Phase I/II trial of BMS-986,205 and nivolumab as first line therapy in hepatocellular carcinoma.

BACKGROUND: Indoleamine-2,3-dioxygenase (IDO) helps orchestrate immune suppression and checkpoint inhibitor resistance in hepatocellular carcinoma (HCC). BMS-986,205 is a novel oral drug that potently and selectively inhibits IDO. This Phase I/II study evaluated the safety and tolerability of BMS-986,205 in combination with nivolumab as first-line therapy in advanced HCC. METHODS: Adults with untreated, unresectable/metastatic HCC received BMS-986,205 at two dose levels (50-100 mg orally daily) in combination with fixed dose nivolumab (240mg/m2 IV on Day 1 of each 14-day cycle). The primary objective was to determine the safety and tolerability of this combination; secondary objectives were to obtain preliminary efficacy. RESULTS: Eight patients received a total of 91 treatment cycles in the dose escalation phase. All patients were Child Pugh A and 6 patients had underlying viral hepatitis. In the 6 evaluable patients, no dose-limiting toxicities (DLTs) were observed. The most common treatment-related adverse events (TRAEs) were aspartate transaminase (AST) and alanine transaminase (ALT) elevation (3 patients) and diarrhea, maculopapular rash and increased alkaline phosphatase (2 patients each). Grade 3 events were diarrhea and AST elevation (1 patient), and hyperglycemia and pancreatitis requiring treatment discontinuation (1 patient). No grade 4-5 events occurred. Partial response was observed in 1 patient (12.5%) and stable disease in 3 patients (37.5%), yielding a disease control rate of 50%. Median PFS was 8.5 weeks; median OS was not reached. CONCLUSION: Combination BMS-986,205 and nivolumab showed a manageable safety profile with durable benefit as first-line therapy in a meaningful subset of advanced HCC patients.

Perioperative Immunotherapy in Muscle-Invasive Bladder Cancer.

OPINION STATEMENT: There is an acute unmet need to develop novel treatment regimens in the perioperative setting since many patients with muscle-invasive bladder cancer (MIBC) are not eligible for the current standard of care (SOC) neoadjuvant treatment with cisplatin-based chemotherapy. The introduction of immune checkpoint inhibitors (ICIs), both as monotherapy and in combination regimens with other ICIs, chemotherapy, or targeted drugs, may provide safe and clinically effective treatment options that could revolutionize current standard of care. In the neoadjuvant setting, compelling data from phase II clinical trials suggests that single-agent immunotherapy, as well as dual-checkpoint blockade, may emerge as reasonable alternatives to traditional cisplatin-based chemotherapy. Prospective studies combining ICIs with chemotherapy or with antibody-drug conjugates have also demonstrated robust outcomes. However, these studies are not yet practice changing and data from larger randomized studies are needed to confirm this benefit. In the adjuvant setting, nivolumab is the FDA-approved treatment based on a disease-free survival benefit relative to placebo in a randomized trial. However, it will be important to confirm an overall survival benefit of this treatment and to better identify patients who need additional adjuvant treatment based on novel biomarker data. The treatment of muscle-invasive bladder cancer is moving toward the individualization of treatment options based on specific tumor and patient characteristics and away from the one-size-fits-all approach that has dominated this space for the last couple of decades. Emerging biomarker data, such as with ctDNA, suggests that immunotherapy may confer greater benefit to selected patients. Identifying who those patients are will be of paramount importance since additional treatments always come with additional toxicities. On the other hand, the more favorable toxicity profiles of certain immunotherapy-based regimens may make them superior options for some patients who would otherwise be unable to tolerate other systemic regimens. In the near future, it is likely that subsets of patients with MIBC will be receiving treatments with predominantly immunotherapy-based regimens while many patients may still be treated with regimens containing a cisplatin-based chemotherapy backbone. Currently ongoing clinical trials will help to better define patient populations optimized for each treatment.

The role of the six factors model of athletic mental energy in mediating athletes' well-being in competitive sports.

