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PDF file - 34K, Effect of BAY36-7620 on prostate cancer cells proliferation

PDF file - 61K, Immunohistochemical staining of metabotropic glutamate receptor 1 (GRM1) in selected non-malignant prostatic tissues

PDF file - 83K

Purpose: During glutaminolysis, glutamine is catabolized to glutamate and incorporated into citric acid cycle and lipogenesis. Serum glutamate levels were measured in patients with primary prostate cancer or metastatic castrate-resistant prostate cancer (mCRPCa) to establish clinical relevance. The effect of glutamate deprivation or blockade by metabotropic glutamate receptor 1 (GRM1) antagonists was investigated on prostate cancer cells' growth, migration, and invasion to establish biologic relevance.Experimental Design: Serum glutamate levels were measured in normal men (n = 60) and patients with primary prostate cancer (n = 197) or mCRPCa (n = 109). GRM1 expression in prostatic tissues was examined using immunohistochemistry (IHC). Cell growth, migration, and invasion were determined using cell cytotoxicity and modified Boyden chamber assays, respectively. Apoptosis was detected using immunoblotting against cleaved caspases, PARP, and γ-H2AX.Results: Univariate and multivariate analyses showed significantly higher serum glutamate levels in Gleason score ≥ 8 than in the Gleason score ≤ 7 and in African Americans than in the Caucasian Americans. African Americans with mCRPCa had significantly higher serum glutamate levels than those with primary prostate cancer or benign prostate. However, in Caucasian Americans, serum glutamate levels were similar in normal research subjects and patients with mCRPC. IHC showed weak or no expression of GRM1 in luminal acinar epithelial cells of normal or hyperplastic glands but high expression in primary or metastatic prostate cancer tissues. Glutamate deprivation or blockade decreased prostate cancer cells' proliferation, migration, and invasion and led to apoptotic cell death.Conclusions: Glutamate expression is mechanistically associated with and may provide a biomarker of prostate cancer aggressiveness. Clin Cancer Res; 18(21); 5888–901. ©2012 AACR.

PDF file - 66K, Descriptives of the study cohort used for serum glutamate quantification

PDF file - 80K, Immunohistochemical staining of metabotropic glutamate receptor 1 (GRM1) in selected prostate cancers

PDF file - 156K, Comparison of serum glutamate levels in African Americans and Caucasian Americans with metastatic-castrate resistant prostate cancer

PDF file - 75K, Multiple covariate adjusted analysis of serum glutamate levels in patients with primary and metastatic castrate-resistant prostate cancer

Background: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status. Patients and methods: Patients were randomized 2: 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis. Results: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms. Conclusions: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure. in press

BACKGROUND: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. DESIGN: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. CONCLUSION: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer. ispartof: ANNALS OF ONCOLOGY vol:33 issue:3 pages:276-287 ispartof: location:England status: published

Dr. Jose Delgado performed audacious demonstrations utilizing brain stimulation to instantly change behavior in animals. These feats spark ethical debates to this day. However, behind his controversial career is an important legacy of neurological discoveries and technological innovation. Delgado pioneered techniques in causally manipulating brain patterns and behavior with electrical stimulation and developed innovative, closed-loop neural devices. His inventive devices and techniques were ahead of his time and remain relevant to the field of neuromodulation today.

Colorectal cancer; Lung cancer; Monoclonal antibody Cáncer colorrectal; Cáncer de pulmón; Anticuerpo monoclonal Càncer colorectal; Càncer de pulmó; Anticòs monoclonal Background The phase I GATTO study (NCT03360734) explored the feasibility, tolerability and preliminary activity of combining gatipotuzumab, a novel humanized monoclonal antibody binding to the tumor-associated epitope of mucin 1 (TA-MUC1) and an anti-epidermal growth factor receptor (anti-EGFR) antibody in refractory solid tumors. Patients and methods Initially the study enrolled primary phase (PP) patients with EGFR-positive metastatic solid tumors, for whom no standard treatment was available. Patients received gatipotuzumab administered at 1400 mg every 2 weeks, 6 weeks after the start of the glyco-optimized anti-EGFR antibody tomuzotuximab at 1200 mg every 2 weeks. As this regimen was proven safe, enrollment continued in an expansion phase (EP) of patients with refractory metastatic colorectal cancer, non-small-cell lung cancer, head and neck cancer and breast cancer. Tomuzotuximab and gatipotuzumab were given at the same doses and gatipotuzumab treatment started 1 week after the first dose of the anti-EGFR antibody. Additionally, investigators could use a commercial anti-EGFR antibody in place of tomuzotuximab. Results A total of 52 patients were enrolled, 20 in the PP and 32 in the EP. The combined treatment was well tolerated and no dose-limiting toxicity was observed in the whole study, nor related serious adverse event or death. Preliminary activity of the combination was observed, with one and four RECIST partial responses in the PP and EP, all in colorectal cancer patients. The trial was accompanied by a comprehensive translational research program for identification of biomarkers, including soluble TA-MUC1 (sTA-MUC1) in serum. In the EP, patients with baseline sTA-MUC1 levels above the median appeared to have improved progression-free survival and overall survival. Conclusions Combination of a TA-MUC1-targeting antibody and an EGFR-targeting antibody is safe and feasible. Interesting antitumor activity was observed in heavily pretreated patients. Future studies should test this combination together with chemotherapy and explore the potential of sTA-MUC1 as a companion biomarker for further development of the combination. This work was supported by Glycotope GmbH (no grant number).

