Neuromuscular junction remodeling and deterioration due to impaired BMP signaling are associated with cancer-induced muscle wasting.

Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although it is responsible for approximately one-third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated. We previously identified the bromodomain and extra-terminal domain (BET) protein BRD4 as an epigenetic regulator of muscle mass. Here we show that the pan-BET inhibitor (+)-JQ1 protects tumor-bearing mice from body weight loss and muscle and adipose tissue wasting. Remarkably, in C26-tumor-bearing mice (+)-JQ1 administration dramatically prolongs survival, without directly affecting tumor growth. By ChIP-seq and ChIP analyses, we unveil that BET proteins directly promote the muscle atrophy program during cachexia. In addition, BET proteins are required to coordinate an IL6-dependent AMPK nuclear signaling pathway converging on FoxO3 transcription factor. Overall, these findings indicate that BET proteins may represent a promising therapeutic target in the management of cancer cachexia.

Compare surgical outcomes for hepatitis B virus (HBV)-hepatocellular carcinoma (HCC) versus hepatitis C virus (HCV)-hepatocellular carcinoma (HCC). HCC is the second leading cause of death from cancer worldwide and is associated with hepatitis virus infection in 80% of cases. Between 1997 and 2011, 1008 patients with hepatitis B (HBV, n = 431) or hepatitis C (HCV, n = 577) underwent resection (n = 567) or transplantation (n = 441). Resection was indicated for Child's A patients with single HCC; transplantation was indicated for patients within Milan criteria. Univariate and multivariate analyses were performed as well as survival and recurrence analysis using log-rank test. Based on uniform application of these criteria, resection: transplantation ratio was 3.6 for patients with HBV and 0.67 for patients with HCV. Resection: Patients with HBV had larger tumors and higher α-fetoprotein but less satellites and macrovascular invasion; 68% of HBV versus 89% of HCV were cirrhotic. Survival was better (P < 0.001) and recurrence was lower (P = 0.009) for HBV. Independent predictors of death included HCV (P = 0.024), transfusion (P = 0.013), and HCC of greater than 5 cm (P = 0.013). Limiting analysis to patients with cirrhosis, survival with HBV remained superior (P = 0.020) but recurrence did not. Transplantation: Tumors were similar in HBV and HCV. Survival was better (P = 0.002) for HBV; recurrence was similar. Independent predictors of death were HCV (P < 0.001), poor differentiation (P = 0.049), vascular invasion (P = 0.002), and outside Milan (P = 0.032). Limiting analysis to patients within Milan, HBV survival remained better for both resection (P = 0.030) and transplantation (P = 0.002). Survival after both resection and transplantation for HCC was better in HBV- than in HCV-related HCC whereas recurrence was also lower for HBV-HCC in the resection group, these differences are influenced by both liver and tumor factors.

One option for using organs from donors with a suboptimal nephron mass, e.g. expanded criteria donors (ECD) kidneys, is dual kidney transplantation (DKT). In adult recipients, DKT can be carried out by several techniques, but the unilateral placement of both kidneys (UDKT) offers the advantages of single surgical access and shorter operating time. One hundred UDKT were performed using kidneys from ECD donors with a mean age of 72 years (Group 1). The technique consists of transplanting both kidneys extraperitoneally in the same iliac fossa. The results were compared with a cohort of single kidney transplants (SKT) performed with the same selection criteria in the same study period (Group 2, n = 73). Ninety-five percent of UDKTs were positioned in the right iliac fossa, lengthening the right renal vein with an inferior vena cava patch. In 69% of cases, all anastomoses were to the external iliac vessels end-to-side. Surgical complications were comparable in both groups. At 3-year follow-up, patient and graft survival rates were 95.6 and 90.9% in Group 1, respectively. UDKT can be carried out with comparable surgical complication rates as SKT, leaving the contralateral iliac fossa untouched and giving elderly recipients a better chance of receiving a transplant, with optimal results up to 3-years follow-up.

Despite improvements to surgical procedures and novel combinations of drugs for adjuvant and neoadjuvant therapies for pancreatic adenocarcinoma, the recurrence rate after radical surgery is still high. Little is known about the role of surgery in the treatment of isolated recurrences of pancreatic cancer. The aim of this study was to review the current literature dealing with surgery for recurrent pancreatic cancer in order to examine its feasibility and effectiveness. An extensive literature review was conducted according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and 14 articles dealing with re-resections for recurrent pancreatic adenocarcinoma were analyzed, focusing on the characteristics of the primary neoplasm and its recurrence, the surgical procedures used, and patient outcomes. Data were retrieved on a total of 301 patients. The interval between surgery for primary pancreatic cancer and the detection of a recurrence ranged from 2 to 120 months. The recurrence was local or regional in 230 patients, and distant in 71. The median overall survival was 68.9 months (range 3–152) after resection of the primary tumor, and 26.0 months (range 0–112) after surgery for recurrent disease. The disease-free interval after the resection of recurrences was 14.2 months (range 4–29). Although data analysis was performed on a heterogeneous and limited number of patients, some of these may benefit from surgery for isolated recurrence of pancreatic adenocarcinoma. Further studies are needed to identify these cases.

Cachexia is a wasting syndrome characterized by devastating skeletal muscle atrophy that dramatically increases mortality in various diseases, most notably in cancer patients with a penetrance of up to 80%. Knowledge regarding the mechanism of cancer‐induced cachexia remains very scarce, making cachexia an unmet medical need. In this study, we discovered strong alterations of iron metabolism in the skeletal muscle of both cancer patients and tumor‐bearing mice, characterized by decreased iron availability in mitochondria. We found that modulation of iron levels directly influences myotube size in vitro and muscle mass in otherwise healthy mice. Furthermore, iron supplementation was sufficient to preserve both muscle function and mass, prolong survival in tumor‐bearing mice, and even rescues strength in human subjects within an unexpectedly short time frame. Importantly, iron supplementation refuels mitochondrial oxidative metabolism and energy production. Overall, our findings provide new mechanistic insights in cancer‐induced skeletal muscle wasting, and support targeting iron metabolism as a potential therapeutic option for muscle wasting diseases.