Impact of gut microbiome in the development and treatment of pancreatic cancer: Newer insights.

The gut microbiome plays an important role in the variation of pharmacologic response. This aspect is especially important in the era of precision medicine, where understanding how and to what extent the gut microbiome interacts with drugs and their actions will be key to individualizing therapy. The impact of the composition of the gut microbiome on the efficacy of newer cancer therapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell treatment has become an active area of research. Pancreatic adenocarcinoma (PAC) has a poor prognosis even in those with potentially resectable disease, and treatment options are very limited. Newer studies have concluded that there is a synergistic effect for immunotherapy in combination with cytotoxic drugs, in the treatment of PAC. A variety of commensal microbiota can affect the efficacy of conventional chemotherapy and immunotherapy by modulating the tumor microenvironment in the treatment of PAC. This review will provide newer insights on the impact that alterations made in the gut microbial system have in the development and treatment of PAC.

Interaction between Age and Primary Site on Survival Outcomes in Primary GI Melanoma over the Past Decade.

BACKGROUND: Primary malignant melanomas of the Gastrointestinal mucosa are uncommon. Most cases of gastrointestinal (GI) melanomas are secondary, arising from metastasis at distant sites. The purpose of this study is to assess to what extent the interaction between independent prognostic factors (age and tumor site) of primary GI melanoma influence survival. Furthermore, we also aimed to investigate the clinical characteristics, survival outcomes, and independent prognostic factors of patients with primary GI melanoma in the past decade. METHODS: A total of 399 patients diagnosed with primary GI melanoma, between 2008 and 2017, were enrolled in our study by retrieving data from the Surveillance, Epidemiology, and End Results (SEER) database. We analyzed demographics, clinical characteristics, and overall mortality (OM) as well as cancer-specific mortality (CSM) of primary GI melanoma. Variables with a p value < 0.1 in the univariate Cox regression were incorporated into the multivariate Cox model (model 1) to determine the independent prognostic factors, with a hazard ratio (HR) of greater than 1 representing adverse prognostic factors. Furthermore, we analyzed the effect of the interaction between age and primary location on mortality (model 2). RESULTS: Multivariate cox proportional hazard regression analyses revealed higher OM in age group 80+ (HR = 5.653, 95% CI 2.212-14.445, p = 0), stomach location of the tumor (HR = 2.821, 95% CI 1.265-6.292, p = 0.011), regional lymph node involvement only (HR = 1.664, 95% CI 1.051-2.635, p < 0.05), regional involvement by both direct extension and lymph node involvement (HR = 1.755, 95% CI 1.047-2.943, p < 0.05) and distant metastases (HR = 4.491, 95% CI 3.115-6.476, p = 0), whereas the lowest OM was observed in patients with small intestine melanoma (HR = 0.383, 95% CI 0.173-0.846, p < 0.05). Multivariate cox proportional hazard regression analyses of CSM also revealed higher mortality of the same groups and lower CSM in small intestine and colon melanoma excluding the rectum. For model 2, considering the interaction between age and primary site on mortality, higher OM was found in age group 80+, followed by age group 40-59 then age group 60-79, regional lymph node involvement only, regional involvement by both direct extension and lymph node involvement and distant metastases. The small intestine had a lower OM. The rectum as primary location and the age range 40-59 interacted to lower the OM (HR = 0.14, 95% CI 0.02-0.89, p = 0.038). Age and primary gastric location did not interact to affect the OM. For the CSM, taking into account the interaction between age and the primary location, higher mortality was found in the same groups and the colon location. The primary colon location also interacted with the age group 40-59 to increase the CSM (HR = 1.38 × 109, 95% CI 7.80 × 107-2.45 × 1010, p = 0). CONCLUSIONS: In this United States population-based retrospective cohort study using the SEER database, we found that only the age range 40-59 interacted with the rectum and colon to lower and increase mortality respectively. Primary gastric location, which was the single most important location to affect mortality, did not interact with any age range to influence mortality. With those results, we hope to shed some light on this rare pathology with a very dismal prognosis.

Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors: A Review.

IMPORTANCE: The development of immune checkpoint inhibitors targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) has significantly improved the treatment of a variety of cancers and led to US Food and Drug Administration approvals for patients with a variety of malignant neoplasms. Immune checkpoint inhibitors enhance antitumor immunity by blocking negative regulators of T-cell function that exist both on immune cells and on tumor cells. Although these agents can lead to remarkable responses, their use can also be associated with unique immune-related adverse effects (irAEs). OBSERVATIONS: In general, use of PD-1 inhibitors such as nivolumab and pembrolizumab has a lower incidence of irAEs compared with those that block CTLA-4 such as ipilimumab. The combination of nivolumab and ipilimumab has a higher rate of irAEs than either approach as monotherapy. Consensus guidelines regarding the treatment of the most common irAEs including rash, colitis, hepatitis, endocrinopathies, and pneumonitis have been established. The mainstay of irAE treatment consists of immunosuppression with corticosteroids or other immunosuppressant agents such as infliximab; most irAEs will resolve with appropriate management. CONCLUSIONS AND RELEVANCE: The clinical use of immune checkpoint inhibitors is expanding rapidly. Oncology practitioners will therefore be required to recognize and manage irAEs in a growing patient population. Early recognition and treatment are essential to prevent patient morbidity and mortality, and adherence to established algorithms is recommended.

Targeting the androgen receptor in prostate and breast cancer: several new agents in development.

