PD-0498: Use of STAT in prostate cancer: correlation with risk factors and identification of residual cohort

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Transcaval versus Supra-Aortic Vascular Accesses for Transcatheter Aortic Valve Replacement: A Systematic Review with Meta-Analysis.

A growing body of evidence suggests that extrathoracic vascular accesses for transcatheter aortic valve replacement (TAVR) yield favorable outcomes and can be considered as primary alternatives when the gold-standard transfemoral access is contraindicated. Data comparing the transcaval (TCv) to supra-aortic (SAo) approaches (transcarotid, transsubclavian, and transaxillary) for TAVR are lacking. We aimed to compare the outcomes and safety of TCv and SAo accesses for TAVR as alternatives to transfemoral TAVR. A systematic review with meta-analysis was performed by searching PubMed/MEDLINE and EMBASE databases for all articles comparing TCv-TAVR against SAo-TAVR published until September 2023. Outcomes included in-hospital or 30-day all-cause mortality (ACM) and postoperative complications. A total of three studies with 318 TCv-TAVR and 179 SAo-TAVR patients were included. No statistically significant difference was found regarding in-hospital or 30-day ACM (relative risk [RR] 1.04, 95% confidence interval [CI] 0.47-2.34, p = 0.91), major bleeding, the need for blood transfusions, major vascular complications, and acute kidney injury. TCv-TAVR was associated with a non-statistically significant lower rate of neurovascular complications (RR 0.39, 95%CI 0.14-1.09, p = 0.07). These results suggest that both approaches may be considered as first-line alternatives to transfemoral TAVR, depending on local expertise and patients' anatomy. Additional data from long-term cohort studies are needed

Has the profile of heart transplantation recipients changed within the last three decades?

Heart transplantation remains the most durable treatment for patients with end-stage heart failure refractory to medical treatment. Central elements of the listing criteria for heart transplantation have remained largely unchanged in the last three decades whereas treatment of heart failure has significantly increased survival and reduced disease-related symptoms. It remains unknown whether the improvement of heart failure therapy changed the profile of heart transplantation candidates or affected post-transplant survival. The study investigated a total of 323 heart transplant recipients of the Lausanne University Hospital with 328 transplant operations between 1987 and 2018. Patients were separated into three groups on the basis of availability of heart failure therapy: period 1 (1987-1998; n = 115) when renin-angiotensin system blockade and diuretic treatment were available; period 2 (1999-2010; n = 106) marked by the addition of beta-blocker and mineralocorticoid receptor antagonist treatment in severe heart failure, and the establishment of cardiac defibrillator and resynchronisation therapy; period 3 (2011-2018; n = 107) characterised by the increasing use of ventricular assist devices for bridge to transplantation. The patient characteristics age (all: 53.4 years), male sex (all: 79%) and body mass index (all: 24.5 kg/m2) did not differ between periods. History of arterial hypertension was less prevalent in period 2 (period 1 vs 2 vs 3: 44 vs 28 vs 43%, p = 0.04) whereas other cardiovascular risk factors were equally distributed. Left ventricular ejection fraction, VO2max, and pulmonary vascular resistance were not different between the three periods. The prevalence of ischaemic cardiomyopathy was higher in periods 1 and 3; dilated non-ischaemic cardiomyopathy was more frequent in period 2. Post-transplant 1-year survival was highest in period 3 (1 vs 2 vs 3: 87.2 ± 3.2% vs 70.8 ± 4.4% vs 93.0 ± 2.6%, p always ≤0.02), and the Kaplan-Meier estimates of survivors of the first year post-transplant were not different between the three periods. In descriptive analysis, early mortality was not associated with acknowledged pretransplant predictors of post-transplant mortality. Availability of different medical heart failure treatments did not result in greatly different pretransplant characteristics of heart transplantation recipients across the three periods. This suggests that the maintained central criteria of listing for heart transplantation still identify end-stage heart failure patients with a similar profile. This finding can explain the unchanged overall mortality on condition of 1-year survival across the three periods, since pretransplant characteristics are relevant for long-term survival after heart transplantation

Comparison of HTK-Custodiol and St-Thomas solution as cardiac preservation solutions on early and midterm outcomes following heart transplantation.

