Pediatric-protocol of multimodal therapy is associated with improved survival in AYAs and adults with rhabdomyosarcoma.

BACKGROUND: Multimodal therapy is the standard treatment for pediatric rhabdomyosarcoma, but for adolescents and young adults (AYAs: ages 15-39) and older adults with rhabdomyosarcoma, the use of adjuvant therapy is variable, and survival is greatly decreased compared with younger patients. METHODS: All patients with rhabdomyosarcoma who had a curative operative were identified from the 1998-2012 National Cancer Database. Regression analyses identified independent factors relating to receipt of multimodal therapy (resection + chemotherapy + radiation) and the influence of multimodal therapy on 5-year overall survival. RESULTS: Of 2,312 patients, 44% were pediatric (age < 15 years), 22% AYA (ages 15-39), and 34% adult (age ≥ 40 years). Adults received multimodal therapy least often (pediatric: 62%, AYA: 46%, adults: 24%; P < .001), even after controlling for demographic characteristics, tumor features, and stage. In the entire cohort, multimodal therapy was associated with a decreased risk of death within 5 years (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.62-0.84), with similar findings after stratification by age (pediatric: HR 0.64, 95% CI 0.48-0.85; AYA: HR 0.72, 95% CI 0.55-0.95; adult: HR 0.74, 95% CI 0.58-0.93). In AYAs only, black and Hispanic patients had an increased risk of death within 5 years (black patients: HR 1.64, 95% CI 1.14-2.37; Hispanic patients: HR 1.62, 95% CI 1.11-2.36). CONCLUSION: This first large national study suggests that multimodal therapy is independently associated with improved survival for both AYAs and adults with rhabdomyosarcoma, similar to pediatric patients, but multimodal therapy is appreciably underused. Implementation of multimodal therapy for all patients could potentially improve overall outcomes of patients with rhabdomyosarcoma.

Sex-Specific Differences in Colon Cancer when Quality Measures Are Adhered to: Results from International, Prospective, Multicenter Clinical Trials.

BACKGROUND: There is no consensus on the relationship between patient sex and the location, stage, and oncologic outcome of colon cancer (CC). We hypothesized that there is a sex-specific difference in the biology and management of CC. STUDY DESIGN: Our cohort was drawn from a database of patients enrolled in international trials of nodal ultrastaging for nonmetastatic CC. These trials required strict adherence to surgical and pathologic quality measures. Postoperative follow-up included colonoscopy at 1 and 4 years and annual CT scans. Sex-specific differences in tumor biology, location, stage, and recurrence were evaluated by chi-square, Fischer's exact, and independent t-tests. RESULTS: The cohort included 435 males (median age 69 years) and 423 females (median age 70 years). Females had more right-sided (p = 0.03) and earlier T stage (p = 0.05) tumors, but there was no sex-based difference in pathologic grade, total lymph nodes retrieved, nodal positivity (p = 0.47) or lymphovascular invasion (p = 0.45). The overall 4-year disease-free survival (DFS) was comparable in females and males (77.9% and 77.5%, respectively). By multivariate analysis, only nodal positivity and cancer recurrence affected overall survival (OS) (p = 0.008). Neither sex nor primary tumor affected DFS or OS. CONCLUSIONS: This is the first prospective study to demonstrate sex-specific differences in location and T stage of CC when surgical and pathologic management adhered to strict quality standards. The predominance of right-sided CC in females suggests that flexible sigmoidoscopy may be inadequate for screening and surveillance. Interestingly, earlier stage and right-sided location did not confer a DFS or OS advantage for women. Additional studies are needed to determine why females have a higher propensity for right-sided lesions and a potential difference in CC biology.

Anatomic Location Is the Primary Determinant of Survival for Paragangliomas.

