression of cytokines of the innate immune responses.</p> <p>Conclusions</p> <p>This data suggests that adaptive immune responses may play an important role in the progression of HR disease whereas innate immune responses may be active in LR patients.</p

Outcomes after HLA-Matched Sibling Transplants or Chemotherapy in Children with Acute Lymphoblastic Leukemia in a Second Remission after an Isolated Central Nervous System Relapse

Abstract The optimal treatment for children with acute lymphoblastic leukemia (ALL) in second remission after an isolated central nervous system relapse is unknown. To address this question, we compared outcomes in 149 patients enrolled on Pediatric Oncology Group chemotherapy trials 9061 (n=79) and 9412 (n=70) and HLA-matched sibling transplant recipients (n=60) reported to the Center for International Blood and Marrow Transplant Research. Patients received treatment between 1990 and 2000. Median follow-up was 8 years and 9 years after chemotherapy and transplantation, respectively. Groups were similar with respect to sex and leukocyte count at diagnosis. Chemotherapy recipients were younger at diagnosis (5 vs. 7 years) and more likely to have had a longer duration of first remission (duration of first remission ≥18 months: 70% vs. 48%). All transplant recipients received bone marrow grafts and 83% received a total body irradiation containing preparatory regimen. The median time to transplantation after achieving a second remission was 2.5 months (range, <1 – 8). To adjust for time-to transplant bias, we used left-truncated Cox regression models to examine treatment outcomes. Risks of a subsequent leukemia relapse were similar in both treatment groups. As expected, risks of a subsequent leukemia relapse were significantly higher in older patients (11–17 years; relative risk [RR] 2.63, p=0.004) and those with a short duration of first remission (<18 months; RR 4.22, p<0.001) regardless of type of treatment. Relative to chemotherapy recipients, risks of treatment-related mortality (RR 4.29, p=0.001), treatment failure (RR 2.37, p=0.003) and overall mortality (RR 2.68, p=0.002) were significantly higher within the first 2 years after achieving a second remission in recipients of HLA-matched sibling transplants. Among transplant recipients who survived the first two years, subsequent mortality and treatment failure risks did not differ by treatment group. In both treatment groups, recurrent leukemia was the commonest cause of death (60% and 56% after chemotherapy and transplantation, respectively). The 8-year probabilities of leukemia-free survival (adjusted for age and duration of first remission) were 66% and 58% after chemotherapy and transplantation, respectively. These data support use of chemotherapy alone for patients with ALL and isolated central nervous system relapse who achieve a second remission regardless of duration of first remission

Florida Pediatric Bone Marrow Transplant and Cell Therapy Consortium (FPBCC) Pediatric Outcomes Analysis Using Enhanced Data Back to Centers (eDBtC) Platform

Florida, with 4.1 million children, has six small pediatric BMT programs which are distributed across the state facilitating access to transplant. However, the literature indicates a survival advantage when transplants are done in a larger center with disease-specific expertise. In addition to lack of expertise across all diseases, it is more difficult for smaller centers to use their experience to improve patient outcomes as each center's analyses are skewed due to small number of transplants. In 2018, five Florida Pediatric BMT centers formed a consortium (Florida Pediatric BMT and Cell Therapy Consortium – FPBCC) with the goal of sharing data, clinical collaboration, and increasing patient base for retrospective and early stage clinical trials. The ultimate goal is to increase knowledge about utilization of pediatric BMT and its outcomes in a geographically defined population of children. This knowledge will help develop interventions for practice improvement. After signing a memorandum of understanding for FPBCC and data use agreements, and after obtaining IRB approvals for retrospective data analyses, we gathered data from all pediatric BMT transplants performed in 5 Florida Pediatric BMT centers between 2014 and 2016. We utilized the CIBMTR eDBtC (enhanced data back to center) platform to gather data reported to the CIBMTR. De-coded CIBMTR data were downloaded by each center and forwarded to the FPBCC for analysis. Four hundred and fifteen transplants were done in the five Florida centers over the 3-year study period. However, we present 377 transplants performed in 301 children who were ≤18 years at the time of transplant. The majority (58%) of first transplant recipients were male, 28% were ≤3 years of age and 68% were ≤10 years of age at time of transplant. By race, the majority of recipients were Caucasians (70%) followed by AA (21%). The majority of transplants (61%) were allogeneic with 81% of them being first, and 9% being second or a subsequent transplant. Unrelated donor was the most common donor type (64%). Among related transplant donors, 25% were mismatched. Bone marrow was used as a stem cell source in 58% of first allogeneic transplants, cord blood in 26%, and PBSCs in 16%. Among autologous transplants, 38% were second or subsequent transplant. The most common indications for allogeneic transplant were acute lymphoblastic leukemia (33%), myelogenous leukemia (20%) sickle cell disease (8%) and primary immune deficiencies (5%). In the autologous group, the most common indication for transplant was neuroblastoma (37%), followed by medulloblastoma and other brain tumors (18% each). We showed that data obtained through collaboration of programs using the eDBtC platform could lead to better understanding of activity and trends in transplant in a defined patient population. This consortium will continue with data validation and analyses in order to identify areas for improvement