The choice of the cardiac preservation solution for myocardial protection at time of heart procurement remains controversial and uncertainties persist regarding its effect on the early and midterm heart transplantation (HTx) outcomes. We retrospectively compared our adult HTx performed with 2 different solutions, in terms of hospital mortality, mid-term survival, inotropic score, primary graft dysfunction and rejection score. From January 2009 to December 2020, 154 consecutive HTx of adult patients, followed up in pre- and post-transplantation by 2 different tertiary centres, were performed at the University Hospital of Lausanne, Switzerland. From 2009 to 2015, the cardiac preservation solution used was exclusively St-Thomas, whereafter an institutional decision was made to use HTK-Custodiol only. Patients were classified in 2 groups accordingly. There were 75 patients in the St-Thomas group and 79 patients in the HTK-Custodiol group. The 2 groups were comparable in terms of preoperative and intraoperative characteristics. Postoperatively, compared to the St-Thomas group, the Custodiol group patients showed significantly lower inotropic scores [median (interquartile range): 35.7 (17.5-60.2) vs 71.8 (31.8-127), P < 0.001], rejection scores [0.08 (0.0-0.25) vs 0.14 (0.05-0.5), P = 0.036] and 30-day mortality rate (2.5% vs 14.7%, P = 0.007) even after adjusting for potential confounders. Microscopic analysis of the endomyocardial biopsies also showed less specific histological features of subendothelial ischaemia (3.8% vs 17.3%, P = 0.006). There was no difference in primary graft dysfunction requiring postoperative extracorporeal membrane oxygenation. The use of HTK-Custodiol solution significantly improved midterm survival (Custodiol versus St-Thomas: hazard ratio = 0.20, 95% confidence interval: 0.069-0.60, P = 0.004). This retrospective study comparing St-Thomas solution and HTK-Custodiol as myocardial protection during heart procurement showed that Custodiol improves outcomes after HTx, including postoperative inotropic score, rejection score, 30-day mortality and midterm survival

Imatinib mesylate in the treatment of newly diagnosed or refractory/resistant c-KIT positive acute myeloid leukemia. Results of an Italian Multicentric Phase II Study

We evaluated safety and efficacy of imatinib (600 mg) in 36 c-KIT+ acute myeloid leukemia patients not amenable to receive conventional chemotherapy. No patient achieved complete remission. One patient obtained a hematologic improvement (platelet increase with transfusion independence). Median overall survival was 3 months (0.5-44+). Non-hematologic toxicity was overall mild

Imatinib mesylate in the treatment of newly diagnosed or refractory/resistant c-KIT positive acute myeloid leukemia. Results of an Italian Multicentric Phase II Study

We evaluated safety and efficacy of imatinib (600 mg) in 36 c-KIT+ acute myeloid leukemia patients not amenable to receive conventional chemotherapy. No patient achieved complete remission. One patient obtained a hematologic improvement (platelet increase with transfusion independence). Median overall survival was 3 months (0.5-44+). Non-hematologic toxicity was overall mild

MiR-205 enhances radiation sensitivity of prostate cancer cells by impairing DNA damage repair through PKCϵ and ZEB1 inhibition

