The Microbiota and Cancer Cachexia

Cancer cachexia is a multifactorial syndrome defined by weight loss, muscle wasting, and systemic inflammation. It affects the majority of patients with advanced cancer and is associated with poor treatment response, early mortality and decreased quality of life. The microbiota has been implicated in cancer cachexia through pathways of systemic inflammation, gut barrier dysfunction and muscle wasting. The imbalance of the microbiota, known as dysbiosis, has been shown to influence cancer cachexia. Bacteria that play beneficial and detrimental roles in the disease pathogenesis have been identified. The phenotype of cancer cachexia is associated with decreased levels of Lactobacillales and increased levels of Enterobacteriaceae and Parabacteroides. Currently, there are no treatment options that demonstrate increased survival or the quality of life in patients suffering from cancer cachexia. Through the manipulation of beneficial bacteria in the gut microbiota, different treatment options have been explored. Prebiotics and probiotics have been shown to improve outcomes in animal models of cachexia. Expounding on this mechanism, fecal microbiota transplant (FMT) holds promise for a future treatment of cancer cachexia. Further research is necessary to address this detrimental disease process and improve the lives of patients suffering from cancer cachexia

A Review of the Clinical Implications of Cachexia, Sarcopenia, and BMI in Patients with Peritoneal Carcinomatosis Receiving Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

Peritoneal carcinomatosis (PC) is the dissemination of cancer throughout the peritoneal cavity. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is the surgical treatment of choice in highly selected patients. The aim of this narrative review was to assess the impact of cachexia, sarcopenia, and body mass index (BMI) on patient outcomes for patients undergoing CRS and HIPEC for peritoneal carcinomatosis. A narrative review was performed and articles pertaining to cachexia, sarcopenia, BMI, peritoneal carcinomatosis, and CRS/HIPEC were reviewed and selected. In total, 3041 articles were screened and seven original studies met the inclusion criteria. In summary, obesity was found to not be a contraindication to surgery, but the impact of BMI was variable across the spectrum. Decreased skeletal muscle mass was found to be associated with poorer postoperative outcomes in three studies and with worse overall survival in two. With limited data, evaluating the impact of BMI, sarcopenia, and cachexia on patients with PC undergoing CRS and HIPEC was difficult as most studies included heterogeneous cancer patient populations; thus, postoperative outcomes and survival were inconsistent across studies. More research is needed to better understand its impact and to better generalize the results for each cancer subset treated with CRS and HIPEC across diverse patient populations

Review of Mechanisms and Treatment of Cancer-Induced Cardiac Cachexia

Cancer cachexia is a multifactorial, paraneoplastic syndrome that impacts roughly half of all cancer patients. It can negatively impact patient quality of life and prognosis by causing physical impairment, reducing chemotherapy tolerance, and precluding them as surgical candidates. While there is substantial research on cancer-induced skeletal muscle cachexia, there are comparatively fewer studies and therapies regarding cardiac cachexia in the setting of malignancy. A literature review was performed using the PubMed database to identify original articles pertaining to cancer-induced cardiac cachexia, including its mechanisms and potential therapeutic modalities. Seventy studies were identified by two independent reviewers based on inclusion and exclusion criteria. While there are multiple studies addressing the pathophysiology of cardiac-induced cancer cachexia, there are no studies evaluating therapeutic options in the clinical setting. Many treatment modalities including nutrition, heart failure medication, cancer drugs, exercise, and gene therapy have been explored in in vitro and mice models with varying degrees of success. While these may be beneficial in cancer patients, further prospective studies specifically focusing on the assessment and treatment of the cardiac component of cachexia are needed

Changing Practice Patterns and Improving Survival for Patients with Pancreatic Ductal Adenocarcinoma

Over the last two decades, there have been many reported advances in the clinical management of pancreatic ductal adenocarcinoma (PDAC). We sought to evaluate changes in survival for patients diagnosed with PDAC between 2004 and 2017. The National Cancer Database was queried for patients diagnosed with PDAC between 2004 and 2017. There were 55,401 patients who underwent surgery and 109,477 patients who underwent non-surgical treatment for PDAC between 2004 and 2017. Patients were categorized into four groups by year of diagnosis. Median survival improved from 15.5 months to 25.3 months for patients treated with surgery between the years 2016 and 2017 compared with between 2004 and 2007 (p p p < 0.001). This increase in survival in the setting of evolving care validates continued efforts aimed at improving survival for patients with this devastating disease

Infiltration of CD3+ and CD8+ lymphocytes in association with inflammation and survival in pancreatic cancer.

BackgroundPancreatic ductal adenocarcinomas (PDAC) have heterogeneous tumor microenvironments relatively devoid of infiltrating immune cells. We aimed to quantitatively assess infiltrating CD3+ and CD8+ lymphocytes in a treatment-naïve patient cohort and assess associations with overall survival and microenvironment inflammatory proteins.MethodsTissue microarrays were immunohistochemically stained for CD3+ and CD8+ lymphocytes and quantitatively assessed using QuPath. Levels of inflammation-associated proteins were quantified by multiplexed, enzyme-linked immunosorbent assay panels on matching tumor and tissue samples.ResultsOur findings revealed a significant increase in both CD3+ and CD8+ lymphocytes populations in PDAC compared with non-PDAC tissue, except when comparing CD8+ percentages in PDAC versus intraductal papillary mucinous neoplasms (IPMN) (p = 0.5012). Patients with quantitatively assessed CD3+ low tumors (lower 50%) had shorter survival (median 273 days) compared to CD3+ high tumors (upper 50%) with a median overall survival of 642.5 days (p = 0.2184). Patients with quantitatively assessed CD8+ low tumors had significantly shorter survival (median 240 days) compared to CD8+ high tumors with a median overall survival of 1059 days (p = 0.0003). Of 41 proteins assessed in the inflammation assay, higher levels of IL-1B and IL-2 were significantly associated with decreased CD3+ infiltration (r = -0.3704, p = 0.0187, and r = -0.4275, p = 0.0074, respectively). Higher levels of IL-1B were also significantly associated with decreased CD8+ infiltration (r = -0.4299, p = 0.0045), but not IL-2 (r = -0.0078, p = 0.9616). Principal component analysis of the inflammatory analytes showed diverse inflammatory responses in PDAC.ConclusionIn this work, we found a marked heterogeneity in infiltrating CD3+ and CD8+ lymphocytes and individual inflammatory responses in PDAC. Future mechanistic studies should explore personalized therapeutic strategies to target the immune and inflammatory components of the tumor microenvironment

