TALAPRO-3 clinical trial protocol: phase III study of talazoparib plus enzalutamide in metastatic castration-sensitive prostate cancer

PARP inhibitor; Androgen receptor; EnzalutamideInhibidor de PARP; Receptor de andrógenos; EnzalutamidaInhibidor de PARP; Receptor d'andrògens; EnzalutamidaPoly(ADP-ribose) polymerase inhibitors in combination with androgen-receptor signaling inhibitors are a promising therapeutic option for patients with metastatic castration-sensitive prostate cancer (mCSPC) and homologous recombination repair (HRR) gene alterations. Here, we describe the design and rationale of the multinational, phase III, TALAPRO-3 study comparing talazoparib plus enzalutamide versus placebo plus enzalutamide in patients with mCSPC and HRR gene alterations. The primary end point is investigator-assessed radiographic progression-free survival (rPFS) per RECIST 1.1 in soft tissue, or per PCWG3 criteria in bone. The TALAPRO-3 study will demonstrate whether the addition of talazoparib can improve the efficacy of enzalutamide as assessed by rPFS in patients with mCSPC and HRR gene alterations undergoing androgen deprivation therapy. Clinical Trial Registration:NCT04821622 (ClinicalTrials.gov) Registry Name: Study of Talazoparib With Enzalutamide in Men With DDR Gene Mutated mCSPC. Date of Registration: 29 March 2021.This study was sponsored by Pfizer. Astellas Pharma Inc. provided enzalutamide

Biophysical neural adaptation mechanisms enable artificial neural networks to capture dynamic retinal computation

Adaptation is a universal aspect of neural systems that changes circuit computations to match prevailing inputs. These changes facilitate efficient encoding of sensory inputs while avoiding saturation. Conventional artificial neural networks (ANNs) have limited adaptive capabilities, hindering their ability to reliably predict neural output under dynamic input conditions. Can embedding neural adaptive mechanisms in ANNs improve their performance? To answer this question, we develop a new deep learning model of the retina that incorporates the biophysics of photoreceptor adaptation at the front-end of conventional convolutional neural networks (CNNs). These conventional CNNs build on 'Deep Retina,' a previously developed model of retinal ganglion cell (RGC) activity. CNNs that include this new photoreceptor layer outperform conventional CNN models at predicting male and female primate and rat RGC responses to naturalistic stimuli that include dynamic local intensity changes and large changes in the ambient illumination. These improved predictions result directly from adaptation within the phototransduction cascade. This research underscores the potential of embedding models of neural adaptation in ANNs and using them to determine how neural circuits manage the complexities of encoding natural inputs that are dynamic and span a large range of light levels

Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial

Olaparib; Castration-resistant prostate cancerOlaparib; Cáncer de próstata resistente a la castraciónOlaparib; Càncer de pròstata resistent a la castracióPurpose Phase III PROfound trial (ClinicalTrials.gov identifier: NCT02987543) met its primary and key secondary objectives, demonstrating significantly longer radiographic progression-free survival (rPFS) and overall survival (OS) with olaparib monotherapy versus abiraterone or enzalutamide (control) in patients with metastatic castration-resistant prostate cancer (mCRPC) with alterations in BRCA1, BRCA2 (BRCA), and/or ATM (cohort A) whose disease had progressed on prior next-generation hormonal agent (NHA). We report exploratory post hoc analysis of the subgroup of patients with mCRPC with BRCA alterations in PROfound. Methods All patients had an alteration in a homologous recombination repair gene by tumor tissue testing, of which 160 had underlying BRCA alterations. rPFS and OS were estimated using the Kaplan-Meier method. Confirmed objective response rate and safety were also assessed. Results Olaparib was associated with longer rPFS (hazard ratio [HR], 0.22 [95% CI, 0.15 to 0.32]) and OS (HR, 0.63 [95% CI, 0.42 to 0.95]) than control. There was an rPFS benefit with olaparib in all zygosity subgroups (biallelic [n = 88]; HR, 0.08 [95% CI, 0.04 to 0.16], heterozygous [n = 15] and unknown [n = 57]; HR, 0.30 [95% CI, 0.16 to 0.60]). Patients with BRCA2 homozygous deletions experienced prolonged responses to olaparib (n = 16; median rPFS, 16.6 months [95% CI, 9.3 to not reached]). Some evaluations are limited by small patient numbers. Germline DNA analysis was performed for 112 (70%) patients; risk of disease progression was similar for patients with germline (n = 61; HR, 0.08 [95% CI, 0.03 to 0.18]) and somatic (n = 51; HR, 0.16 [95% CI, 0.07 to 0.37]) BRCA alterations. Conclusion In all subgroups assessed, olaparib improved outcomes versus abiraterone or enzalutamide for patients with mCRPC with BRCA alterations whose disease had progressed on previous NHA.Supported by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ

Influence of pH on the Cytotoxic Activity of Inositol Hexakisphosphate (IP6) in Prostate Cancer

Objectives: In the present study, we investigated whether the pH of IP6 could influence its anti-tumoral activity in vitro. Methods: PC-3 cells were exposed to IP6 at pH 5, pH 7, and pH 12 and we evaluated the metabolic activity (WST-1 assay), cell proliferation (cell count), cell cycle distribution (FACS), and mitochondrial depolarization (JC-1 staining) in vitro. Results: Our results demonstrated that IP6 at pH 5 and pH 12 were more potent at lowering the metabolic activity of PC-3 cells than IP6 at pH 7. Treatment with IP6 at pH 12 also caused the greatest inhibition in cellular proliferation and accumulation of PC-3 cells in sub-G1. Finally, IP6 at pH 12 lead to a reduction in phospho-AKT and phospho-PDK1 and upregulated phospho-ERK. Conclusion: Together, our data strongly suggest that the pH of IP6 effectively modulates its anti-tumoral activity and should be reported in future studies

Securing the appendiceal stump in laparoscopic appendectomy: Evidence for routine stapling?

