Nicolas Veyrie

Fibrosis in Human Adipose Tissue: Composition, Distribution, and Link With Lipid Metabolism and Fat Mass Loss

OBJECTIVE Fibrosis is a newly appreciated hallmark of the pathological alteration of human white adipose tissue (WAT). We investigated the composition of subcutaneous (scWAT) and omental WAT (oWAT) fibrosis in obesity and its relationship with metabolic alterations and surgery-induced weight loss. RESEARCH DESIGN AND METHODS Surgical biopsies for scWAT and oWAT were obtained in 65 obese (BMI 48.2 ± 0.8 kg/m2) and 9 lean subjects (BMI 22.8 ± 0.7 kg/m2). Obese subjects who were candidates for bariatric surgery were clinically characterized before, 3, 6, and 12 months after surgery, including fat mass evaluation by dual energy X-ray absorptiometry. WAT fibrosis was quantified and characterized using quantitative PCR, microscopic observation, and immunohistochemistry. RESULTS Fibrosis amount, distribution and collagen types (I, III, and VI) present distinct characteristics in lean and obese subjects and with WAT depots localization (subcutaneous or omental). Obese subjects had more total fibrosis in oWAT and had more pericellular fibrosis around adipocytes than lean subjects in both depots. Macrophages and mastocytes were highly represented in fibrotic bundles in oWAT, whereas scWAT was more frequently characterized by hypocellular fibrosis. The oWAT fibrosis negatively correlated with omental adipocyte diameters (R = −0.30, P = 0.02), and with triglyceride levels (R = −0.42, P < 0.01), and positively with apoA1 (R = 0.25, P = 0.05). Importantly, scWAT fibrosis correlated negatively with fat mass loss measured at the three time points after surgery. CONCLUSIONS Our data suggest differential clinical consequences of fibrosis in human WAT. In oWAT, fibrosis could contribute to limit adipocyte hypertrophy and is associated with a better lipid profile, whereas scWAT fibrosis may hamper fat mass loss induced by surgery.

Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and being overweight is a significant risk factor. The aim was to build an algorithm along with a scoring system for histopathologic classification of liver lesions that covers the entire spectrum of lesions in morbidly obese patients. A cohort of 679 obese patients undergoing liver biopsy at the time of bariatric surgery was studied. An algorithm for segregating lesions into normal liver, NAFLD, or nonalcoholic steatohepatitis (NASH) was built based on semiquantitative evaluation of steatosis, hepatocellular ballooning, and lobular inflammation. For each case, the SAF score was created including the semiquantitative scoring of steatosis (S), activity (A), and fibrosis (F). Based on the algorithm, 230 obese patients (34%) were categorized as NASH, 291 (43%) as NAFLD without NASH, and 158 (23%) as not NAFLD. The activity score (ballooning + lobular inflammation) enabled discriminating NASH because all patients with NASH had A ≥ 2, whereas no patients with A < 2 had NASH. This score was closely correlated with both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P < 0.0001, analysis of variance [ANOVA]). Comparison of transaminase levels between patients with normal liver and pure steatosis did not reveal significant differences, thus lending support to the proposal not to include steatosis in the activity score but to report it separately in the SAF score. In the validation series, the interobserver agreement for the diagnosis of NASH was excellent (κ = 0.80) between liver pathologists. There was no discrepancy between the initial diagnosis and the diagnosis proposed using the algorithm. Conclusion: We propose a simple but robust algorithm for categorizing liver lesions in NAFLD patients. Because liver lesions in obese patients may display a continuous spectrum of histologic lesions, we suggest describing liver lesions using the SAF score. (HEPATOLOGY 2012;56:1751–1759)

