Overt gastrointestinal bleeding following haploidentical haematopoietic stem cell transplantation: incidence, outcomes and predictive models.
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SUBMITTER: Sun X
PROVIDER: S-EPMC8189916 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesPaediatric and adolescent patients in need of allogeneic haematopoietic stem cell transplantation (HSCT) generally receive stem cells from older, unrelated or parental donors when a sibling donor is not available. Despite encouraging clinical outcomes, it has been suggested that immune reconstitution accompanied by increased replicative stress and a large difference between donor and recipient age may worsen immunosenescence in paediatric recipients.MethodsIn this study, paired samples were collected at the same time from donors and recipients of haploidentical haematopoietic stem cell transplantation (HaploSCT). We then conducted flow cytometry-based phenotypic and functional analyses and telomere length (TL) measurements of 21 paired T-cell sets from parental donors and children who received T-cell-replete HaploSCT with post-transplant cyclophosphamide (PTCy).ResultsSenescent T cells, CD28- or CD57+ cells, were significantly expanded in patients. Further, not only CD4+CD28- T cells, but also CD4+CD28+ T cells showed reduced cytokine production capacity and impaired polyfunctionality compared with parental donors, whereas their TCR-mediated proliferation capacity was comparable. Of note, the TL in patient T cells was preserved, or even slightly longer, in senescent T cells compared with donor cells. Regression analysis showed that senescent features of CD4+ and CD8+ T cells in patients were influenced by donor age and the frequency of CD28- cells, respectively.ConclusionOur data suggest that in paediatric HaploSCT, premature immunosenescent changes occur in T cells from parental donors, and therefore, long-term immune monitoring should be conducted.
| S-EPMC7142179 | biostudies-literature
Project description:BackgroundUpper gastrointestinal (GI) bleeding is one of the most common, high risk emergency disorders in the western world. Almost nothing has been reported on longer term prognosis following upper GI bleeding. The aim of this study was to establish mortality up to three years following hospital admission with upper GI bleeding and its relationship with aetiology, co-morbidities and socio-demographic factors.MethodsSystematic record linkage of hospital inpatient and mortality data for 14 212 people in Wales, UK, hospitalised with upper GI bleeding between 1999 and 2004 with three year follow-up to 2007. The main outcome measures were mortality rates, standardised mortality ratios (SMRs) and relative survival.ResultsMortality at three years was 36.7% overall, based on 5215 fatalities. It was highest for upper GI malignancy (95% died within three years) and varices (52%). Compared with the general population, mortality was increased 27-fold during the first month after admission. It fell to 4.3 by month four, but remained significantly elevated during every month throughout the three years following admission. The most important independent prognostic predictors of mortality at three years were older age (mortality increased 53 fold for people aged 85 years and over compared with those under 40 years); oesophageal and gastric/duodenal malignancy (48 and 32 respectively) and gastric varices aetiologies (2.8) when compared with other bleeds; non-upper GI malignancy, liver disease and renal failure co-morbidities (15, 7.9 and 3.9); social deprivation (29% increase for quintile V vs I); incident bleeds as an inpatient (31% vs admitted with bleeding) and male patients (25% vs female).ConclusionOur study shows a high late as well as early mortality for upper GI bleeding, with very poor longer term prognosis following bleeding due to malignancies and varices. Aetiologies with the worst prognosis were often associated with high levels of social deprivation.
| S-EPMC3520969 | biostudies-literature
Project description: Not available
| S-EPMC9319563 | biostudies-literature
Project description:Heparin is commonly given during hemodialysis (HD). Patients undergoing HD have a high rate of gastrointestinal bleeding (GIB). It is unclear whether or when it is safe to give heparin after acute GIB. We describe the patterns and safety of heparin use with outpatient HD following an acute GIB.We identified patients aged ? 67 who, from 2004-2008, experienced GIB requiring hospitalization within 2 days of receiving maintenance HD with heparin. We used Cox regression to estimate the risk of recurrent GIB and death associated with receiving heparin the day they resumed outpatient HD post-GIB.Of the 1,342 patients who had GIB, 1,158 (86%) received heparin at a median dose of 4,000 units with their first outpatient HD session after discharge from GIB. On average, their post-GIB doses were slightly lower than their pre-GIB doses (mean change: -214 ± 3,266 units, p < 0.02). However, only 27% of patients had a decrease in their dose, while 21% had their dose increased. We did not find an increased risk of death or recurrent GIB associated with using heparin post-GIB (HR; 95% confidence interval (CI), for death: 1.01; 0.69-1.48; for recurrent GIB: 0.78; 0.39-1.57).The vast majority of these high-risk patients received heparin on the very first day they resumed outpatient HD post-GIB, and the majority at unchanged doses to those received pre-GIB. Even if the practice was not associated with increased risks of death or re-bleeding, it highlights an area for possible system-based improvement to the care for patients on HD.
