Allo-HSCT in transplant-naive patients with Hodgkin lymphoma: a single-arm, multicenter study

We evaluated the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in transplant-naïve patients with relapsed/refractory Hodgkin lymphoma (HL) who failed to attain metabolic complete response (mCR) to 1 to 2 lines of salvage chemotherapyThose with residual but nonprogressive disease assessed by positron emission tomography/computed tomography scanning were eligible. An additional 1 to 2 cycles of salvage therapy were permissible in those with progressive disease or when required to bridge to allo-HSCT, with additional imaging at baseline before transplantation. Conditioning consisted of carmustine, etoposide, cytarabine, melphalan, and alemtuzumab. Donor lymphocyte infusions (DLI) were administered for mixed chimerism or residual or relapsed disease. Eleven patients had sibling donors, 13 had HLA-matched unrelated donors, and 7 had HLA-mismatched unrelated donors. There were no graft failures, and no episodes of grade 4 acute graft-versus-host disease (GVHD); only 19.4% of patients had grade 2 to 3 GVHD, and 22.2% had extensive chronic GVHD. The non-relapse mortality rate was 16.1% (95% confidence interval [CI], 7.1%-34.5%). Relapse incidence was 18.7% (95% CI, 8.2%-39.2%). The study met its primary objective, with a 3-year progression-free survival of 67.7% (95% CI, 48.4%-81.2%). Survival outcomes were equivalent in those with residual metabolically active disease immediately before transplantation (n = 24 [70.8%; 95% CI, 17.2%-83.7%]). Two of the 5 patients who relapsed received DLI and remained in mCR at latest follow-up, with a 3-year overall survival of 80.7% (95% CI, 61.9%-90.8%). We demonstrate encouraging results that establish a potential role for allo-HSCT in selected high-risk patients with HL. This trial was registered at www.clinicaltrials.gov as #NCT00908180

Self-Reported Physical Activity: Its Correlates and Relationship with Health-Related Quality of Life in a Large Cohort of Colorectal Cancer Survivors

Background: Physical activity (PA) is suggested to be an important non-pharmacologic means to improve health-related outcomes among cancer survivors. We aimed to describe the PA level, its correlates, and association with health-related quality of life (HRQoL) in colorectal cancer (CRC) survivors. Methods: CRC survivors identified from the Eindhoven Cancer Registry treated between 1998 and 2007 were included. Survivors completed validated questionnaires on PA, distress, fatigue, and HRQoL. Moderate-to-vigorous physical activity (MVPA) levels were calculated by summing the time spent on walking, bicycling, gardening and sports ($3 MET). Multiple linear regression analyses were conducted to study which socio-demographic and clinical factors were associated with MVPA. Furthermore, we examined associations between MVPA and physical and mental HRQoL, and whether these associations were mediated by fatigue and distress. Results: Cross-sectional data of 1371 survivors (response: 82%) were analysed. Participants were 69.5 (SD 9.7) years old, 56% were male, and survival duration was 3.9 (SD 2.5) years. Participants self-reported on average 95.5 (SD 80.3) min on MVPA per day. Younger age, male sex, being employed, non-smoking, lower BMI, colon cancer (vs. rectal cancer), chemotherapy treatment and having no co-morbidities were associated with higher MVPA (p,0.05). MVPA was positively associated with physical HRQoL (regression coefficient of total association (c) = 0.030; se = 0.004) after adjusting for socio-demographic an

A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell

Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, and therapy response in graft recipients are insufficient. Here, we investigated whether epigenetic marks measured in peripheral blood of healthy graft donors stratify aGVHD severity in human leukocyte antigen (HLA)-matched sibling recipients prior to T cell-depleted HSCT. Methods We measured DNA methylation levels genome-wide at single-nucleotide resolution in peripheral blood of 85 HSCT donors, matched to recipients with various transplant outcomes, with Illumina Infinium HumanMethylation450 BeadChips. Results Using genome-wide DNA methylation profiling, we showed that epigenetic signatures underlying aGVHD severity in recipients correspond to immune pathways relevant to aGVHD etiology. We discovered 31 DNA methylation marks in donors that associated with aGVHD severity status in recipients, and demonstrated strong predictive performance of these markers in internal cross-validation experiments (AUC = 0.98, 95 % CI = 0.96–0.99). We replicated the top-ranked CpG classifier using an alternative, clinical DNA methylation assay (P = 0.039). In an independent cohort of 32 HSCT donors, we demonstrated the utility of the epigenetic classifier in the context of a T cell-replete conditioning regimen (P = 0.050). Conclusions Our findings suggest that epigenetic typing of HSCT donors in a clinical setting may be used in conjunction with HLA genotyping to inform both donor selection and transplantation strategy, with the ultimate aim of improving patient outcome

Predictors of recovery following allogeneic CD34+-selected cell infusion without conditioning to correct poor graft function