Paragangliomas (PGL) are rare neuroendocrine tumors. This study describes the largest collection of PGLs and evaluates factors that impact survival. Patients with PGL from 1998 to 2013 in the NCDB were reviewed. Independent predictors of overall survival (OS) were identified for patients with non-central nervous system (CNS) tumors. Of 867 PGLs, the primary site was CNS (39.9%), abdomen/pelvis (A&P) (21.0%), head and neck (H&N) (17.5%), thoracic (15.1%), bladder (3%), or unspecified (3.5%). Of 521 non-central nervous system (CNS) PGLs, there were differences in sex, comorbidities, treatment facility, tumor size, treatment modality (P < 0.001). Five-year OS for this cohort was 66 per cent and 10-year OS was 51 per cent. Median OS differed significantly between primary sites (H&N 106.0 months, thoracic 89.0 months, A&P 81.7 months, bladder 69.7 months, and unspecified 27.2, P < 0.001). After controlling for multiple factors, age greater than 50 (HR 1.97; CI 1.38-2.81), primary site A&P (HR 2.01; CI) 1.17-3.48) or bladder (HR 4.03; CI 1.64-9.89) as compared with H&N, distant metastasis (HR 2.25; CI 1.44-3.53) and those who did not receive surgery (HR 2.85; CI 1.89-4.31) all exhibited decreased OS. This is the largest series of PGLs and the first to demonstrate significant survival differences based on PGL site. Abdominal/pelvic and bladder PGLs had the lowest survival in addition to patients that did not have a surgical resection, those with distant metastases, and >50 years of age.

Resource utilization in esophagectomy: When higher costs are associated with worse outcomes.

INTRODUCTION: Care of the esophagectomy patient requires significant resources. We sought to determine which patient and provider variables contribute to resource utilization and their association with clinical outcomes. METHODS: 6,737 patients undergoing esophagectomy were identified from the University Healthsystem Consortium (UHC). Linear and logistic regression models were used to determine whether characteristics, including age, severity of illness (SOI) and procedural volume were associated with mortality, length of stay (LOS), discharge disposition, readmission rates, and cost. RESULTS: Older patients were twice as likely to suffer post-operative death (OR 2.12; 95%CI 1.7-2.7), three times more likely to be discharged to extended care facilities (31.9% vs. 10.6%, P < 0.001), and cost 8.4% more ($27,628 vs. $25,481, P < 0.001). Similarly, patients with higher SOI were more likely to suffer post- operative death (OR 14.6; 4.7-45.9), be readmitted (OR 1.3; 1.1-1.6), and have longer hospital stays (RR 1.3; 1.8-2.1). Patients with the highest index hospital costs were five times more likely to be discharged to an extended care facility (P < 0.001). CONCLUSION: Older patients and those with a higher SOI have higher perioperative mortality, readmission rates, hospital costs, and require more post- operative care. With increasingly scrutinized health care costs, these data provide guidance for more careful patient selection.

Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats.

Fibroblast growth factor-19 (FGF19) and its rodent ortholog, FGF15, are hormones produced in the distal small intestine and secreted into the circulation after a meal. In addition to controlling the enterohepatic circulation of bile acids, FGF15/19 also regulates systemic lipid and glucose metabolism. In these experiments we investigated the hypothesis that, like other gut-derived postprandial hormones, FGF15/19 can act in the central nervous system to elicit its metabolic effects. We found that FGF-receptors 1 and 4 are present in rat hypothalamus, and that their expression was reduced by up to 60% in high-fat fed rats relative to lean controls. Consistent with a potential role for brain FGF15/19 signaling to regulate energy and glucose homeostasis, and with a previous report that intracerebroventricular (i.c.v.) administration of FGF19 increases energy expenditure, we report that acute i.c.v. FGF19 reduces 24-h food intake and body weight, and acutely improves glucose tolerance. Conversely, i.c.v. administration of an FGF-receptor inhibitor increases food intake and impairs glucose tolerance, suggesting a physiological role for brain FGF receptor signaling. Together, these findings identify the central nervous system as a potentially important target for the beneficial effects of FGF19 in the treatment of obesity and diabetes.

The role of the gut hormone GLP-1 in the metabolic improvements caused by ileal transposition.

