Joshua K. Kays

Differential Bone Loss in Mouse Models of Colon Cancer Cachexia

Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and ApcMin/+. The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the ApcMin/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia.

Three cachexia phenotypes and the impact of fat-only loss on survival in FOLFIRINOX therapy for pancreatic cancer: Distinct cachexia phenotypes and survival in PDAC

By the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here, we measure the longitudinal body composition changes in patients with advanced PDAC undergoing 5‐fluorouracil, leucovorin, irinotecan, and oxaliplatin therapy.

Identification of circulating protein biomarkers for pancreatic cancer cachexia

Background Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) suffer from cachexia, characterized by severe muscle and fat loss. Although various model systems have improved our understanding of cachexia, translating the findings to human cachexia has remained a challenge. In this study, our objectives were to i) identify circulating protein biomarkers using serum for human PDAC cachexia, (ii) identify the ontological functions of the identified biomarkers and (iii) identify new pathways associated with human PDAC cachexia by performing protein co-expression analysis. Methods Serum from 30 patients with PDAC was collected. Body composition measurements of skeletal muscle index (SMI), skeletal muscle density (SMD), total adipose index (TAI) were obtained from computed tomography scans (CT). Cancer associated weight loss (CAWL), an ordinal classification of history of weight loss and body mass index (BMI) was obtained from medical record. Serum protein profiles and concentrations were generated using SOMAscan, a quantitative aptamer-based assay. Ontological analysis of the proteins correlated with clinical variables (r≥ 0.5 and p<0.05) was performed using DAVID Bioinformatics. Protein co-expression analysis was determined using pairwise Spearman’s correlation. Results Overall, 111 proteins of 1298 correlated with these clinical measures, 48 proteins for CAWL, 19 for SMI, 14 for SMD, and 30 for TAI. LYVE1, a homolog of CD44 implicated in tumor metastasis, was the top CAWL-associated protein (r= 0.67, p=0.0001). Other proteins such as INHBA, MSTN/GDF11, and PIK3R1 strongly correlated with CAWL. Proteins correlated with cachexia included those associated with proteolysis, acute inflammatory response, as well as B cell and T cell activation. Protein co-expression analysis identified networks such as activation of immune related pathways such as B-cell signaling, Th1 and Th2 pathways, natural killer cell signaling, IL6 signaling, and mitochondrial dysfunction. Conclusion Taken together, these data both identify immune system molecules and additional secreted factors and pathways not previously associated with PDAC and confirm the activation of previously identified pathways. Identifying altered secreted factors in serum of PDAC patients may assist in developing minimally invasive laboratory tests for clinical cachexia as well as identifying new mediators.

IP231. Short- and Long-Term Outcomes After Abdominal Aortic Aneurysm Repair Are Noninferior at a Veterans Affairs Hospital Staffed by Academic Vascular Surgeons

Results: In this study, 33 patients (16 diabetic, 17 nondiabetic) who underwent femoral endarterectomy for high-grade occlusive disease were evaluated. No significant difference in key demographics was observed. Tissue plaque FAS content was 69.8% higher in diabetic compared with nondiabetic patients (P 1⁄4 .011); cFAS was also elevated by 41.7% in diabetic patients compared with nondiabetic patients (P 1⁄4 .048). Correlation analysis of 23 patients’ paired samples revealed a significant correlation between cFAS and plaque FAS content (Spearman r 1⁄4 0.4711; r 1⁄4 0.229; P 1⁄4 .023). Conclusions: Our study is the first to evaluate cFAS levels in patients with high-grade, symptomatic, lower extremity peripheral artery disease and demonstrates evidence that cFAS and tissue FAS levels correlate in patients withdiabetes. Future studieswill helpdeterminewhether cFAS is a relevant biomarker for disease severity and progression in diabetic patients.

Sarcopenia is a Significant Predictor of Mortality After Abdominal Aortic Aneurysm Repair

Repair of abdominal aortic aneurysms (AAA) decreases the incidence of rupture and death. In cancer patients, sarcopenia has been associated with increased surgical complications and mortality. The impact of sarcopenia on survival after AAA repair has yet to be described.

Understanding the critical role for surgery in the management of wild-type gastrointestinal stromal tumor (GIST)

Recently in the Journal of Clinical Oncology , Weldon and coworkers from the National Institutes of Health reported a retrospective single institution experience with patient outcomes following the surgical treatment of WT gastrointestinal stromal tumor (GIST). Main outcomes examined was the association of surgery with event free survival (EFS) (1). Overall, the study reported a 1-, 5-, and 10-year EFS of 73%, 24%, and 16% respectively. Tumor biology factors such as metastatic disease [adjusted hazard ratio (AHR) =2.3; confidence interval (CI): 1.0–5.1; P=0.04) and >5 mitoses per 50 high-power fields (AHR =2.5; CI: 1.1–6.0; P=0.03) had a significantly increased hazard of disease progression or recurrence. In contrast, surgical considerations such as microscopic resection margin and type of gastric resection (wedge vs. anatomic) were not significantly associated with EFS.

Resection or transplantation for hepatocellular carcinoma: is the decision clear for patients beyond Milan criteria?

Hepatocellular carcinoma (HCC) is the second leading cause of cancer related mortality worldwide, and in western countries, its incidence is on the rise (1,2).