Background: This metaanalysis aimed to compare endoscopic linear stapling and loop ligatures used to secure the base of the appendix. Methods: Randomized controlled trials on appendix stump closure during laparoscopic appendectomy were systematically searched and critically appraised. The results in terms of complication rates, operating time, and hospital stay were pooled by standard metaanalytic techniques. Results: Data on 427 patients from four studies were included. The operative time was 9 min longer when loops were used (p = 0.04). Superficial wound infections (odds ratio [OR], 0.21; 95% confidence interval (CI), 0.06-0.71; p = 0.01) and postoperative ileus (OR, 0.36; 95% CI, 0.14-0.89; p = 0.03) were significantly less frequent when the appendix stump was secured with staples instead of loops. Of 10 intraoperative ruptures of the appendix, 7 occurred in loop-treated patients (p = 0.46). Hospital stay and frequency of postoperative intraabdominal abscess also were comparable in loop-treated and staple-treated patients. Conclusions: The clinical evidence on stump closure methods in laparoscopic appendectomy favors the routine use of endoscopic staplers

Ebp1 expression in benign and malignant prostate

<p>Abstract</p> <p>Background</p> <p>ErbB3-binding protein 1 (Ebp1) is a member of the <it>PA2G4 </it>family of proliferation-regulated proteins that is expressed in multiple malignant and non-malignant cells. ErbB3 and other members of the EGFR family have been implicated in cancer progression, it however remains unknown whether Ebp1 participate in prostate cancer progression <it>in vivo</it>. Therefore, the present study examines Ebp1 expression in cancerous and non-cancerous prostates tissues. Ebp1 expression was also correlated to known Ebp1 regulated proteins (Androgen receptor (AR), Cyclin D1 & ErbB3) and the proliferation marker Ki67. Furthermore we evaluated whether Ebp1 expression correlated with biochemical recurrence (BCR) following radical prostatectomy.</p> <p>Methods</p> <p>The expression of Ebp1, AR, Cyclin D1, ErbB3 and Ki67 were evaluated by immunohistochemistry using three separate tissue micro-arrays containing normal prostate tissues, non-cancerous tissue adjacent to the primary tumor, hormone-sensitive and hormone-refractory cancerous tissues. Multivariate COX regression analysis was performed with four clinical parameters in order to correlate Ebp1 expression with PCa progression.</p> <p>Results</p> <p>The expression of Ebp1 significantly increased with the progression from normal to hormone sensitive and to hormone refractory PCa. Furthermore, we observed strong correlation between Ebp1 expression and the nuclear expression of AR, Cyclin D1 and ErbB3 in both normal adjacent and cancer tissues. The expression of AR, Cyclin D1 and ErbB3 in normal adjacent tissues correlated with PSA relapse, whereas Ebp1 on its own did not significantly predict PSA relapse. Finally, in a multivariate analysis with a base clinical model (Gleason, Pre-op PSA, surgical margins and P-stage) we identified the multi-marker combination of Ebp1+/Cyclin D1- as an independent predictor of PSA relapse with a hazard ratio of 4.79.</p> <p>Conclusion</p> <p>Although not related to disease recurrence, this is the first <it>in vivo </it>study to report that Ebp1 expression correlates with PCa progression.</p

Wide-field optical spectroscopy system integrating reflectance and spatial frequency domain imaging to measure attenuation-corrected intrinsic tissue fluorescence in radical prostatectomy specimens

The development of a multimodal optical imaging system is presented that integrates endogenous fluorescence and diffuse reflectance spectroscopy with single-wavelength spatial frequency domain imaging (SFDI) and surface profilometry. The system images specimens at visible wavelengths with a spatial resolution of 70 microm, a field of view of 25 cm(2) and a depth of field of approximately 1.5 cm. The results of phantom experiments are presented demonstrating the system retrieves absorption and reduced scattering coefficient maps using SFDI with <6% reconstruction errors. A phase-shifting profilometry technique is implemented and the resulting 3-D surface used to compute a geometric correction ensuring optical properties reconstruction errors are maintained to <6% in curved media with height variations <20 mm. Combining SFDI-computed optical properties with data from diffuse reflectance spectra is shown to correct fluorescence using a model based on light transport in tissue theory. The system is used to image a human prostate, demonstrating its ability to distinguish prostatic tissue (anterior stroma, hyperplasia, peripheral zone) from extra-prostatic tissue (urethra, ejaculatory ducts, peri-prostatic tissue). These techniques could be integrated in robotic-assisted surgical systems to enhance information provided to surgeons and improve procedural accuracy by minimizing the risk of damage to extra-prostatic tissue during radical prostatectomy procedures and eventually detect residual cancer