Background: Radiotherapy is one of the main treatment options for non-metastatic prostate cancer (PCa). Although treatment technical optimization has greatly improved local tumor control, a considerable fraction of patients still experience relapse due to the development of resistance. Radioresistance is a complex and still poorly understood phenomenon involving the deregulation of a variety of signaling pathways as a consequence of several genetic and epigenetic abnormalities. In this context, cumulative evidence supports a functional role of microRNAs in affecting radioresistance, suggesting the modulation of their expression as a novel radiosensitizing approach. Here, we investigated for the first time the ability of miR-205 to enhance the radiation response of PCa models. Methods: miR-205 reconstitution by a miRNA mimic in PCa cell lines (DU145 and PC-3) was used to elucidate miR-205 biological role. Radiation response in miRNA-reconstituted and control cells was assessed by clonogenic assay, immunofluorescence-based detection of nuclear \u3b3-H2AX foci and comet assay. RNAi was used to silence the miRNA targets PKC\u3f5 or ZEB1. In addition, target-protection experiments were carried out using a custom oligonucleotide designed to physically disrupt the pairing between the miR-205 and PKC\u3f5. For in vivo experiments, xenografts generated in SCID mice by implanting DU145 cells stably expressing miR-205 were exposed to 5-Gy single dose irradiation using an image-guided animal micro-irradiator. Results: miR-205 reconstitution was able to significantly enhance the radiation response of prostate cancer cell lines and xenografts through the impairment of radiation-induced DNA damage repair, as a consequence of PKC\u3f5 and ZEB1 inhibition. Indeed, phenocopy experiments based on knock-down of either PKC\u3f5 or ZEB1 reproduced miR-205 radiosensitizing effect, hence confirming a functional role of both targets in the process. At the molecular level, miR-205-induced suppression of PKC\u3f5 counteracted radioresistance through the impairment of EGFR nuclear translocation and the consequent DNA-PK activation. Consistently, disruption of miR-205-PKC\u3f5 3'UTR pairing almost completely abrogated the radiosensitizing effect. Conclusions: Our results uncovered the molecular and cellular mechanisms underlying the radiosensitizing effect of miR-205. These findings support the clinical interest in developing a novel therapeutic approach based on miR-205 reconstitution to increase PCa response to radiotherapy

Core Biopsies from Prostate Cancer Patients in Active Surveillance Protocols Harbor PTEN and MYC Alterations

Background: Genomic characterization of prostate cancer (PCa) biopsies may improve criteria for the selection of patients suitable for active surveillance (AS). Objective: To identify somatic genomic aberrations associated with adverse outcome as AS protocol exclusion indicators. Design, setting and participants: Whole-exome sequencing profiles were generated for Gleason score (GS) = 3 + 3 biopsies obtained from 54 PCa patients enrolled in two AS protocols. Patients were selected as representative of a nonindolent population, consisting of 27 patients who dropped out from AS due to upgrading (ie, finding of GS > 3 + 3 at a follow-up biopsy) within 2 yr, and a potentially indolent population, consisting of 27 patients in AS for 654 yr without any evidence of reclassification. Outcome measurements and statistical analysis: The genomic alteration landscape of core biopsies was analyzed using an integrated computational pipeline and correlated with patient reclassification due to upgrading. Results and limitations: Of all the GS = 3 + 3 biopsies of the study cohort, 34% showed clear evidence of somatic copy number aberrations along the genome. Of these, 39% came from the potentially indolent and 61% from the nonindolent population. Single-nucleotide variants demonstrated low allelic fractions and included a common F133C mutation in the SPOP gene. The minimally altered genomic landscape of the study cohort presented a distinct set of monoallelic deletions, including on 8p, 13q, 16q, and 21q, and rare amplifications of 8q, which were observed in both AS patient populations. Concerning lesions typically associated with adverse outcome, PTEN deletions and MYC amplification, though observed in a small number of cases, were detected exclusively or preferentially, respectively, in nonindolent patients. Such molecular findings were confirmed by immunohistochemistry on the same tissue blocks. The small sample size and the retrospective nature of the analysis represent the main study limitations. Conclusions: Genomic features enriched in aggressive tumors can be detected in GS = 3 + 3 core biopsies of AS patients. Patient summary: PTEN and MYC alterations at the time of diagnosis would deserve investigation in larger cohorts of AS patients to assess their potential as biomarkers for a more precise/earlier identification of patients at risk of reclassification. The presence of adverse outcome-related genomic lesions, such as PTEN deletion and MYC amplification, in GPS = 3 + 3 diagnostic core biopsies of prostate cancer patients could be considered for a more precise/earlier selection of patients not suitable for active surveillance

Space Applications of the FLUKA Monte-Carlo Code: Lunar and Planetary Exploration

NASA has recognized the need for making additional heavy-ion collision measurements at the U.S. Brookhaven National Laboratory in order to support further improvement of several particle physics transport-code models for space exploration applications. FLUKA has been identified as one of these codes and we will review the nature and status of this investigation as it relates to high-energy heavy-ion physics