From Mouth to Muscle: Exploring the Potential Relationship between the Oral Microbiome and Cancer-Related Cachexia

Cancer cachexia is a multifactorial wasting syndrome associated with skeletal muscle and adipose tissue loss, as well as decreased appetite. It affects approximately half of all cancer patients and leads to a decrease in treatment efficacy, quality of life, and survival. The human microbiota has been implicated in the onset and propagation of cancer cachexia. Dysbiosis, or the imbalance of the microbial communities, may lead to chronic systemic inflammation and contribute to the clinical phenotype of cachexia. Though the relationship between the gut microbiome, inflammation, and cachexia has been previously studied, the oral microbiome remains largely unexplored. As the initial point of digestion, the oral microbiome plays an important role in regulating systemic health. Oral dysbiosis leads to the upregulation of pro-inflammatory cytokines and an imbalance in natural flora, which in turn may contribute to muscle wasting associated with cachexia. Reinstating this equilibrium with the use of prebiotics and probiotics has the potential to improve the quality of life for patients suffering from cancer-related cachexia

Abstract 1172: Disparities in pancreatic ductal adenocarcinoma - the significance of Hispanic ethnicity, by subgroup analysis, and treatment facility on clinical outcomes

Abstract Background: Disparities exist among patients with pancreatic ductal adenocarcinoma (PDAC). Non-White race is regarded as a negative predictor of expected treatment and overall survival. Data suggest Academic Research Programs (ARP) provide better outcomes for minorities, but ethnic/minority outcomes are underreported. We sought to evaluate outcomes among diverse patients with PDAC, with a focus on Hispanic subgroups. We hypothesize that outcomes among racially/ethnically diverse PDAC patients may be influenced by treatment facility. Methods: The National Cancer Database was used to identify 170,327 patients diagnosed with PDAC between 2004 and 2015. Cox proportional-hazard regression was used to compare survival between race/ethnic groups across facilities. Results: In unadjusted models, compared to Non-Hispanic Whites (NHW), Non-Hispanic Blacks (NHB) had the worst overall survival (HR=1.05, 95%CI:1.03-1.06, p<0.001) and Hispanics had the best overall survival (HR=0.92, 95%CI:0.90-0.94, p<0.001). After controlling for socioeconomic and clinical covariates, NHB (HR=0.95, 95%CI:0.93-0.96, p<0.001) had better overall survival compared to NHW, and Hispanics continued to have the best comparative outcomes (HR=0.84, 95%CI:0.82-0.86, p<0.001). Amongst Hispanics, Dominicans and South/Central Americans lived the longest, at 10.25 and 9.82 months, respectively. The improved survival in Hispanics was most pronounced at ARP (HR=0.80, 95%CI:0.77-0.84, p<0.001) and Integrated Network Cancer Programs (HR=0.78, 95%CI:0.73-0.84, p<0.001). NHB had improved survival over NHW at Comprehensive Community Care Programs (HR=0.96, 95%CI:0.93-0.98, p=0.002) and ARP (HR=0.96, 95%CI:0.94-0.98, p=0.001), which was influenced by income, education, and surgical resection. Conclusion: Hispanics with PDAC have better overall survival compared to Non-Hispanics at all facilities, but most profoundly at ARP and INCP. Dominicans and South/Central Americans in particular have significantly improved survival at ARP. Survival was improved at ARP for all populations. NHB had improved overall survival at higher volume centers, but this was dependent upon income, education, and surgical resection. Citation Format: Andrea N. Riner, Patrick W. Underwood, Kai Yang, Kelly M. Herremans, Miles E. Cameron, Srikar Chamala, Peihua Qiu, Thomas George, Jennifer Permuth, Nipun B. Merchant, Jose G. Trevino. Disparities in pancreatic ductal adenocarcinoma - the significance of Hispanic ethnicity, by subgroup analysis, and treatment facility on clinical outcomes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1172

Expression of cytokines by CD8+ infiltration in PDAC.

(A) Expression of 41 analytes in PDAC (n = 58) and non-PDAC (Pancreatitis (n = 13), IPMN (n = 4), Other (n = 7)) expression is normalized to protein concentration (B) Spearman correlation analyses showing increased expression of IL-1B significantly associated with decreased CD8+ infiltration (r = -0.4299, p = 0.0045). (C) Principal component analysis plot of inflammatory signatures in different tissues, PCA was performed using 31 analytes, as 10 analytes (G-CSF, IL-9,IL-1B,IL-2,IL-3,IL-4,IL-5,MIP-1A,RANTES and TNFB) had limited detection across our patient cohort. PDAC (blue) is noted to be heterogenous in its inflammatory profile compared to non-PDAC tissue (Pancreatitis = red, Other = purple, IPMN = green).</p