CD14dimCD16+ and CD14+CD16+ Monocytes in Obesity and During Weight Loss

Objective—Studies suggest the implication of CD16+ subpopulations (CD14+CD16+, CD14dimCD16+) in inflammatory diseases. We aimed to determine the frequency of these subpopulations during weight loss in obesity and diabetes, conditions associated with changes in systemic inflammation, and we tested the link with subclinical atherosclerosis. Methods and Results—CD14dimCD16+ and CD14+CD16+ frequencies were measured by flow cytometry in lean subjects, obese subjects before and after a hypocaloric diet or gastric surgery, and obese diabetic subjects before and after gastric surgery. Both monocyte subsets were increased in obese subjects, with a significant enrichment of the CD14dimCD16+ subpopulation in obese diabetic patients. Multivariate analysis demonstrated a link between the percentages of CD14dimCD16+ monocytes and glycemia, independent of fat mass. Drastic weight loss led to a sharp decrease of this subset, the variations of which were strongly related to fat mass changes. A reduction of at least 5% of fat mass was sufficient to observe a significant decrease of CD14dimCD16+ monocytes. A diminution of the CD14+CD16+ subset was also observed during weight loss and was associated with a decrease in intima-media thickness. Conclusion—This work demonstrates a major impact of fat mass variations on CD14dimCD16+ monocyte subsets and that the decrease in the CD14+CD16+ subpopulation is linked to a reduction of subclinical atherosclerosis. Clinical Trial Registration—URL: http://clinicaltrials.gov. Unique identifier: NCT00476658.

SMRT-GPS2 corepressor pathway dysregulation coincides with obesity-linked adipocyte inflammation

Low-grade chronic inflammation is a major characteristic of obesity and results from deregulated white adipose tissue function. Consequently, there is interest in identifying the underlying regulatory mechanisms and components that drive adipocyte inflammation. Here, we report that expression of the transcriptional corepressor complex subunits GPS2 and SMRT was significantly reduced in obese adipose tissue, inversely correlated to inflammatory status, and was restored upon gastric bypass surgery-induced weight loss in morbid obesity. These alterations correlated with reduced occupancy of the corepressor complex at inflammatory promoters, providing a mechanistic explanation for elevated inflammatory transcription. In support of these correlations, RNAi-mediated depletion of GPS2 and SMRT from cultured human adipocytes promoted derepression of inflammatory transcription and elevation of obesity-associated inflammatory markers, such as IL-6 and MCP-1. Furthermore, we identified a regulatory cascade containing PPARγ and TWIST1 that controlled the expression of GPS2 and SMRT in human adipocytes. These findings were clinically relevant, because treatment of diabetic obese patients with pioglitazone, an antidiabetic and antiinflammatory PPARγ agonist, restored expression of TWIST1, GPS2, and SMRT in adipose tissue. Collectively, our findings identify alterations in a regulatory transcriptional network in adipocytes involving the dysregulation of a specific corepressor complex as among the initiating events promoting adipose tissue inflammation in human obesity.

Use of sealants in pancreatic surgery: critical appraisal of the literature.

Background/Aims: Fibrin sealants containing both fibrin and thrombin have been used to control bleeding, reinforce suture lines and enhance tissue healing. However, the literature provides contradictory results. Methods: A systematic literature search was performed to determine the use of fibrin sealants in pancreatic surgery. These articles were then critically appraised according to their methodologies, outcomes and conclusions. Results: Twenty-four studies were found, including 6 controlled randomized trials. Of these, 16 studies were analyzed. Many methodological flaws and lack of consistency in definitions were found, making comparisons between studies difficult if not impossible. Conclusion: Because of the heterogeneity and lack of high-level evidence, the current literature does not allow us any conclusion: neither is there proof that fibrin sealants are of any real utility in pancreatic surgery, nor that they do not work. Further large-scale controlled trials are necessary before concluding that they do or do not provide any advantages in pancreatic surgery.

Similar postoperative safety between primary and revisional gastric bypass for failed gastric banding.

