Yves Van Nieuwenhove

Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer: A systematic review and meta-analysis

Combining chemotherapy with preoperative radiotherapy (RT) has a sound radiobiological rationale. We performed a systematic review and meta‐analysis of trials comparing preoperative RT with preoperative chemoradiation (CRT) in rectal cancer patients. The Cochrane Central Register of Controlled Trials, Web of Science, Embase and Medline (Pubmed) were searched from 1975 until June 2007. Dichotomous parameters were summarized using the odds ratio while time to event data were analyzed using the pooled hazard ratio for death. From the primary search result of 324 trials, 4 relevant randomized trials were identified. The addition of chemotherapy significantly increased grade III and IV acute toxicity (p = 0.002) while no differences were observed in postoperative morbidity or mortality. Preoperative CRT significantly increased the rate of pathological complete response (p < 0.001) although this did not translate into a higher sphincter preservation rate (p = 0.29). The local recurrence rate was significantly lower in the CRT group (p < 0.001). No statistically significant differences were observed in disease free survival (p = 0.89) or overall survival (p = 0.79). Compared to preoperative RT alone, preoperative CRT improves local control in rectal cancer but is associated with a more pronounced treatment related toxicity. The addition of chemotherapy does not benefit sphincter preservation rate or long‐term survival. Future trials should address improvements in the rate of distant metastasis and overall survival by incorporating more active chemotherapy.

Anastomotic complications after Ivor Lewis esophagectomy in patients treated with neoadjuvant chemoradiation are related to radiation dose to the gastric fundus.

PURPOSE Neoadjuvant chemoradiation (CRT) is increasingly used in locally advanced esophageal cancer. Some studies have suggested that CRT results in increased surgical morbidity. We assessed the influence of CRT on anastomotic complications in a cohort of patients who underwent CRT followed by Ivor Lewis esophagectomy. PATIENTS AND METHODS Clinical and pathologic data were collected from all patients treated with neoadjuvant CRT (36 Gy combined with 5-fluorouracil and cisplatin) followed by Ivor Lewis esophagectomy. On the radiotherapy (RT) planning computed tomography scans, normal tissue volumes were drawn encompassing the proximal esophageal region and the gastric fundus. Within these volumes, dose-volume histograms were analyzed to generate the total dose to 50% of the volume (D(50)). We studied the ability of the D(50) to predict anastomotic complications (leakage, ischemia, or stenosis). Dose limits were derived using receiver operating characteristics analysis. RESULTS Fifty-four patients were available for analysis. RT resulted in either T or N downstaging in 51% of patients; complete pathologic response was achieved in 11%. In-hospital mortality was 5.4%, and major morbidity occurred in 36% of patients. Anastomotic complications (AC) developed in 7 patients (13%). No significant influence of the D(50) on the proximal esophagus was noted on the anastomotic complication rate. The median D(50) on the gastric fundus, however, was 33 Gy in patients with AC and 18 Gy in patients without AC (p = 0.024). Using receiver operating characteristics analysis, the D(50) limit on the gastric fundus was defined as 29 Gy. CONCLUSIONS In patients undergoing neoadjuvant CRT followed by Ivor Lewis esophagectomy, the incidence of AC is related to the RT dose on the gastric fundus but not to the dose received by the proximal esophagus. When planning preoperative RT, efforts should be made to limit the median dose on the gastric fundus to 29 Gy with a V(30) below 40%.

Lymphatic spread, nodal count and the extent of lymphadenectomy in cancer of the colon

In colon cancer, the biological significance of lymphatic tumour spread remains a matter of debate, which impacts on related questions such as the ideal extent of lymphadenectomy and the prognostic significance of lymph node counts. Several lines of evidence suggest that metastasis to locoregional nodes occurs early and is a stochastic, rather than a stepwise phenomenon, and in essence reflects the tumour-host-metastasis relationship. Not surprisingly, therefore, several clinical trials failed to identify a survival benefit from extensive lymphadenectomy compared to standard resection. The recently described complete mesocolic excision technique, which aims to improve survival by maximizing nodal clearance, should be subjected to a prospective randomized trial. There has been a fairly consistent and intriguing relation between nodal counts and survival in colon cancer. Therapeutic effects of more extensive removal of invaded nodes seem an unlikely explanation for the observed association. Similarly, several findings argue against stage migration as the only or even the most important explanation. The available literature shows an extensive array of factors confounding the nodal count-survival relationship, which are correlated to the patients clinical characteristics, pathology variables, and factors relating to the individual (treating surgeon and pathologist) and institutional healthcare levels. More research into the biology of nodal spread and the nodal count-survival relationship is indicated and may have important implications for therapy such as the further introduction of minimally invasive surgery and the identification of novel and potentially modifiable factors impacting on both nodal counts and survival.

