OC-0052: Late toxicity in the randomized phase III Dutch Hypofractionation Trial for prostate cancer patients (HYPRO)

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Peptide exchange on MHC-I by TAPBPR is driven by a negative allostery release cycle.

Chaperones TAPBPR and tapasin associate with class I major histocompatibility complexes (MHC-I) to promote optimization (editing) of peptide cargo. Here, we use solution NMR to investigate the mechanism of peptide exchange. We identify TAPBPR-induced conformational changes on conserved MHC-I molecular surfaces, consistent with our independently determined X-ray structure of the complex. Dynamics present in the empty MHC-I are stabilized by TAPBPR and become progressively dampened with increasing peptide occupancy. Incoming peptides are recognized according to the global stability of the final pMHC-I product and anneal in a native-like conformation to be edited by TAPBPR. Our results demonstrate an inverse relationship between MHC-I peptide occupancy and TAPBPR binding affinity, wherein the lifetime and structural features of transiently bound peptides control the regulation of a conformational switch located near the TAPBPR binding site, which triggers TAPBPR release. These results suggest a similar mechanism for the function of tapasin in the peptide-loading complex

The Amazon Epiphyte Network: A First Glimpse Into Continental-Scale Patterns of Amazonian Vascular Epiphyte Assemblages

Epiphytes are still an understudied plant group in Amazonia. The aim of this study was to identify distributional patterns and conservation priorities for vascular epiphyte assemblages (VEA) across Amazonia. We compiled the largest Amazonian epiphyte plot database to date, through a multinational collaborative effort of 22 researchers and 32 field sites located across four Amazonian countries – the Amazonian Epiphyte Network (AEN). We addressed the following continental-scale questions by utilizing the AEN database comprising 96,448 epiphyte individuals, belonging to 518 vascular taxa, and growing on 10,907 tree individuals (phorophytes). Our objectives here are, first, to present a qualitative evaluation of the geographic distribution of the study sites and highlight regional lacunae as priorities for future quantitative inventories. Second, to present the floristic patterns for Amazonia-wide VEA and third, to combine multivariate analyses and rank abundance curves, controlled by major Amazonian habitat types, to determine how VEA vary geographically and ecologically based on major Amazonian habitat types. Three of the most striking patterns found are that: (1) VEA are spatially structured as floristic similarity decays with geographic distance; (2) a core group of 22 oligarchic taxa account for more than a half of all individuals; and (3) extensive floristic sampling gaps still exist, mainly across the highly threatened southern Amazonian deforestation belt. This work represents a first step toward unveiling distributional pattern of Amazonian VEA, which is important to guide future questions on ecology and species distribution ranges of VEA once the collaborative database grows allowing a clearer view of patterns

Permissivity of the NCI-60 cancer cell lines to oncolytic Vaccinia Virus GLV-1h68

<p>Abstract</p> <p>Background</p> <p>Oncolytic viral therapy represents an alternative therapeutic strategy for the treatment of cancer. We previously described GLV-1h68, a modified Vaccinia Virus with exclusive tropism for tumor cells, and we observed a cell line-specific relationship between the ability of GLV-1h68 to replicate in vitro and its ability to colonize and eliminate tumor in vivo.</p> <p>Methods</p> <p>In the current study we surveyed the in vitro permissivity to GLV-1h68 replication of the NCI-60 panel of cell lines. Selected cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain. In order to identify correlates of permissity to viral infection, we measured transcriptional profiles of the cell lines prior infection.</p> <p>Results</p> <p>We observed highly heterogeneous permissivity to VACV infection amongst the cell lines. The heterogeneity of permissivity was independent of tissue with the exception of B cell derivation. Cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain and a significant correlation was found suggesting a common permissive phenotype. While no clear transcriptional pattern could be identified as predictor of permissivity to infection, some associations were observed suggesting multifactorial basis permissivity to viral infection.</p> <p>Conclusions</p> <p>Our findings have implications for the design of oncolytic therapies for cancer and offer insights into the nature of permissivity of tumor cells to viral infection.</p

Local Failure Events in Prostate Cancer Treated with Radiotherapy: A Pooled Analysis of 18 Randomized Trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN).

CONTEXT: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear. OBJECTIVE: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT. EVIDENCE ACQUISITION: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states. EVIDENCE SYNTHESIS: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06-1.30), PCSS (HR 2.02, 95% CI 1.75-2.33), and DMFS (HR 1.94, 95% CI 1.75-2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36-1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21-0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups. CONCLUSIONS: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a "second wave" of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis. PATIENT SUMMARY: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.</p

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events