Introduction/Background* Standard therapy for advanced ovarian cancer (OC) includes radical debulking surgery followed by first-line platinum-based chemotherapy, although neo-adjuvant chemotherapy can be used. Most women with newly diagnosed advanced OC relapse within 3 years of standard treatment. In SOLO1, patients with advanced OC and a BRCA1 and/or BRCA2 mutation (BRCAm), in complete or partial response following first-line platinum-based chemotherapy, received maintenance olaparib or placebo for up to 2 years or until progression. At 5-year follow-up, median progression-free survival (PFS) was 56 months with olaparib vs 14 months with placebo (hazard ratio 0.33; 95% confidence interval 0.25–0.43). The OVAL-1 study will provide evidence on real-world effectiveness of olaparib in patients with BRCAm advanced OC treated in the first-line maintenance setting in France, Italy and the UK. Methodology Retrospective cohort, pan-European multicentre observational study with data abstracted from medical records at several time points until ≥3 years after first olaparib dose (index date). Eligible patients are adult females with a BRCAm and advanced (FIGO stage III/IV) OC, who received their first olaparib (tablet) dose between January 2019 and June 2020 in the first-line maintenance setting via Early Access Programmes (Italy, UK), Temporary Use Authorization (France) or reimbursement following regulatory approval (Italy, UK). Main study endpoint is real-world PFS. Secondary endpoints include overall survival and response rates. The study will also describe surrogate measures of response and tolerability, including time to discontinuation, dose modifications (with reasons) and time to first and second subsequent treatment. Outcomes will be described by key subgroup status pre-index, including performance status, FIGO stage, BRCAm status, debulking surgery outcome and clinical response to chemotherapy. The study aims to include 350 patients. Retrospective data collection began in December 2020 and is planned to end by Q3 2023. As of April 2021, 69 patients have participated.

Introduction/Background* Nowadays, after the recent insights about the molecular Endometrial cancer (EC) classification, the usual key histological parameters (i.e histotype and grade) have been shown to have poor reproducibility and adequacy in EC stratification risk. The need to define a more precise guidance of surgical and adjuvant approaches has suggested the possibility to refine the prognostic assessing, considering other EC characteristics. Inspired by these concepts, the aim of this study is to assess the clinical reproducibility and the oncological validity of the EC risk stratification based on the molecular information given by the immunohistochemistry (IHC). Methodology Retrospective IHC analyses were conducted in a large series of 778 pre-operative uterine-confined ECs, studying the presence/absence of MLH1, MSH2, MSH6, to define the mismatch repair (MMR) stable or instable phenotype; the presence of p53 mutations and other molecular features. The molecular profile was correlated with histological, clinical and prognostic EC patients data. Result(s)* Based on the IHC, we defined 3 EC populations: MMR stable (MMRs), instable (MMRi) and p53 mutated (p53+) patients. Our result demonstrated that the IHC stratification statistically correlated with the most relevant anatomo-clinical features: FIGO stage (p 60 years and the ER-status in DFS (p=0.004 and p=0.041). Conclusion* In this large series, we demonstrated that the pragmatic and sistematic use of IHC may have an important role to properly stratify, in terms of histological features and clinical outcome, the pre-operative uterine-confined EC patients.

Workplace chaplaincy is an intriguing phenomenon, wherein organizations hire clergy persons to serve the social, spiritual, and psychological needs of their employees. The authors interviewed 56 employees in nine organizations to explore employee perceptions and experiences with chaplaincy. The results indicate that employees perceive chaplaincy as a demonstration of management’s care and concern for then as whole persons by having chaplains meet their work and nonwork needs. Employees report that workplace chaplains care for them in five ways: attending to their work-related issues; addressing their practical and social needs; meeting their psychotherapeutic needs; facilitating urgent care as first responders in a crisis; and providing religious or pastoral services. The study suggests that employees’ experience of such care from chaplains can be interpreted as perceived organizational support, which enhances their sense of well-being and their organizational commitment. The article concludes with recommendations for future research.

Workplace chaplaincy represents one way that workplace spirituality manifests itself today in corporate America. Rigorous scholarly research into workplace (or corporate) chaplaincy remains scant. This article seeks to remedy that by focusing on human resource professionals’ perceptions and experiences with workplace chaplaincy in five organizations in the United States. Using data gathered from qualitative interviews with HR executives and staff, five themes emerged regarding their views of chaplaincy in their organizations: chaplains support and enhance a positive organizational culture; they complement or serve as an alternative to employee assistance programs; they provide psychosocial and pastoral care support to employees; they help to bridge cultural divides; and they enhance HR’s efforts in religious diversity and accommodation. Overall, HR felt that chaplains contribute to a positive organizational culture through employee care and contributions to diversity and inclusion. Article ends with implications for theory and practice.

Patients with proximal malignant jaundices are often diagnosed in an advanced stage and need biliary decompression treatments, such as percutaneous transhepatic biliary drainage (PTBD) and bare metal stenting (BMS), to improve the hepatic function. Whether it is better to perform those two procedures together or in a separate time, it is not well understood. The aim of this study was to investigate the effectiveness and cost-benefit of a combined "one-stage" PTBD/BMS procedure in patients with malignant jaundices.Forty-five patients with malignant jaundice treated with "one-stage" PTBD/BMS were retrospectively enrolled to evaluate technical success, complications, survival, and length of hospitalization.A full technical success of the procedures was reported for all patients, with only one major complication among 45 treated patients. A better performance in terms of hospitalization rate was achieved by the one-stage procedure compared to the two-stage, also resulting in global saving of costs. A high survival rate was observed at the 3rd and 6th month (97.7% and 86.6%, respectively), with a median overall survival time of 271,58 days.Our study shows that performing PTBD/BMS as a "one-stage" procedure is useful, safe, and cost-effective with a high percentage of technical success and a similar occurrence of complications compared to the two-stage procedure.