Mehdi Ouaissi

Incidence and prevention of ventral incisional hernia

OBJECTIVE Ventral incisional hernia is a common complication of abdominal surgery. The incidence ranges from 2% to 20% and varies greatly from one series to another. The goal of this study was to determine the incidence, risk factors, and preventive measures for ventral incisional hernia. MATERIALS AND METHODS An analysis of the surgical literature was performed using the search engines EMBASE, Cochrane Library, and PubMed with the keywords: abdominal hernia, wound dehiscence, incisional hernia, incidence, trocar site hernia, and hernia prevention. RESULTS The overall incidence of incisional hernia after laparotomy was 9.9%. The incidence was significantly higher for midline incisions compared with transverse incisions (11% vs. 4.7%; P=0.006). In contrast, the incidence of ventral hernia was only 0.7% after laparoscopy. A compilation of all the studies comparing laparotomy to laparoscopy showed a significantly higher incidence of incisional hernia after laparotomy (P=0.001). Independent risk factors for incisional hernia included age and infectious complications. Only two meta-analyses were able to show a significant decrease in risk-related to the use of non absorbable or slowly absorbable suture material. No difference in incisional hernia risk was shown with different suture techniques (11.1% for running suture, 9.8% for interrupted sutures: NS). CONCLUSION A review of the literature shows that only the choice of incisional approach (transverse incision or laparotomy vs. midline laparotomy) allows a significant decrease in the incidence of ventral incisional hernia.

Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma

Significance Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030. Advances in therapeutic treatments are urgently required to fight against this fatal disease. Here, elucidation of the metabolic signature of PDAC has identified the low-density lipoprotein receptor (LDLR), which facilitates cholesterol uptake, as a promising therapeutic target. Blocking of LDLR reduces the proliferative and clonogenic potential of PDAC cells and decreases activation of the ERK1/2 survival pathway. Moreover, LDLR silencing sensitizes PDAC cells to chemotherapeutic drugs and potentiates the tumoral regression promoted by chemotherapy. Finally, Ldlr is highly expressed at all stages of human PDAC and expression is associated with an increased risk of PDAC recurrence. The malignant progression of pancreatic ductal adenocarcinoma (PDAC) is accompanied by a profound desmoplasia, which forces proliferating tumor cells to metabolically adapt to this new microenvironment. We established the PDAC metabolic signature to highlight the main activated tumor metabolic pathways. Comparative transcriptomic analysis identified lipid-related metabolic pathways as being the most highly enriched in PDAC, compared with a normal pancreas. Our study revealed that lipoprotein metabolic processes, in particular cholesterol uptake, are drastically activated in the tumor. This process results in an increase in the amount of cholesterol and an overexpression of the low-density lipoprotein receptor (LDLR) in pancreatic tumor cells. These findings identify LDLR as a novel metabolic target to limit PDAC progression. Here, we demonstrate that shRNA silencing of LDLR, in pancreatic tumor cells, profoundly reduces uptake of cholesterol and alters its distribution, decreases tumor cell proliferation, and limits activation of ERK1/2 survival pathway. Moreover, blocking cholesterol uptake sensitizes cells to chemotherapeutic drugs and potentiates the effect of chemotherapy on PDAC regression. Clinically, high PDAC Ldlr expression is not restricted to a specific tumor stage but is correlated to a higher risk of disease recurrence. This study provides a precise overview of lipid metabolic pathways that are disturbed in PDAC. We also highlight the high dependence of pancreatic cancer cells upon cholesterol uptake, and identify LDLR as a promising metabolic target for combined therapy, to limit PDAC progression and disease patient relapse.

Histone Deacetylase Enzymes as Potential Drug Targets in Cancer and Parasitic Diseases

The elucidation of the mechanisms of transcriptional activation and repression in eukaryotic cells has shed light on the important role of acetylation-deacetylation of histones mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Another group belonging to the large family of sirtuins (silent information regulators (SIRs)) has an (nicotinamide adenine dinucleotide) NAD+-dependent HDAC activity. Several inhibitors of HDACs (HDIs) have been shown to exert antitumor effects. Interestingly, some of the HDIs exerted a broad spectrum of antiprotozoal activity. The purpose of this review is to analyze some of the current data related to the deacetylase enzymes as a possible target for drug development in cancer and parasitic diseases with special reference to protozoan infections. Given the structural differences among members of this family of enzymes, development of specific inhibitors will not only allow selective therapeutic intervention, but may also provide a powerful tool for functional study of these enzymes.

