Patrick Rat

Hypermethylator Phenotype in Sporadic Colon Cancer: Study on a Population-Based Series of 582 Cases

The CpG island methylator phenotype (CIMP) is a distinct phenotype in colorectal cancer, associated with specific clinical, pathologic, and molecular features. However, most of the studies stratified methylation according to two subgroups (CIMP-High versus No-CIMP/CIMP-Low). In our study, we defined three different subgroups of methylation (No-CIMP, CIMP-Low, and CIMP-High) and evaluated the prognostic significance of methylation status on a population-based series of sporadic colon cancers. A total of 582 colon adenocarcinomas were evaluated using methylation-specific PCR for 5 markers (hMLH1, P16, MINT1, MINT2, and MINT31). No-CIMP status was defined as no methylated locus, CIMP-Low status as one to three methylated loci, and CIMP-High status as four or five methylated loci. Clinicopathologic and molecular characteristics were correlated to the methylation status. Crude and relative survival was compared according to methylation status. In the microsatellite-stable (MSS) group, CIMP-High was significantly associated with proximal location (P = 0.011) and BRAF mutation (P < 0.001). KRAS mutations were more associated with CIMP-High and CIMP-Low status (P = 0.008). A shorter 5-year survival was observed in MSS cancer patients with CIMP-Low or CIMP-High status. These results remained significant in multivariate analysis adjusted for age, stage, and BRAF and KRAS mutational status [CIMP-Low: hazard ratio (HR), 1.85; 95% confidence interval (95% CI), 1.37-2.51; CIMP-High, HR, 2.90; 95% CI, 1.53-5.49 compared with No-CIMP]. Within the high-level microsatellite instability group, no difference in survival was observed between the different CIMP groups. Our results show the interest of defining three subgroups of patients according to their methylation status (No-CIMP/CIMP-Low/CIMP-High). Methylation is an independent prognostic factor in MSS colon cancer.

A comparative study of complete cytoreductive surgery plus intraperitoneal chemotherapy to treat peritoneal dissemination from colon, rectum, small bowel, and nonpseudomyxoma appendix.

Objective:To report a large number of patients with peritoneal carcinomatosis (PC) treated with complete cytoreductive (CCR-0) plus intraperitoneal chemotherapy, and to compare the results according to the origin of the primary: colon, rectum, small bowel, and appendix (excluding peritoneal pseudomyxoma). Patients and Methods:Among 615 patients treated for PC originating from these 4 types of primaries in 23 French centers, 440 were retrospectively selected as having undergone complete cytoreductive surgery and with complete data retrieval. Primary sites were: colon (n = 341), rectum (n = 27), appendix (n = 41), and small bowel (n = 31). Results:Postoperative mortality and morbidity (3.9% and 31%, respectively) did not differ according to the origin of the primary tumor. The mean follow-up was 60 months. The 5-year overall survival rates were not statistically different for the colon (29.7%), rectum (37.9%), nor the small bowel (33.8%), but was higher (P = 0.01) for appendix adenocarcinoma (63.2%). The multivariate analysis of prognostic factors singled out the extent of peritoneal seeding (P < 0.0001), positive lymph nodes (P = 0.001), and adjuvant systemic chemotherapy (P = 0.002), whereas the origin of the tumor was borderline (P = 0.06) in favor of appendix tumors. Conclusion:Cytoreductive surgery plus intraperitoneal chemotherapy yields satisfying and similar survival results in the treatment of PC from colon, rectum, and small bowel adenocarcinomas. Results were better for appendix adenocarcinoma. When feasible, this combined approach should become the gold standard treatment of PC.

High Intra-abdominal Pressure Enhances the Penetration and Antitumor Effect of Intraperitoneal Cisplatin on Experimental Peritoneal Carcinomatosis