Oral bioavailability of moxifloxacin after Roux-en-Y gastric bypass surgery

OBJECTIVES Roux-en-Y gastric bypass surgery is the most commonly performed procedure for the treatment of morbid obesity. This anatomical alteration may affect the absorption and consequently the bioavailability of oral drugs. This study aims to investigate the oral bioavailability of moxifloxacin in 12 healthy volunteers who underwent gastric bypass surgery. PATIENTS AND METHODS In this randomized crossover study, each subject received two single standard doses of 400 mg of moxifloxacin orally or intravenously administered on two occasions separated by a washout period of 1 week. Serial venous blood samples were drawn up to 72 h after dosing and moxifloxacin plasma levels were measured by a validated HPLC method with fluorescence detection. [clinicaltrials.gov database (identifier: NCT01130922).] RESULTS After oral dosing, moxifloxacin plasma concentrations reached a maximum (C(max)) of 3.38 ± 1.41 mg/L after 1.75 h (0.75-4.00). After intravenous dosing, C(max) and T(max) were 4.53 ± 1.43 mg/L and 1.03 h (0.75-2.50), respectively. The mean areas under the plasma concentration time curve extrapolated to infinity (AUC(∞)) were 46.2 ± 1.4 mg · h/L after oral dosing and 52.3 ± 1.3 mg · h/L after intravenous dosing, resulting in a mean oral bioavailability of 88.32% [90% confidence interval (CI) 85.64%-91.08%]. CONCLUSIONS This study confirms that exposure to moxifloxacin is equivalent for oral and intravenous administration of 400 mg dosages in healthy volunteers who underwent gastric bypass surgery. But these exposures were more than 50% higher than those described for subjects without gastric bypass. This may suggest a higher enterohepatic recirculation of moxifloxacin after gastric bypass.

Chemerin as biomarker for insulin sensitivity in males without typical characteristics of metabolic syndrome

To allow early detection and prevention of metabolic disorders, circulating levels of adipokines involved in insulin sensitivity were compared with the hyperinsulinemic-euglycemic clamp. Twenty non-obese normo-glycaemic men (age 32.1 ± 6 years) underwent a clamp procedure. Levels of leptin, adiponectin, resistin, visfatin, omentin and chemerin levels were determined in fasting blood samples. Pearson correlation coefficients between the M-value for insulin sensitivity and fasting levels of chemerin (r = −0.63, P = 0.003) and leptin (r = −0.54, P = 0.013) performed better than conventional surrogate measures of insulin sensitivity (HOMA-IR: r = −0.45, P = 0.048; Quicki: r = 0.36, P = 0.12). However, only the relation between M-valueLBM and chemerin remained significant when adjusting for BMI and fasting insulin levels (r = −0.559, P = 0.016). In conclusion, fasting levels of chemerin might be used as biomarker to identify insulin resistance in healthy men without typical characteristics of metabolic disorders.

Risk factors and consequences of anastomotic leakage after Ivor Lewis oesophagectomy

OBJECTIVES Oesophageal carcinoma (EC) remains an aggressive disease. Despite extensive changes in therapeutic modalities, surgical resection remains the first choice therapy for curable oesophageal cancer patients. Anastomotic sites are prone to serious complications such as leakage, fistula, bleeding and stricture. Leakage of the anastomosis (AL) remains one of the main causes of postoperative morbidity and mortality. The purpose of this study was to identify predictors associated with postoperative leakage after Ivor Lewis oesophagectomy and its consequences in a single centre. METHODS We performed a retrospective analysis of 412 Ivor Lewis oesophageal resections in a single institute between 2005 and 2014. Univariable and multivariable logistic regression have been used to identify predictors of AL and its impact on postoperative outcome and overall survival. Kaplan-Meier curve was used to analyse overall survival and log-rank analysis to determine odds ratio. RESULTS A total of 412 patients were evaluated. Mean age was 62 ± 11 years (77% male). Overall leak rate was 2.9%. In-hospital or 30-day mortality was 4.4%. Mean intensive care unit (ICU) stay was 1 day and mean hospital stay was 19 days. A history of renal failure, diabetes, higher American Society of Anaesthesiologists score and current cigarette and corticosteroid use were identified as predictors of AL on univariable analysis. Multivariable analysis identified active smoking [P = 0.05, odds ratio (OR) 4.34, 95% confidence interval (CI): 0.98-19.28] and active corticosteroid use (P < 0.001, OR 15.8, 95% CI: 3.25-76.7) as independent significant predictors. A history of diabetes tended to be associated with a higher leakage rate but failed to reach statistical significance. AL was associated with a longer ICU and hospital stay and a significantly higher mortality (42% in the AL group vs 3% in the control group, P < 0.0001). CONCLUSIONS Anastomotic leakage after oesophagectomy is a major cause of postoperative morbidity and mortality. Identifying risk factors preoperatively can contribute to the prevention of postoperative complications.