IMPORTANCE Adjustable gastric bands are widely used because of low postoperative morbidity, but their long-term results are poor, often leading to revisional surgery. OBJECTIVE To assess the safety of revisional procedures by comparing the 30-day outcomes of primary gastric bypass vs revisions following failed adjustable gastric banding. DESIGN, SETTING, AND PARTICIPANTS Retrospective review using logistic regression models to compute odds ratios (95% CIs) across preoperative body mass index (calculated as weight in kilograms divided by height in meters squared) quartiles to evaluate the risk for major adverse outcomes at 30 days (death, venous thromboembolism, reinterventions, and failure to be discharged). The prospective database of a single university surgical center in Paris, France, was queried for clinical and other relevant data among all patients undergoing primary or revisional laparoscopic gastric bypass between January 1, 2004, and June 30, 2013. MAIN OUTCOMES AND MEASURES The primary outcome was a comparison between 30-day outcomes of primary gastric bypass and procedures following failed adjustable gastric banding. RESULTS In total, 831 patients had a primary procedure (group 1), and 177 patients had a secondary procedure after failed adjustable gastric banding (group 2). Overall, 78.7% of patients were female, the mean (SD) patient age was 42.6 (11.6) years, the mean (SD) body mass index was 47.6 (7.6), and mortality at 30 days was 0.5%. The rates of major adverse outcomes were similar in group 1 (7.8%) and group 2 (8.5%) (P = .77). In multivariate analyses, odds ratios for major adverse outcomes across preoperative body mass index quartiles (<42, 42-46, >46 to 52, and >52) were 1.00, 0.39 (95% CI, 0.20-0.77; P = .006), 0.55 (95% CI, 0.30-1.02; P = .06), and 0.50 (95% CI, 0.27-0.94; P = .03), respectively. CONCLUSIONS AND RELEVANCE The 30-day major adverse outcome rates were similar for primary gastric bypass and for procedures following failed adjustable gastric banding. Long-term comparative studies are required to better understand the quadratic relationship between body mass index and early postoperative outcomes.

Endothelial Cells From Visceral Adipose Tissue Disrupt Adipocyte Functions in a Three-Dimensional Setting: Partial Rescue by Angiopoietin-1

During obesity, chronic inflammation of human white adipose tissue (WAT) is associated with metabolic and vascular alterations. Endothelial cells from visceral WAT (VAT-ECs) exhibit a proinflammatory and senescent phenotype and could alter adipocyte functions. We aimed to determine the contribution of VAT-ECs to adipocyte dysfunction related to inflammation and to rescue these alterations by anti-inflammatory strategies. We developed an original three-dimensional setting allowing maintenance of unilocular adipocyte functions. Coculture experiments demonstrated that VAT-ECs provoked a decrease in the lipolytic activity, adipokine secretion, and insulin sensitivity of adipocytes from obese subjects, as well as an increased production of several inflammatory molecules. Interleukin (IL)-6 and IL-1β were identified as potential actors in these adipocyte alterations. The inflammatory burst was not observed in cocultured cells from lean subjects. Interestingly, pericytes, in functional interactions with ECs, exhibited a proinflammatory phenotype with diminished angiopoietin-1 (Ang-1) secretion in WAT from obese subjects. Using the anti-inflammatory Ang-1, we corrected some deleterious effects of WAT-ECs on adipocytes, improving lipolytic activity and insulin sensitivity and reducing the secretion of proinflammatory molecules. In conclusion, we identified a negative impact of VAT-ECs on adipocyte functions during human obesity. Therapeutic options targeting EC inflammation could prevent adipocyte alterations that contribute to obesity comorbidities.

Laparoscopic Approach to Colonic Cancer: Critical Appraisal of the Literature

Background/Aims: As laparoscopic colectomy finds its place in the surgical armamentarium, the literature concerning the safety, efficacy, and oncological rational for treatment of colonic cancer is also enriched. A review and critical appraisal of the literature on this subject was the aim of this paper. Methods: A systematic research and a hand search were conducted to gain access to all controlled studies involving laparoscopic colectomy using the Medline, Embase, HealthSTAR, Cumulative Index for Nursing and Allied Health Literature, CancerLit data bases and the Cochrane Central Register of Controlled Trials for the years 1991–2006. Results: Over 40 controlled randomized trials and ten systematic reviews and/or meta-analyses were found. Several of the completed controlled randomized trials have published either short- or long-term results; only partial and short-term results are available in rectal cancer. The principal conclusions are that the laparoscopic approach affords better short-term outcomes including surgical site morbidity, but with increased operative times and direct costs. Among the proven long-term outcomes, cancer recurrence and survival do not seem to be worse. Whether conversion, a source of increased operative time and costs, is responsible for poorer outcomes or whether specific settings associated with poorer outcomes are among the causes of conversion remains to be shown. However, there are still concerns as regards specific laparoscopic-related complications. Conclusion: There seems to no real safety problems in performing laparoscopic colectomy for cancer; improvement in operative times, conversion rates, and complications should make laparoscopy the best cost-effective approach to colectomy.

