Morbidity and mortality after surgery for cancer of the oesophagus and gastro-oesophageal junction: A randomized clinical trial of neoadjuvant chemotherapy vs. neoadjuvant chemoradiation.

OBJECTIVE: To compare the incidence and severity of postoperative complications after oesophagectomy for carcinoma of the oesophagus and gastro-oesophageal junction (GOJ) after randomized accrual to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT). BACKGROUND: Neoadjuvant therapy improves long-term survival after oesophagectomy. To date, evidence is insufficient to determine whether combined nCT, or nCRT alone, is the most beneficial. METHODS: Patients with carcinoma of the oesophagus or GOJ, resectable with a curative intention, were enrolled in this multicenter trial conducted at seven centres in Sweden and Norway. Study participants were randomized to nCT or nCRT followed by surgery with two-field lymphadenectomy. Three cycles of cisplatin/5-fluorouracil was administered in all patients, while 40 Gy of concomitant radiotherapy was administered in the nCRT group. RESULTS: Of the randomized 181 patients, 91 were assigned to nCT and 90 to nCRT. One-hundred-and-fifty-five patients, 78 nCT and 77 nCRT, underwent resection. There was no statistically significant difference between the groups in the incidence of surgical or nonsurgical complications (P-value = 0.69 and 0.13, respectively). There was no 30-day mortality, while the 90-day mortality was 3% (2/78) in the nCT group and 6% (5/77) in the nCRT group (P = 0.24). The median Clavien-Dindo complication severity grade was significantly higher in the nCRT group (P = 0.001). CONCLUSION: There was no significant difference in the incidence of complications between patients randomized to nCT and nCRT. However, complications were significantly more severe after nCRT. REGISTRATION TRIAL DATABASE: The trial was registered in the Clinical Trials Database (registration number NCT01362127).

Expertise-based randomized clinical trial of laparoscopic versus small-incision open cholecystectomy.

BACKGROUND: Several randomized clinical trials have compared laparoscopic cholecystectomy (LC) and small-incision open cholecystectomy (SIOC). Most have had wide exclusion criteria and none was expertise-based. The aim of this expertise-based randomized trial was to compare healthcare costs, quality of life (QoL), pain and clinical outcomes after LC and SIOC. METHODS: Patients scheduled for cholecystectomy were randomized to treatment by one of two teams of surgeons with a preference for either LC or SIOC. Each team performed their specific method (SIOC or LC) as a first-choice operation, but converted to open cholecystectomy and common bile duct exploration when necessary. Intraoperative cholangiography was carried out routinely. The intention was to include all patients undergoing cholecystectomy, including emergency operations and procedures involving surgical training for residents. RESULTS: Some 74·9 per cent of all patients undergoing cholecystectomy were included. Of 355 patients randomized, 333 were analysed. Self-estimated QoL scores in 258 patients, analysed by the area under the curve method, were significantly lower in the SIOC group at 1 month after surgery: median 2326 (95 per cent confidence interval 2187 to 2391) compared with 2411 (2334 to 2502) for the LC group (P = 0·030). The mean(s.d.) duration of operation was shorter for SIOC: 97(41) versus 120(48) min (P < 0·001). There were no significant differences between the groups in conversion rate, pain, complications, length of hospital stay or readmissions. CONCLUSION: SIOC had comparable surgical results but slightly worse short-term QoL compared with LC. REGISTRATION NUMBER: NCT00370344 (http://www.clinicaltrials.gov).

Sex- and depot-specific lipolysis regulation in human adipocytes: interplay between adrenergic stimulation and glucocorticoids.

The purpose of this investigation was to explore interactions between adrenergic stimulation, glucocorticoids, and insulin on the lipolytic rate in isolated human adipocytes from subcutaneous and omental fat depots, and to address possible sex differences. Fat biopsies were obtained from 48 nondiabetic subjects undergoing elective abdominal surgery. Lipolysis rate was measured as glycerol release from isolated cells and proteins involved in lipolysis regulation were assessed by immunoblots. Fasting blood samples were obtained and metabolic and inflammatory variables were analyzed. In women, the rate of 8-bromo-cAMP- and isoprenaline-stimulated lipolysis was approximately 2- and 1.5-fold higher, respectively, in subcutaneous compared to omental adipocytes, whereas there was no difference between the two depots in men. Dexamethasone treatment increased the ability of 8-bromo-cAMP to stimulate lipolysis in the subcutaneous depot in women, but had no consistent effects in fat cells from men. Protein kinase A, Perilipin A, and hormone sensitive lipase content in adipocytes was not affected by adipose depot, sex, or glucocorticoid treatment. In conclusion, catecholamine and glucocorticoid regulation of lipolysis in isolated human adipocytes differs between adipose tissue depots and also between sexes. These findings may be of relevance for the interaction between endogenous stress hormones and adipose tissue function in visceral adiposity and the metabolic syndrome.

Depot-specific messenger RNA expression of 11 beta-hydroxysteroid dehydrogenase type 1 and leptin in adipose tissue of children and adults.