Prostate cancer (PCa) and breast cancer (BCa) share similarities as hormone-sensitive cancers with a wide heterogeneity of both phenotype and biology. The androgen receptor (AR) is a hormone receptor involved in both benign and malignant processes. Targeting androgen synthesis and the AR pathway has been and remains central to PCa therapy. Recently, there has been increased interest in the role of the AR in BCa development and growth, with results indicating AR co-expression with estrogen, progesterone, and human epidermal growth factor receptors, across all intrinsic subtypes of BCa. Targeting the AR axis is an evolving field with novel therapies in development which may ultimately be applicable to both tumor types. In this review, we offer an overview of available agents which target the AR axis in both PCa and BCa and provide insights into the novel drugs in development for targeting this signaling pathway.

Risk of venous thromboembolism in patients with cancer treated with Cisplatin: a systematic review and meta-analysis.

PURPOSE: Several reports suggest that cisplatin is associated with an increased risk of thromboembolism. However, because the excess risk of venous thromboembolic events (VTEs) with cisplatin-based chemotherapy has not been well described, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of VTEs associated with cisplatin-based chemotherapy. METHODS: PubMed was searched for articles published from January 1, 1990, to December 31, 2010. Eligible studies included prospective randomized phase II and III trials evaluating cisplatin-based versus non-cisplatin-based chemotherapy in patients with solid tumors. Data on all-grade VTEs were extracted. Study quality was calculated using Jadad scores. Incidence rates, relative risks (RRs), and 95% CIs were calculated using a random effects model. RESULTS: A total of 8,216 patients with various advanced solid tumors from 38 randomized controlled trials were included. The incidence of VTEs was 1.92% (95% CI, 1.07 to 2.76) in patients treated with cisplatin-based chemotherapy and 0.79% (95% CI, 0.45 to 1.13) in patients treated with non-cisplatin-based regimens. Patients receiving cisplatin-based chemotherapy had a significantly increased risk of VTEs (RR, 1.67; 95% CI, 1.25 to 2.23; P = .01). Exploratory subgroup analysis revealed the highest RR of VTEs in patients receiving a weekly equivalent cisplatin dose > 30 mg/m(2) (2.71; 95% CI, 1.17 to 6.30; P = .02) and in trials reported during 2000 to 2010 (1.72; 95% CI, 1.27 to 2.34; P = .01). CONCLUSION: Cisplatin is associated with a significant increase in the risk of VTEs in patients with advanced solid tumors when compared with non-cisplatin-based chemotherapy.

Arterial thromboembolism in cancer patients treated with cisplatin: a systematic review and meta-analysis.

Cisplatin has been associated with an increased risk of arterial thromboembolic events (ATEs). However, because this association is mostly based on case reports and retrospective studies, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of ATEs associated with cisplatin. Eligible studies included prospective randomized phase II and III trials evaluating cisplatin-based vs non-cisplatin-based chemotherapy in patients with solid tumors, which were identified from PubMed articles published between 1990 and 2010. Incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using a random effects model. A total of 8216 patients from 38 trials were included. Among patients treated with cisplatin-based chemotherapy, the summary incidence of ATEs was 0.67% (95% CI = 0.40% to 0.95%), and the RR of ATEs was 1.36 (95% CI = 0.86 to 2.17; P = .19). No increase in ATEs was detected in any prespecified subgroup.

Unique phenotype of hepatocellular cancers with exon-3 mutations in beta-catenin gene.

UNLABELLED: Wnt/beta-catenin signaling plays an important role in liver development and regeneration. Its aberrant activation, however, is observed in a subset of primary hepatocellular cancers (HCCs). In the current study, we compare and contrast the tumor characteristics of HCC in the presence or absence of mutations in the beta-catenin gene (CTNNB1). Frozen HCCs (n = 32), including five fibrolamellar (FL) variants, and control livers (n = 3) from Health Sciences Tissue Bank and Department of Surgery at the University of Pittsburgh Medical Center, were examined for mutations in CTNNB1, protein levels of beta-catenin, tyrosine-654-phosphorylated-beta-catenin (Y654-beta-catenin), and glutamine synthetase (GS). Missense mutations in the exon-3 of CTNNB1were identified in 9/32 HCCs. Total beta-catenin levels were higher than controls in most tumors; however, GS was exclusively increased in HCCs with mutations. Phenotypically, greater percentages of mutated HCCs showed macrovascular and microvascular invasion. Also, the tumor size was greater than double in mutated HCCs. High levels of total beta-catenin protein were observed in multinodular tumors independent of beta-catenin mutations. In addition, significant cases with mutations showed absence of cirrhosis. Finally, the highest levels of Y654-beta-catenin were exclusively observed in fibrolamellar (FL)-HCC cases. CONCLUSION: Thus, HCCs that harbor missense mutations in exon-3 of CTNNB1 exhibit, histologically, a more aggressive phenotype. Also, CTNNB1 mutations might lead to HCC in the absence of cirrhosis. Finally, FL-HCC cases display a unique up-regulation of tyrosine-phosphorylated-beta-catenin, suggesting robust receptor tyrosine kinase signaling in this tumor type.

Knowledge, attitudes and beliefs of women about the importance of prostate cancer screening.

OBJECTIVES: To understand women's knowledge, attitudes and beliefs about prostate cancer. METHODS: A survey was self-administered to 324 women age >18 years. It contained 42 questions that assessed women's knowledge about prostate cancer, possible risk factors, and opinions regarding screening and early detection. Women were grouped as married or unmarried for convenient comparisons. Chi-squared and F statistics were performed. RESULTS: Ninety-seven percent of married women reported having some influence over the healthcare decisions of their spouse. Married women's worst fear about their spouse or family member's diagnosis of prostate cancer was death. The most important benefit of prostate cancer screening was the possibility of cure, while the main hindrance was fear of the digital rectal exam. Marital status, age, educational level and income were all significantly associated with women's knowledge about prostate cancer (p<0.001). CONCLUSIONS: Women play an important role in health-related matters in the home. Educating women on prostate cancer may improve early detection efforts and reduce the devastating impact of this disease on their family.