The sentinel-node concept: a dramatic improvement in breast-cancer surgery

Until the late 1990s, axillary lymph-node dissection was considered the gold standard to assess lymph-node invasion in patients with breast cancer, although the procedure was associated with considerable morbidity. Roughly 50 years have passed since Gould and colleagues 1 investigated the idea of a possible sentinel lymph node (SLN), on the basis of Sappey’s works 2 regarding a specifi c centre in the lymphatic drainage of the breast. The SLN concept is based on the theory that tumour invasion of the fi rst node of the regional nodal basin reveals the tumour status of the entire basin. Hence, if the fi rst node is found to be metastasis-free, the rest of the regional nodal basin is also metastasis-free, and if the fi rst node is metastatic, radical lymph-node dissection is warranted. As a consequence, it seems possible to assess the complete nodal status with the excision of a unique node. The considerable morbidity associated with axillary lymph-node dissection 3 makes this less invasive approach more attractive. The SLN concept was fi rst described in parotid gland carcinoma, rather than breast cancer, by Gould and colleagues 1 in 1960. Their paper stressed the usefulness of radical neck dissection in patients with parotid tumours, given the high incidence of lymph-node invasion in malignant parotid tumours and the risk of false-negatives in pathological examination. Indeed, these latter considerations were illustrated by a case report of a primary tumour that appeared histologically benign until a biopsy of a macroscopically normal-appearing node revealed metastatic spread. The authors did not describe how this node was identifi ed during the surgical procedure. Gould and colleagues 1 also described 28 SLN biopsies of malignant or benign parotid tumours. The SLN was positive in three of eight patients with malignant tumours, who subsequently underwent radical neck dissection. Survival was similar in patients with or without radical lymph-node dissection. In 1977, Cabanas and co-workers 4 investigated the SLN concept in 46 cases of penile carcinoma. Instead of preoperative identifi cation of the SLN, they injected contrast media into the dorsal lymphatics of the penis, and found that the biopsy of the contrast-enhanced sentinel node could indicate the tumour status of the entire nodal basin. Reports of SLN biopsy in patients with breast cancer emerged in the 1990s, 5,6 along with the development of alternative methods for identifi cation of the SLN. These methods, including the use of radioactive tracers and patent blue dye, 7,8 were further investigated in cervical cancer, endometrial cancer, and melanoma. Nowadays, SLN biopsy is well accepted and recommended as a valuable alternative to axillary lymph-node dissection. 3,9 In patients with breast cancer, up to 70% of axillary lymph-node dissections can be avoided with SLN biopsy, which positively aff ects a patient’s quality of life—reducing postoperative pain, lymphoedema, paresthesia, and diminished arm mobility.

Anti-cancer agents for breast cancer treatment during pregnancy.

We read with great interest the recent article by Guidroz et al. [1] on the management of pregnant women with breast cancer. We agree with the authors that chemotherapy should be postponed until the second trimester of pregnancy, and that some regimens can be introduced during pregnancy with limited short-term toxicity for both the mother and the fetus [2]. However, the authors assume that taxanes should be avoided during pregnancy given the absence of data regarding their safety, whereas recent clinical data (n1⁄4 42) seem to be quite reassuring [3]. Moreover, recommendations from a recent international experts meeting stated that taxanes may be safely used during the second and third trimesters of pregnancy [4]. Finally, recent data indicate that pregnancy-associated breast cancers are as chemosensitive as other breast cancers, highlighting the potential role of taxanes in this setting [5]. Otherwise, we strongly disagree with Guidroz et al. regarding the use of trastuzumab during pregnancy. Trastuzumab likely crosses the placenta, similarly to other IgG1 [6], and has deleterious effects on embryo implantation [7] and embryo-fetal development [2]. More than half of 15 pregnant patients exposed to trastuzumab developed anhydramnios, a condition potentially leading to prematurity, fetal morbidity and mortality. Guidroz et al. did not mention that in four cases, the neonate died shortly after delivery, leaving highly questionable the safety of trastuzumab during pregnancy [8]. In conclusion, recent data suggest that taxanes may be considered in pregnant cancer patients. In contrast, the use of trastuzumab should be definitely avoided during pregnancy [4,6]. Physicians should be aware of these clinical data. Additional clinical reports are warranted in order to better delineate the optimal use of anti-cancer agents during pregnancy.