| S-EPMC4246045 | biostudies-literature
Project description:Delayed immune reconstitution and the consequently high rates of leukemia relapse and infectious complications are the main limitations of haploidentical hematopoietic stem cell transplantation. Donor T cell addback can accelerate immune reconstitution but the therapeutic window between graft-vs.-host disease and protective immunity is very narrow in the haploidentical transplant setting. Hence, strategies to improve the safety and efficacy of adoptive T cell transfer are particularly relevant in this setting. Adoptive T cell transfer strategies in haploidentical transplantation include the use of antigen-specific T cells, allodepletion and alloanergy induction, immune modulation by the co-infusion of regulatory cell populations, and the use of safety switch gene-modified T cells. Whilst common principles apply, there are features that are unique to haploidentical transplantation, where HLA-mismatching directly impacts on immune reconstitution, and shared vs. non-shared HLA-allele can be an important consideration in antigen-specific T cell therapy. This review will also present an update on safety switch gene-modified T cells, which can be conditionally deleted in the event of severe graft- vs.-host disease or other adverse events. Herpes Virus Simplex Thymidine Kinase (HSVtk) and inducible caspase-9 (iCasp9) are safety switches that have undergone multicenter studies in haploidentical transplantation with encouraging results. These gene-modified cells, which are trackable long-term, have also provided important insights on the fate of adoptively transferred T cells. In this review, we will discuss the biology of post-transplant T cell immune reconstitution and the impact of HLA-mismatching, and the different cellular therapy strategies that can help accelerate T cell immune reconstitution after haploidentical transplantation.
| S-EPMC6691120 | biostudies-literature
Project description:ObjectivesIn recent years, policies have been proposed in order to guide the safer use of non-steroidal anti-inflammatory drugs (NSAIDs) and antiulcer therapy. We aimed to investigate the incidence of upper gastrointestinal bleeding (UGIB) before and after the introduction of these policies, 2007-2009, in a well-defined population in southwest Scotland.MethodsAll patients with non-variceal upper gastrointestinal bleeding (NV-UGIB), diagnosed at a single regional unit, were included. Total drugs prescribed in our population were noted, including antiulcer drugs, antithrombotic drugs and both cyclo-oxygenase-2 enzyme-selective and non-selective inhibiting NSAIDs.ResultsThe incidence, the number of cases per 100 000 population per annum, of NV-UGIB fell from 134.7 in 2007 to 125.1 in 2008, and to 90.3 cases in 2009 (p<0.001). There was also a significant rise in the use of non-selective NSAIDs, proton pump inhibitors and antithrombotic drugs.ConclusionsAlthough a cause-and-effect relationship cannot be fully proven, physician education through drug-use policies is associated with a drop in the incidence of NV-UGIB. This is relevant to the prevention of this common condition.
| S-EPMC5369816 | biostudies-literature
Project description:Improving survival rates in children with malignancy have been achieved at the cost of a high frequency of late adverse effects of treatment, especially in intensively treated patients such as those undergoing haematopoietic stem cell transplantation (HSCT), many of whom suffer the high burden of chronic toxicity. Secondary malignant neoplasms (SMNs) are one of the most devastating late effects, cause much morbidity and are the most frequent cause of late (yet still premature) treatment-related mortality. They occur in up to 7% of HSCT recipients by 20 years post-HSCT, and with no evidence yet of a plateau in incidence with longer follow-up. This review describes the epidemiology, pathogenesis, clinical features and risk factors of the three main categories of post-HSCT SMNs. A wide range of solid SMNs has been described, usually occurring 10 years or more post-HSCT, related most often to previous or conditioning radiotherapy. Therapy-related acute myeloid leukaemia/myelodysplasia occurs earlier, typically three to seven years post-HSCT, mainly in recipients of autologous transplant and is related to previous alkylating agent or topoisomerase II inhibitor chemotherapy. Post-transplant lymphoproliferative disorders occur early (usually within two years) post-HSCT, usually presenting as Epstein-Barr virus-related B cell non-Hodgkin lymphoma.