Pediatric HCT in Florida (2014 ‐2016): A report from the FPBCC

FPBCC was formed in 2018 by five pediatric transplant programs in Florida. One of the key objectives of the consortium is to provide outcome analyses by combining HCT data from all the participating centers in order to identify areas for improvement. In this first FPBCC landscape report we describe the patient and transplant characteristics of pediatric patients undergoing first allo and auto HCT between 2014 and 2016 in Florida. The source of data was eDBtC of the CIBMTR. Over the span of 3 years, a total of 230 pediatric patients underwent allo-HCT and 104 underwent auto-HCT at the participating centers. The most significant predictor of survival in allo-HCT recipients with malignant disorders was the degree of HLA- match, while in the recipients of allo-HCT with non-malignant disorders the predictors of survival included age, donor relationship and degree of HLA match. Our analyses identified the need to improve reporting of primary cause of death and improve on donor selection process given that the degree of HLA match remains the most important predictor of survival. This first FPBCC-wide review describes the trends in pediatric HCT activity between 2014 and 2016 among the participating centers in Florida and confirms feasibility of using eDBtC data platform and collaborative approach in order to identify areas for improvement in outcomes

Unrelated Donor Transplantation in Children with Thalassemia using Reduced-Intensity Conditioning: The URTH Trial

•Hematopoietic stem cell transplantation from unrelated bone marrow and cord blood after reduced-intensity conditioning resulted in high rates of engraftment in children with transfusion-dependent thalassemia in a prospective multicenter trial.•Strategies that provide more effective prophylaxis against graft-versus-host disease and viral infections can improve outcomes further. Allogeneic hematopoietic stem cell transplantation (HSCT) can cure transfusion-dependent thalassemia (TDT). In a multicenter trial we investigated the efficacy of reduced-intensity conditioning (RIC) before unrelated donor (URD) HSCT in children with TDT. Thirty-three children, ages 1 to 17 years, received bone marrow (BM) or umbilical cord blood (UCB) allografts. Median time to neutrophil engraftment was 13 days (range, 10 to 25) and 24 days (range, 18 to 49) and platelet engraftment 23 days (range, 12 to 46) and 50 days (range, 31 to 234) after BM and UCB allografts, respectively. With a median follow-up of 58 months (range, 7 to 79), overall and thalassemia-free survival was 82% (95% CI, .64% to .92%) and 79% (95% CI, .6% to .9%), respectively. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) after BM and UCB allografts was 24% and 44%; the 2-year cumulative incidence of chronic extensive GVHD was 29% and 21%, respectively; 71% of BM and 91% of UCB recipients discontinued systemic immunosuppression by 2 years. Six patients who had Pesaro risk class 2 (n = 5) and class 3 (n = 1) died of GVHD (n = 3), viral pneumonitis (n = 2) and pulmonary hemorrhage (n = 1). Outcomes after this RIC compared favorably with URD HSCT outcomes for TDT and supported engraftment in 32 of 33 patients. Efforts to reduce GVHD and infectious complications are being pursued further