Cancer-associated fibroblast-derived annexin A6 + extracellular vesicles support pancreatic cancer aggressiveness

The intratumoral microenvironment, or stroma, is of major importance in the pathobiology of pancreatic ductal adenocarcinoma (PDA), and specific conditions in the stroma may promote increased cancer aggressiveness. We hypothesized that this heterogeneous and evolving compartment drastically influences tumor cell abilities, which in turn influences PDA aggressiveness through crosstalk that is mediated by extracellular vesicles (EVs). Here, we have analyzed the PDA proteomic stromal signature and identified a contribution of the annexin A6/LDL receptor-related protein 1/thrombospondin 1 (ANXA6/LRP1/TSP1) complex in tumor cell crosstalk. Formation of the ANXA6/LRP1/TSP1 complex was restricted to cancer-associated fibroblasts (CAFs) and required physiopathologic culture conditions that improved tumor cell survival and migration. Increased PDA aggressiveness was dependent on tumor cell-mediated uptake of CAF-derived ANXA6+ EVs carrying the ANXA6/LRP1/TSP1 complex. Depletion of ANXA6 in CAFs impaired complex formation and subsequently impaired PDA and metastasis occurrence, while injection of CAF-derived ANXA6+ EVs enhanced tumorigenesis. We found that the presence of ANXA6+ EVs in serum was restricted to PDA patients and represents a potential biomarker for PDA grade. These findings suggest that CAF-tumor cell crosstalk supported by ANXA6+ EVs is predictive of PDA aggressiveness, highlighting a therapeutic target and potential biomarker for PDA.

Histone deacetylase (HDAC) encoding gene expression in pancreatic cancer cell lines and cell sensitivity to HDAC inhibitors.

Purpose: Multiple biochemical and molecular alterations occur in pancreatic cancer cells. In the present study, attempts were made for the first time, to explore the level of expression of members of histone deacetylase encoding genes (HDACs) in four pancreatic tumor cell lines: Panc-1, BxPC-3, SOJ-6 and MiaPaCa-2; and two non-related tumor cells: Jurkat and HeLa. Furthermore, we examined the possible relationship between the levels of HDACs expression and the sensitivity/resistance to HDAC inhibitors (TSA, Nicotinamide and Sirtinol). Methods: We have used four human pancreatic tumor cell lines and two-non related tumor cells, to evaluate the expression of HDAC encoding genes by RT-PCR and Western blot analysis. We also measured the effect of certain HDAC inhibitors (HDIs) on cell growth, cell cycle alteration, membrane phosphatidyl-serine exposure, DNA fragmentation, and mitochondrial membrane potential loss.Results: We have found that although a slight variation in the profiles of gene expression among cell lines could be evidenced, HDACs protein synthesis seem to be similar. Furthermore, the cells were equally sensitive to inhibition by Sirtinol whereas some variation in the IC50 could be seen in the case of TSA. We also demonstrate that the drugs had the capacity to induce the death of cells by apoptosis. Conclusions: Taken together, our data support the notion that the level of cell sensitivity to the HDIs might be related to the level of expression of genes such as those encoding proteins playing a role in cell cycle checkpoints control but not HDAC per se.

Laparoscopic 3-step restorative proctocolectomy: comparative study with open approach in 45 patients.

Background To compare the results of a total laparoscopic versus open approach 3-time ileal pouch anal anastomosis (IPAA) for patients with acute or severe colitis complicating inflammatory bowel disease. Methods Consecutive subtotal colectomy was followed by IPAA then by stoma closure. Between 2000 and 2006, 23 consecutive patients, operated through a total laparoscopic approach were well matched with 22 patients operated by open approach. Results Overall major complications rate was lower after laparoscopic than after open approach (5/23 vs. 9/22; NS). Mean hospital stay for the 3 consecutive procedures was significantly reduced after laparoscopic versus open approach (27±7 d vs. 39±27 d; P<0.05). Conclusions Our case-control study suggests that, in experienced centers, a total laparoscopic approach can be viewed as a viable alternative to conventional open 3-step IPAA for the treatment of acute or severe colitis complicating inflammatory bowel disease.

Long-Term Outcome After Ampullectomy for Ampullary Lesions Associated With Familial Adenomatous Polyposis