| S-EPMC4928755 | biostudies-other
Project description:AimsOf all spontaneous bleeding complications in patients with acute myocardial infarction (MI), upper gastrointestinal bleeding (UGIB) is common and of specific interest since it could be prevented by several prophylactic measures. We aimed to determine the incidence, associated outcomes, and predictors of UGIB following acute MI.Methods and resultsAll patients with acute MI enrolled in the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) registry from January 2007 to June 2016 and discharged alive on any antithrombotic therapy (n = 149 477) were followed regarding UGIB for 1 year. Associated outcomes were determined by Cox proportional hazards regression with UGIB as a time-dependent covariate, adjusting for baseline characteristics, invasive treatment, and medical treatment at discharge. Predictors of UGIB were determined by logistic regression and machine learning models.At 1 year, UGIB had occurred in 2230 patients (cumulative incidence 1.5%) and was significantly associated with an increased risk of all-cause death [hazard ratio (HR) 2.86, 95% confidence interval (CI) 2.58-3.16] and stroke (HR 1.80, 95% CI 1.32-2.45) but not with recurrent MI (HR 1.17, 95% CI 0.97-1.42). The most important predictors of UGIB were haemoglobin, age, systolic blood pressure, blood glucose, smoking status, previous upper gastrointestinal bleeding, and antithrombotic and gastroprotective treatment.ConclusionAfter acute MI, readmission because of UGIB is common and significantly associated with poor prognosis. By using machine learning in addition to traditional logistic regression, new predictors of UGIB, such as blood glucose and smoking status, were identified.
| S-EPMC9366628 | biostudies-literature
Project description:A cure for HIV-1 remains unattainable as only one case has been reported, a decade ago1,2. The individual-who is known as the 'Berlin patient'-underwent two allogeneic haematopoietic stem-cell transplantation (HSCT) procedures using a donor with a homozygous mutation in the HIV coreceptor CCR5 (CCR5?32/?32) to treat his acute myeloid leukaemia. Total body irradiation was given with each HSCT. Notably, it is unclear which treatment or patient parameters contributed to this case of long-term HIV remission. Here we show that HIV-1 remission may be possible with a less aggressive and toxic approach. An adult infected with HIV-1 underwent allogeneic HSCT for Hodgkin's lymphoma using cells from a CCR5?32/?32 donor. He experienced mild gut graft-versus-host disease. Antiretroviral therapy was interrupted 16 months after transplantation. HIV-1 remission has been maintained over a further 18 months. Plasma HIV-1 RNA has been undetectable at less than one copy per millilitre along with undetectable HIV-1 DNA in peripheral CD4 T lymphocytes. Quantitative viral outgrowth assays from peripheral CD4 T lymphocytes show no reactivatable virus using a total of 24 million resting CD4 T cells. CCR5-tropic, but not CXCR4-tropic, viruses were identified in HIV-1 DNA from CD4 T cells of the patient before the transplant. CD4 T cells isolated from peripheral blood after transplantation did not express CCR5 and were susceptible only to CXCR4-tropic virus ex vivo. HIV-1 Gag-specific CD4 and CD8 T cell responses were lost after transplantation, whereas cytomegalovirus-specific responses were detectable. Similarly, HIV-1-specific antibodies and avidities fell to levels comparable to those in the Berlin patient following transplantation. Although at 18 months after the interruption of treatment it is premature to conclude that this patient has been cured, these data suggest that a single allogeneic HSCT with homozygous CCR5?32 donor cells may be sufficient to achieve HIV-1 remission with reduced intensity conditioning and no irradiation, and the findings provide further support for the development of HIV-1 remission strategies based on preventing CCR5 expression.
| S-EPMC7275870 | biostudies-literature
Project description:Use of haematopoietic cell transplantation (HCT) in the treatment of haematologic and neoplastic diseases may lead to life-threatening complications that cause substantial morbidity and mortality if untreated. In addition to patient- and disease-related factors, toxicity associated with HCT puts patients at risk for complications that share a similar pathophysiology involving endothelial cells (ECs). Normally, the endothelium plays a role in maintaining homeostasis, including regulation of coagulation, vascular tone, permeability and inflammatory processes. When activated, ECs acquire cellular features that may lead to phenotypic changes that induce procoagulant, pro-inflammatory and pro-apoptotic mediators leading to EC dysfunction and damage. Elevated levels of coagulation factors, cytokines and adhesion molecules are indicative of endothelial dysfunction, and endothelial damage may lead to clinical signs and symptoms of pathological post-HCT conditions, including veno-occlusive disease/sinusoidal obstruction syndrome, graft-versus-host disease, transplant-associated thrombotic microangiopathy and idiopathic pneumonia syndrome/diffuse alveolar haemorrhage. The endothelium represents a rational target for preventing and treating HCT complications arising from EC dysfunction and damage. Additionally, markers of endothelial damage may be useful in improving diagnosis of HCT-related complications and monitoring treatment effect. Continued research to effectively manage EC activation, injury and dysfunction may be important in improving patient outcomes after HCT.
| S-EPMC7496350 | biostudies-literature