In the realm of high-performance sports, athletes often prioritize success at the expense of their well-being. Consequently, sports psychology researchers are now focusing on creating psychological profiles for athletes that can forecast their performance while safeguarding their overall well-being. A recent development in this field is the concept of athletic mental energy (AME), which has been associated with both sporting success and positive emotions. Therefore, the aim of this study was to explore if AME in athletes can mediate this directly observed relationship between performance and psychological well-being. For stronger predictive validity these relationships were examined across two studies with each involving distinct sets of participants engaged in various sports disciplines, including football, cricket, basketball, archery, and more. The self-report measures of sports performance, athletic mental energy (AME), and psychological well-being (PWB) were administered post-competition on the local, regional, state, national, international, and professional level athletes of age 18 and above. Our study found that both, the affective and cognitive components of AME mediated the athletes' performance and psychological well-being relationship. Interestingly, the study found no significant gender differences in AME and PWB scores. While family structures didn't yield significant variations in AME scores, there were some descriptive distinctions in PWB scores across different family structures. Our research offers preliminary evidence suggesting that AME can play a pivotal role in preserving athletes' psychological well-being following competitive events.

Are we well? A post-pandemic snapshot of dental educator wellness, well-being, and fulfillment.

INTRODUCTION: The COVID-19 pandemic brought unprecedented changes to oral care and dental education delivery. To date, the vast majority of studies focus on the impact COVID-19 had on the well-being and wellness of patients, practitioners, and students; however, limited literature addresses the pandemic's impact on dental educators. PURPOSE: The aim of this study was to investigate the wellness, well-being, and fulfillment of dental educators in the years following the onset of the COVID-19 pandemic. METHODS: Following Institutional Review Board approval, an anonymous electronic Qualtrics survey was emailed to full-time and adjunct faculty across five (5) dental education institutions in the US. Faculty self-reported on their wellness, general well-being, physical well-being, mental well-being, fulfillment, and work-life balance. Group differences were examined using analysis of variance and the Tukey-Kramer test for multiple comparisons at the p < 0.05 level. RESULTS: The results revealed females and younger dental faculty members reported statistically significantly lower levels of wellness (F2, 123  = 11.16, p < 0.001, F3, 121  = 8.53, p < 0.001), physical (F2, 123  = 11.53, p < 0.001, F3, 121  = 5.54, p = 0.001) and mental well-being (F2, 123  = 12.49, p < 0.001, F3, 121  = 8.63, p < 0.001), fulfillment (F3, 121  = 5.01, p < 0.003), and higher levels of burnout (F2, 123  = 5.53, p = 0.005, F3, 121  = 4.85, p < 0.003). Those who expressed higher levels of burnout also had statistically lower mean well-being scores (F4, 119  = 10.54, p < 0.001). Females also reported a significantly lower work-life balance score compared to male respondents (F2, 121  = 10.37, p < 0.002). CONCLUSION: Despite the social and environmental challenges faced over the last couple of years post-pandemic, dental educators demonstrate a quick ability to adapt, however, disproportional differences in gender and age groups were identified as being significantly correlated to dental educators' self-reports on wellness, well-being, and fulfillment. Insight into these variables can help inform strategies in the academic setting to help support and strengthen the academic workforce.

Localized Synovial Sarcoma: A Population-Based Analysis of Treatment Patterns and Survival.

Purpose: Synovial sarcoma (SS) is a rare, high-grade soft tissue tumor that requires multidisciplinary and multimodal care with surgery, radiotherapy, and chemotherapy. We examined the impact of sociodemographic and clinical factors on treatment patterns and survival in localized SS patients. Methods: Adolescents and young adults (AYAs, 15-39 years) and older adults ("adults," ≥40 years) diagnosed with localized SS from 2000 to 2018 were identified in the California Cancer Registry. Multivariable logistic regression identified clinical and sociodemographic factors associated with receipt of chemotherapy and/or radiotherapy. Cox proportional hazards regression identified factors associated with overall survival (OS). Results are reported as odds ratios (ORs) and hazard ratios (HRs), respectively, with 95% confidence intervals (CIs). Results: More AYAs (n = 346) than adults (n = 272) received chemotherapy (47.7% vs. 36.4%) and radiotherapy (62.1% vs. 58.1%). Age at diagnosis, tumor size, treatment at National Cancer Institute-Children's Oncology Group (NCI-COG)-designated facilities, insurance status, and neighborhood socioeconomic status (SES) influenced treatment patterns. Among AYAs, treatment at NCI-COG-designated facilities was associated with receiving chemotherapy (OR 2.74, CI 1.48-5.07) and low SES was associated with worse OS (HR 2.28, 1.09-4.77). In adults, high SES was associated with receiving chemoradiotherapy (OR 3.20, CI 1.40-7.31), whereas public insurance was associated with decreased odds of chemoradiotherapy (OR 0.44, CI 0.20-0.95). With regard to treatment, absence of radiotherapy (HR 1.94, CI 1.18-3.20) was associated with worse OS in adults. Conclusion: In localized SS, both clinical and sociodemographic factors influenced treatment patterns. Further research should investigate how SES-related factors produce treatment disparities and identify interventions to improve treatment equity and outcomes.