Poor graft function is a serious complication following allogeneic hematopoietic stem cell transplantation. Infusion of CD34+-selected stem cells without pre-conditioning has been used to correct poor graft function, but predictors of recovery are unclear. We report the outcome of 62 consecutive patients who had primary or secondary poor graft function who underwent a CD34+-selected stem cell infusion from the same donor without further conditioning. Forty-seven of 62 patients showed hematological improvement and became permanently transfusion and growth factor-independent. In multivariate analysis, parameters significantly associated with recovery were shared CMV seronegative status for recipient/donor, the absence of active infection and matched recipient/donor sex. Recovery was similar in patients with mixed and full donor chimerism. Five -year overall survival was 74.4% (95% CI 59-89) in patients demonstrating complete recovery, 16.7% (95% CI 3-46) in patients with partial recovery and 22.2% (CI 95% 5-47) in patients with no response. In patients with count recovery, those with poor graft function in 1-2 lineages had superior 5-year overall survival (93.8%, 95% CI 82-99) than those with tri-lineage failure (53%, 95% CI 34-88). New strategies including cytokine or agonist support, or second transplant need to be investigated in patients who do not recover

Improved intensive care unit survival for critically ill allogeneic haematopoietic stem cell transplant recipients following reduced intensity conditioning.

The use of allogeneic haematopoietic stem cell transplantation (Allo-HSCT) is a standard treatment option for many patients with haematological malignancies. Historically, patients requiring intensive care unit (ICU) admission for transplant-related toxicities have fared extremely poorly, with high ICU mortality rates. Little is known about the impact of reduced intensity Allo-HSCT conditioning regimens in older patients on the ICU and subsequent long-term outcomes. A retrospective analysis of data collected from 164 consecutive Allo-HSCT recipients admitted to ICU for a total of 213 admissions, at a single centre over an 11·5-year study period was performed. Follow-up was recorded until 31 March 2011. Autologous HSCT recipients were excluded. In this study we report favourable ICU survival following Allo-HSCT and, for the first time, demonstrate significantly better survival for patients who underwent Allo-HSCT with reduced intensity conditioning compared to those treated with myeloablative conditioning regimens. In addition, we identified the need for ventilation (invasive or non-invasive) as an independently significant adverse factor affecting short-term ICU outcome. For patients surviving ICU admission, subsequent long-term overall survival was excellent; 61% and 51% at 1 and 5 years, respectively. Reduced intensity Allo-HSCT patients admitted to ICU with critical illness have improved survival compared to myeloablative Allo-HSCT recipients

The IGNITE (investigation to guide new insight into translational effectiveness) trial: Protocol for a translational study of an evidenced-based wellness program in fire departments

<p>Abstract</p> <p>Background</p> <p>Worksites are important locations for interventions to promote health. However, occupational programs with documented efficacy often are not used, and those being implemented have not been studied. The research in this report was funded through the American Reinvestment and Recovery Act Challenge Topic 'Pathways for Translational Research,' to define and prioritize determinants that enable and hinder translation of evidenced-based health interventions in well-defined settings.</p> <p>Methods</p> <p>The IGNITE (investigation to guide new insights for translational effectiveness) trial is a prospective cohort study of a worksite wellness and injury reduction program from adoption to final outcomes among 12 fire departments. It will employ a mixed methods strategy to define a translational model. We will assess decision to adopt, installation, use, and outcomes (reach, individual outcomes, and economic effects) using onsite measurements, surveys, focus groups, and key informant interviews. Quantitative data will be used to define the model and conduct mediation analysis of each translational phase. Qualitative data will expand on, challenge, and confirm survey findings and allow a more thorough understanding and convergent validity by overcoming biases in qualitative and quantitative methods used alone.</p> <p>Discussion</p> <p>Findings will inform worksite wellness in fire departments. The resultant prioritized influences and model of effective translation can be validated and manipulated in these and other settings to more efficiently move science to service.</p

Heteroskedasticity testing through a comparison of Wald statistics

This paper shows that a test for heteroskedasticity within the context of classical linear regression can be based on the difference between Wald statistics in heteroskedasticity-robust and nonrobust forms. The test is asymptotically distributed under the null hypothesis of homoskedasticity as chi-squared with one degree of freedom. The power of the test is sensitive to the choice of parametric restriction used by the Wald statistics, so the supremum of a range of individual test statistics is proposed. Two versions of a supremum-based test are considered: the first version does not have a known asymptotic null distribution, so the bootstrap is employed to approximate its empirical distribution. The second version has a known asymptotic distribution and, in some cases, is asymptotically pivotal under the null. A simulation study illustrates the use and finite-sample performance of both versions of the test. In this study, the bootstrap is found to provide better size control than asymptotic critical values, namely with heavy-tailed, asymmetric distributions of the covariates. In addition, the use of well-known modifications of the heteroskedasticity consistent covariance matrix estimator of OLS coefficients is also found to benefit the tests’ overall behaviour.info:eu-repo/semantics/publishedVersio