PURPOSEUp to 90 percent of patients with familial adenomatous polyposis develop adenomas in the upper gastrointestinal tract. Besides pancreaticoduodenectomy, which remains indicated in duodenal and ampullary cancer, less aggressive surgical procedure (such as ampullectomy) must be evaluated in selected patients with familial adenomatous polyposis patients presenting low-risk benign duodenal adenomas.METHODSFrom 1995 to 2000, we performed a retrospective, observational study, which included eight patients (5 females) with familial adenomatous polyposis underwent ampullectomy (with frozen sections) for presumed benign polyposis lesions. Six patients had an ileal pouch-anal anastomosis performed 2 to 27 years before ampullectomy. The remaining two patients had ampullectomy during the same operation than ileal pouch-anal anastomosis.RESULTSNo patient died postoperatively. Mean hospital stay was 15 ± 6.5 (range, 10–21) days. There was one major complication (pancreatic fistula), which was treated conservatively. Final pathologic examination of the specimens revealed that three patients had a severe dysplasia. Mean follow-up of the patients was 58 ± 37 (range, 24–119) months. During endoscopic follow-up, although all the patients underwent endoscopic resection of duodenal polyps, none presented recurrence at the ampullectomy site.CONCLUSIONSAmpullectomy could be safely proposed in selected familial adenomatous polyposis patients. Our low morbidity and the absence of recurrence after almost five years of follow-up suggests that such conservative treatment could be proposed before pancreaticoduodenectomy in patients with high-risk ampullary adenomas without invasive carcinoma.

Rationale for Possible Targeting of Histone Deacetylase Signaling in Cancer Diseases with a Special Reference to Pancreatic Cancer

There is ongoing interest to identify signaling pathways and genes that play a key role in carcinogenesis and the development of resistance to antitumoral drugs. Given that histone deacetylases (HDACs) interact with various partners through complex molecular mechanims leading to the control of gene expression, they have captured the attention of a large number of researchers. As a family of transcriptional corepressors, they have emerged as important regulators of cell differentiation, cell cycle progression, and apoptosis. Several HDAC inhibitors (HDACis) have been shown to efficiently protect against the growth of tumor cells in vitro as well as in vivo. The pancreatic cancer which represents one of the most aggressive cancer still suffers from inefficient therapy. Recent data, although using in vitro tumor cell cultures and in vivo chimeric mouse model, have shown that some of the HDACi do express antipancreatic tumor activity. This provides hope that some of the HDACi could be potential efficient anti-pancreatic cancer drugs. The purpose of this review is to analyze some of the current data of HDACi as possible targets of drug development and to provide some insight into the current problems with pancreatic cancer and points of interest for further study of HDACi as potential molecules for pancreatic cancer adjuvant therapy.

Transcriptomic Analysis Predicts Survival and Sensitivity to Anticancer Drugs of Patients with a Pancreatic Adenocarcinoma

A major impediment to the effective treatment of patients with pancreatic ductal adenocarcinoma (PDAC) is the molecular heterogeneity of this disease, which is reflected in an equally diverse pattern of clinical outcome and in responses to therapies. We developed an efficient strategy in which PDAC samples from 17 consecutive patients were collected by endoscopic ultrasound-guided fine-needle aspiration or surgery and were preserved as breathing tumors by xenografting and as a primary culture of epithelial cells. Transcriptomic analysis was performed from breathing tumors by an Affymetrix approach. We observed significant heterogeneity in the RNA expression profile of tumors. However, the bioinformatic analysis of these data was able to discriminate between patients with long- and short-term survival corresponding to patients with moderately or poorly differentiated PDAC tumors, respectively. Primary culture of cells allowed us to analyze their relative sensitivity to anticancer drugs in vitro using a chemogram, similar to the antibiogram for microorganisms, establishing an individual profile of drug sensitivity. As expected, the response was patient dependent. We also found that transcriptomic analysis predicts the sensitivity of cells to the five anticancer drugs most frequently used to treat patients with PDAC. In conclusion, using this approach, we found that transcriptomic analysis could predict the sensitivity to anticancer drugs and the clinical outcome of patients with PDAC.

Predictors of long-term survival following resection for ampullary carcinoma: a large retrospective French multicentric study.

Objectives Ampullary carcinoma is a rare tumor. There are neither sufficient available data related to management after resection of the neoplasm of the ampulla of Vater, nor any international recommendations. The aim of this study was to identify factors associated with recurrence and survival after curative resection. Methods A retrospective follow-up study was conducted including patients with ampullary carcinoma who underwent resection with curative intent in 12 French surgical centers between January 1990 and November 2011. Results In this study, 319 patients underwent surgical resection for an ampullary neoplasm. Disease recurred in 120 patients (37.6%), and the 5- and 10-year disease-free survival rates were 48.9% and 40.4%, respectively. In multivariable Cox regression, preoperative bilirubin, T stage, pancreaticobiliary histology subtype, and lymph node involvement were each significantly associated with the risk of recurrence. Conclusions Ampullary carcinomas are a heterogeneous group that can be classified as intestinal and pancreaticobiliary subtypes. Our findings indicate that pancreaticobiliary differentiation, advanced stage, and lymph node involvement are predictors of both poor disease-free and poor overall survival. It is still unclear what adjuvant treatment after curative resection of ampullary carcinoma is optimal. It would be informative to evaluate adjuvant therapy according to histological subtype.