Case report: Treatment of metastatic dedifferentiated chondrosarcoma with pembrolizumab yields sustained complete response.

Dedifferentiated chondrosarcomas (DDCS) are aggressive tumors with poor outcomes. Treatment of localized DDCS is primarily surgical, though most patients present with unresectable or metastatic disease. Systemic treatment options for advanced DDCS are limited, and the benefits of chemotherapy in this patient population remain controversial. Among other systemic therapy options, there is emerging clinical evidence to support the use of immunotherapy in patients with advanced DDCS. However, studies regarding the efficacy of immunotherapy in advanced DDCS are limited. Here, we present the case of a patient with metastatic, programmed death-ligand 1 (PD-L1)-positive DDCS treated with pembrolizumab who showed a sustained complete response for 24 months after initiation of therapy. To our knowledge, this case represents one of few documented cases of metastatic chondrosarcoma with sustained response to immunotherapy. The impressive response seen with PD-L1 inhibition in our patient indicates that immunotherapy is a successful treatment option in a subset of DDCS patients, and further investigation is needed to identify potential responders to immunotherapy.

Immunotherapy Updates in Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. HCC tumor development and treatment resistance are impacted by changes in the microenvironment of the hepatic immune system. Immunotherapy has the potential to improve response rates by overcoming immune tolerance mechanisms and strengthening anti-tumor activity in the tumor microenvironment. In this review, we characterize the impact of immunotherapy on outcomes of advanced HCC, as well as the active clinical trials evaluating novel combination immunotherapy strategies. In particular, we discuss the efficacy of atezolizumab and bevacizumab as demonstrated in the IMbrave150 study, which created a new standard of care for the front-line treatment of advanced HCC. However, there are multiple ongoing trials that may present additional front-line treatment options depending on their efficacy/toxicity results. Furthermore, the preliminary data on the application of chimeric antigen receptor (CAR-T) cell therapy for treatment of HCC suggests this may be a promising option for the future of advanced HCC treatment.

A knowledge-based approach for identification of drugs against vivapain-2 protein of Plasmodium vivax through pharmacophore-based virtual screening with comparative modelling.

Malaria is one of the most infectious diseases in the world. Plasmodium vivax, the pathogen causing endemic malaria in humans worldwide, is responsible for extensive disease morbidity. Due to the emergence of resistance to common anti-malarial drugs, there is a continuous need to develop a new class of drugs for this pathogen. P. vivax cysteine protease, also known as vivapain-2, plays an important role in haemoglobin hydrolysis and is considered essential for the survival of the parasite. The three-dimensional (3D) structure of vivapain-2 is not predicted experimentally, so its structure is modelled by using comparative modelling approach and further validated by Qualitative Model Energy Analysis (QMEAN) and RAMPAGE tools. The potential binding site of selected vivapain-2 structure has been detected by grid-based function prediction method. Drug targets and their respective drugs similar to vivapain-2 have been identified using three publicly available databases: STITCH 3.1, DrugBank and Therapeutic Target Database (TTD). The second approach of this work focuses on docking study of selected drug E-64 against vivapain-2 protein. Docking reveals crucial information about key residues (Asn281, Cys283, Val396 and Asp398) that are responsible for holding the ligand in the active site. The similarity-search criterion is used for the preparation of our in-house database of drugs, obtained from filtering the drugs from the DrugBank database. A five-point 3D pharmacophore model is generated for the docked complex of vivapain-2 with E-64. This study of 3D pharmacophore-based virtual screening results in identifying three new drugs, amongst which one is approved and the other two are experimentally proved. The ADMET properties of these drugs are found to be in the desired range. These drugs with novel scaffolds may act as potent drugs for treating malaria caused by P. vivax.