OBJECTIVE: To compare expression of messenger RNA (mRNA) coding for the cortisol regenerating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), and the adipocytokines leptin and resistin in paired biopsies of subcutaneous adipose tissue (SC) and omental adipose tissue (OM) from children. DESIGN: Paired biopsies (SC and OM) were obtained from 54 children (age 0.17-16 years, body mass index (BMI) 12.5-28.3 kg/m(2), BMI standard deviation score (SDS) -2.5-4.5) and 16 adults (age 27-79 years, BMI 19-46 kg/m(2)) undergoing open abdominal surgery. mRNA levels of 11beta-HSD1, leptin and resistin were measured using quantitative real-time polymerase chain reaction (PCR). RESULTS: 11beta-HSD1 mRNA level was higher in OM than in SC (P<0.05), whereas leptin mRNA was higher in SC than in OM (P<0.001). There was no difference in the resistin mRNA level between SC and OM. These results were consistent in children and adults. In children, 11beta-HSD1 mRNA in SC was positively associated with BMI SDS (P<0.05), whereas in OM it was positively associated with age (P<0.05). The association between 11beta-HSD1 expression and age remained significant after adjustment for BMI SDS and gender. Leptin mRNA was positively associated with BMI SDS (SC: P<0.001, OM: P<0.001) but not with age in children. In multiple regression analyses, including anthropometric variables and age, BMI SDS was independently associated with mRNA levels of 11beta-HSD1 (P<0.05) and leptin (P<0.001) in SC. When normal weight and overweight children were analyzed separately, 11beta-HSD1 mRNA levels were positively associated with leptin in OM in the overweight group (P<0.05). CONCLUSION: There are depot-specific differences in mRNA levels of 11beta-HSD1 and leptin in children and adults. The positive association of 11beta-HSD1 mRNA in OM with age may reflect a causal role in visceral fat accumulation during growth. Increasing 11beta-HSD1 and leptin mRNA in SC with increasing BMI SDS could suggest that the risk of metabolic consequences of obesity may be established early in life.

Lipoprotein lipase activity/mass ratio is higher in omental than in subcutaneous adipose tissue.

BACKGROUND: Lipoprotein lipase (LPL) is important for lipid deposition in adipose tissue (AT) and responds rapidly to changes in the nutritional state. Animal experiments indicate that short-term regulation of LPL is mainly post-translational. Different processing of LPL in different AT depots may play a role in the distribution of lipids in the body. MATERIALS AND METHODS: Lipoprotein lipase mRNA, mass and activity were measured in pieces of omental adipose tissue (OAT) and subcutaneous adipose tissue (SAT) from 15 subjects undergoing gastrointestinal surgery (four male and 11 female subjects, mean age 54 +/- 5 years, BMI 28 +/- 2 kg m(-2)). RESULTS: Lipoprotein lipase activity was higher in OAT than in SAT (18 +/- 2.1 compared with 12 +/- 1.6 mU g(-1), P < 0.01), whereas LPL mass was lower in OAT than in SAT (100 +/- 9 compared with 137 +/- 16 mU g(-1), P < 0.05). Consequently, the specific LPL activity (ratio of activity over mass) was approximately twofold greater in OAT compared with SAT. There was correlation between LPL mRNA and LPL activity in SAT (P < 0.05) and a similar tendency in OAT (P = 0.08). There were strong correlations (P < 0.01) for mRNA abundance as well as for LPL activity between the two depots. In contrast there was no correlation between the LPL mass and LPL mRNA or activity in any of the depots. CONCLUSIONS: These results indicate that long-term regulation, as reflected in the mRNA abundance, is similar in the two types of adipose tissue. The displayed activity reflects the mRNA abundance and the fraction of newly synthesized LPL molecules which the post-translational mechanism allows to become/remain active. This fraction was on average twofold greater in OAT compared with SAT.

Glucocorticoids down-regulate glucose uptake capacity and insulin-signaling proteins in omental but not subcutaneous human adipocytes.

Visceral adiposity is associated with insulin resistance and type 2 diabetes. This study explores the metabolic differences between s.c. and visceral fat depots with respect to effects in vitro of glucocorticoids and insulin on glucose uptake. Adipocytes from human s.c. and omental fat depots were obtained during abdominal surgery in 18 nondiabetic subjects. Cells were isolated, and metabolic studies were performed directly after the biopsies and after a culture period of 24 h with or without dexamethasone. After washing, basal and insulin-stimulated [14C]glucose uptake as well as cellular content of insulin signaling proteins and glucose transporter 4 (GLUT4) was assessed. Omental adipocytes had an approximately 2-fold higher rate of insulin-stimulated glucose uptake compared with s.c. adipocytes (P < 0.01). Dexamethasone treatment markedly inhibited (by approximately 50%; P < 0.05) both basal and insulin-stimulated glucose uptake in omental adipocytes but had no consistent effect in s.c. adipocytes. The cellular content of insulin receptor substrate 1 and phosphatidylinositol 3-kinase did not differ significantly between the depots, but the expression of protein kinase B (PKB) tended to be increased in omental compared with s.c. adipocytes (P = 0.09). Dexamethasone treatment decreased the expression of insulin receptor substrate 1 (by approximately 40%; P < 0.05) and PKB (by approximately 20%; P < 0.05) in omental but not in s.c. adipocytes. In contrast, dexamethasone pretreatment had no effect on insulin-stimulated Ser473 phosphorylation of PKB. GLUT4 expression was approximately 4-fold higher in omental than s.c. adipocytes (P < 0.05). Dexamethasone treatment did not alter the expression of GLUT4. In conclusion, human omental adipocytes display approximately 2-fold higher glucose uptake rate compared with s.c. adipocytes, and this could be explained by a higher GLUT4 expression. A marked suppression is exerted by glucocorticoids on glucose uptake and on the expression of insulin signaling proteins in omental but not in s.c. adipocytes. These findings may be of relevance for the interaction between endogenous glucocorticoids and visceral fat in the development of insulin resistance.