BACKGROUND: Bariatric surgery alters the gastrointestinal hormonal milieu leading to improved glucose homeostasis, though the mechanism leading to these changes is poorly understood. Ileal transposition (IT) is a procedure that is neither restrictive nor malabsorptive but nevertheless produces profound improvements in glucose regulation. Ileal transposition involves a short segment of distal ileum being transposed to the proximal jejunum in an isoperistaltic direction, thereby avoiding any gastric resection or intestinal bypass. METHODS: Diet-induced obese rats underwent either ileal transposition (IT) or Sham procedures. The Sham operated rats were pair-fed to the IT surgical group to control for the effects of reduced food intake. Body composition data were recorded at specific time points, and glucose tolerance tests were performed at 5 and 6 wk, both in the presence and absence of Exendin 9-39, a known glucose-like peptide 1 (GLP-1) receptor antagonist. A subset of naïve rats were also maintained for comparison. RESULTS: IT and Sham operated rats had no differences in food intake and body weight, however, IT rats had a significant decrease in their body fat composition (P < 0.05). No difference existed in glucose tolerance when exposed to an intraperitoneal glucose load, however, IT rats showed markedly improved glucose tolerance when submitted to an oral glucose tolerance test (P < 0.001). Blocking GLP-1 receptors reversed these important improvements in rats with IT surgery. CONCLUSIONS: The present work recapitulates what is seen in rodents and humans that IT improves glucose tolerance and body composition. The present data provide compelling evidence that these improvements are a product of increased GLP-1 secretion that results from placing the key GLP-1 secreting cells closer to chyme coming from the stomach. Such data support the notion that rather than restriction or malabsorption, the underling molecular mechanisms that mediate the potent improvements produced by bariatric procedures involve increased activation of GLP-1 signaling.

Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats.

BACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) reduce weight and improve glucose metabolism in obese patients, although it is not clear if metabolic changes are independent of weight loss. We investigated alterations in glucose metabolism in rats following RYGB or VSG. METHODS: Rats underwent RYGB or VSG and were compared to sham-operated rats fed ad lib or pair-fed to animals that received RYGB. Intraperitoneal glucose tolerance and insulin sensitivity tests were performed to assess glycemic function independent of incretin response. A hyperinsulinemic euglycemic clamp was used to compare tissue-specific changes in insulin sensitivity following each procedure. A mixed-meal tolerance test was used to assess the effect of each surgery on postprandial release of glucagon-like peptide 1 (GLP-1)(7-36) and glucose tolerance, and was also performed in rats given GLP-1 receptor antagonist exendin(9-39). RESULTS: Following RYGB or VSG, glucose tolerance and insulin sensitivity improved in proportion to weight loss. Hepatic insulin sensitivity was significantly better in rats that received RYGB or VSG compared with rats fed ad lib or pair-fed, whereas glucose clearance was similar in all groups. During the mixed-meal tolerance test, plasma levels of GLP-1(7-36) and insulin were greatly and comparably increased in rats that received RYGB and VSG compared with those that were pair-fed or fed ad lib. Administration of a GLP-1 receptor antagonist prevented improvements in glucose and insulin responses after a meal among rats that received RYGB or VSG. CONCLUSIONS: In obese rats, VSG is as effective as RYGB for increasing secretion of GLP-1 and insulin and improving hepatic sensitivity to insulin; these effects are independent of weight loss.

Similar effects of roux-en-Y gastric bypass and vertical sleeve gastrectomy on glucose regulation in rats.

Bariatric surgery is the most efficacious procedure for eliciting weight loss in humans, and many patients undergoing the procedure experience significant lessening of their symptoms of type-2 diabetes in addition to losing weight. We have adapted two bariatric surgical procedures commonly employed in humans to a rat model to begin to understand the mechanisms underlying the improvements in energy homeostasis. Young adult male rats received either roux-en-Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG) and were assessed for body weight, food intake and parameters of glucose homeostasis over a 28-week period. Control rats received either a sham surgical procedure or else were unoperated. RYGB and VSG had comparable beneficial effects relative to controls. They ate less food and lost more weight, and they both had improved glucose parameters. The most intriguing aspect of the findings is that the two surgical procedures had such similar effects in spite of quite different rearrangements of the gastrointestinal system.