N-glycan based biomarker distinguishing non-alcoholic steatohepatitis from steatosis independently of fibrosis

BACKGROUND Non-alcoholic fatty liver disease is a spectrum of disorders ranging from steatosis to non-alcoholic steatohepatitis (NASH). Steatosis of the liver is benign, whereas NASH can progress to cirrhosis or even hepatocellular carcinoma. Currently, a liver biopsy is the only validated method to distinct NASH from steatosis. AIM The objective of this study was to identify a biomarker specific for NASH based on the N-glycosylation of serum proteins. METHODS N-glycosylation patterns were assessed using DNA sequencer-assisted fluorophore-assisted capillary electrophoresis and compared with histology. RESULTS Initially, a glycomarker (log[NGA2F]/[NA2]) was developed based on the results obtained in 51 obese non-alcoholic patients scheduled for bariatric surgery. Multivariate analysis showed that our glycomarker had the lowest P-value of all biomarkers in distinguishing NASH from steatosis (P=0.069). The glycomarker was validated in a cohort of 224 non-alcoholic fatty liver disease patients. In both pilot and validation study, glycomarker score increased in ascending amount of lobular inflammation (single-factor ANOVA, P ≤ 0.001 and P=0.012, respectively). The N-glycan profile of immunoglobulin G in the NASH population confirmed the significantly increased undergalactosylation present in these patients. CONCLUSION Our glycomarker specifically recognises liver inflammation in obese individuals which is the main trigger for the development of steatohepatitis and can differentiate between steatosis and NASH.

Combined Gene and Protein Expression of Hormone-Sensitive Lipase and Adipose Triglyceride Lipase, Mitochondrial Content, and Adipocyte Size in Subcutaneous and Visceral Adipose Tissue of Morbidly Obese Men

Aims: Lipotoxicity in obesity might be a failure of adipocytes to respond sufficiently adequate to persistent energy surplus. To evaluate the role of lipolytic enzymes or mitochondria in lipotoxicity, we studied expression levels of genes and proteins involved in lipolysis and mitochondrial DNA (mtDNA) content. Methods: As differences in lipid metabolism between men and women are extremely complex, we recruited only men (lean and morbidly obese) and collected subcutaneous and visceral adipose tissue during abdominal surgery for real-time PCR gene expression, protein expression, and microscopic study. Results: Although mRNA levels of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) were increased in visceral adipose tissue of morbidly obese men, this was not paralleled by alterations in protein expression and phosphorylation of HSL and ATGL. mtDNA content of visceral adipose tissue was increased in morbidly obese men as compared to lean controls (p < 0.013). Positive correlations were observed between visceral adipocyte size and serum triacylglycerol (r = 0.6, p < 0.007) as well as between visceral adipocyte size and CRP (r = 0.6, p < 0.009) in analyses performed separately in obese men. Conclusion: Lipotoxicity of morbidly obese men might be related to the quantitative impact of the visceral fat depot rather than to important dysregulation of involved lipolytic enzymes or adipocyte mitochondria.

Bariatric Surgery Induces Weight Loss but Does Not Improve Glycemic Control in Patients With Type 1 Diabetes

Brethauer et al. (1) report an improvement of glycemic control following bariatric surgery in patients with type 1 diabetes. However, the small sample size and limited time of follow-up of this latest and other previous reports preclude drawing firm conclusions (1–3). We collected data from 22 patients with confirmed type 1 diabetes and BMI ≥35 kg/m2 from three Belgian bariatric surgery centers. Six patients underwent sleeve gastrectomy and 16 had Roux-en-Y gastric bypass surgery. Overall, we compared BMI, glycemic control (as assessed by A1C), and daily insulin dose between pre- and postsurgery using a linear mixed model with a random patient and a fixed period effect. P values < 0.05 are considered significant. At each time point, mean ± SEM is given in Fig. 1. …

Sex Steroid-Induced Changes in Circulating Monocyte Chemoattractant Protein-1 Levels May Contribute to Metabolic Dysfunction in Obese Men

CONTEXT Low testosterone accompanied by elevated estradiol associates with the development of metabolic dysfunction in men. OBJECTIVE The aim of the study was to explore the hypothesis that alterations in sex steroid levels induce metabolic dysfunction through adipokines. DESIGN Circulating levels of sex steroids and 28 adipokines were determined in a cross-sectional study of morbidly obese men and aged-matched controls, as well as in a randomized clinical trial with healthy young men in which obesity-related alterations in sex steroid levels were mimicked by treatment with an aromatase inhibitor plus estradiol patches. RESULTS Morbidly obese men had lower testosterone levels than normal-weight controls. Estradiol levels were increased in morbidly obese men (without DM2) as compared to normal-weight controls. Circulating levels of multiple proinflammatory cytokines, including IL-1Ra, IL-5, IL-6, IL-10, leptin, monocyte chemoattractant protein 1 (MCP1), and macrophage inflammatory protein 1α, positively associated with estradiol and negatively with testosterone. The associations with estradiol, but not with testosterone, remained significant after adjusting for adipocyte cell size. In a separate clinical trial, the direct adverse effects of lowering testosterone and raising estradiol on MCP1 were substantiated in vivo. CONCLUSIONS Initial alterations in sex steroid levels may contribute to metabolic dysfunction through adverse effects on adipokine levels in obese men. The direct adverse effects on MCP1, a chemokine highly linked to the development of metabolic dysfunction, were substantiated in a trial mimicking obesity-related alterations of sex steroid levels in healthy young males.