Objective:To investigate the role of increased intra-abdominal pressure (IAP) on the intratumoral accumulation and the antitumor effect of intraperitoneal cisplatin in rats with advanced peritoneal carcinomatosis. To evaluate the tolerance of IAP in pigs, as it is a large animal with a body size equivalent to humans. Summary Background Data:To investigate if an active convection, driven by a positive IAP, increases cisplatin penetration and antitumor effectiveness in a model of advanced peritoneal carcinomatosis in rats. Experimental Design:BDIX rats with macroscopic peritoneal tumors received cisplatin administered as intravenous injection (IV), conventional intraperitoneal injection (IP), or sustained intraperitoneal injection of cisplatin given in a large volume of solvent for maintaining IAP for 1 hour. Platinum tissue concentration was measured by atomic absorption spectroscopy (AAS), and platinum distribution into the tumor nodules was assessed by the particular-induced x-ray emission (PIXE) method. The antitumor effect was assessed in a survival experiment. The hemodynamic, local, and systemic tolerance of IAP, with or without cisplatin, was evaluated in Large White pigs. Results:The maximum tolerated IAP was 22 mm Hg for 1 hour in nonventilated rats. IAP, in comparison with IV or conventional IP injections, resulted in the increased concentration and depth of diffusion of platinum into diaphragm and peritoneal tumor nodules. Consequently, IAP treatment induced an extended survival of rats treated at an advanced stage of carcinomatosis. In 7 50- to 70-kg ventilated pigs, a 40-mm Hg IAP was well tolerated when maintained stable for 2 hours. Renal failure occurred in pigs receiving a total dose of 200 and 400 mg of cisplatin with IAP, but a dose of 100 mg was well tolerated. Conclusions:Intraperitoneal chemotherapy with increased IAP, in comparison with conventional IP or IV chemotherapy, improved the tumor accumulation and the antitumor effect of cisplatin in rats bearing advanced peritoneal carcinomatosis. In preclinical conditions, the tolerance of sustained IAP was manageable in ventilated pigs.

Immunologic effects of rituximab on the human spleen in immune thrombocytopenia

Immune thrombocytopenia (ITP) is an autoimmune disease with a complex pathogenesis. As in many B cell-related autoimmune diseases, rituximab (RTX) has been shown to increase platelet counts in some ITP patients. From an immunologic standpoint, the mode of action of RTX and the reasons underlying its limited efficacy have yet to be elucidated. Because splenectomy is a cornerstone treatment of ITP, the immune effect of RTX on this major secondary lymphoid organ was investigated in 18 spleens removed from ITP patients who were treated or not with RTX. Spleens from ITP individuals had follicular hyperplasia consistent with secondary follicles. RTX therapy resulted in complete B-cell depletion in the blood and a significant reduction in splenic B cells, but these patients did not achieve remission. Moreover, whereas the percentage of circulating regulatory T cells (Tregs) was similar to that in controls, splenic Tregs were reduced in ITP patients. Interestingly, the ratio of proinflammatory Th1 cells to suppressive Tregs was increased in the spleens of patients who failed RTX therapy. These results indicate that although B cells are involved in ITP pathogenesis, RTX-induced total B-cell depletion is not correlated with its therapeutic effects, which suggests additional immune-mediated mechanisms of action of this drug.

Refractory bleeding from gastroduodenal ulcers: arterial embolization in high-operative-risk patients.

Goals and Background We evaluated the efficacy and medium-term outcomes of transcatheter embolization to control massive bleeding from gastroduodenal ulcers after failed endoscopic treatment in high-operative-risk patients. Study Retrospective study of 35 consecutive emergency embolization procedures in hemodynamically unstable patients (24 men, 11 women, mean age 71±11.6 y) referred from 1999 to 2006 for selective angiography after failed endoscopic treatment. Mean follow-up was 27 months. Results Endovascular treatment was feasible in 33 patients and consistently stopped the bleeding. “Sandwich” coiling of the gastroduodenal artery was performed in 11 patients and superselective occlusion of the terminal feeding artery with glue, coils, or gelatine particles in 22 patients. Early rebleeding occurred in 6 patients and was managed successfully using endoscopy (n=2), reembolization (n=1), or surgery (n=3). No major complications related to catheterization occurred. Seven patients died within 30 days of embolization and 3 died later during the follow-up, but none of the deaths were due to rebleeding. No late bleeding recurrences were reported. Conclusions Selective angiographic embolization is safe and effective for controlling life-threatening bleeding from gastroduodenal ulcers, usually obviating the need for emergency surgery in critically ill patients, whose immediate survival depends on their underlying conditions.

C-reactive protein and procalcitonin for the early detection of anastomotic leakage after elective colorectal surgery: pilot study in 100 patients.

INTRODUCTION Anastomotic leakage is the most important complication after colorectal surgery. Its prognosis depends on its early diagnosis. C-reactive protein (CRP) has already shown its usefulness for the early detection of anastomotic leaks. Procalcitonin (PCT) is widely used in intensive care units and is more expensive, but its usefulness in the postoperative period of digestive surgery is not well established. PATIENTS AND METHODS Between May 2010 and June 2011, 100 patients undergoing elective colorectal surgery were prospectively included in a database. CRP and PCT were measured before surgery and daily until postoperative day 4. All intraabdominal infections were considered as anastomotic leaks, regardless of their clinical impact and their management. The kinetics of PCT and CRP were recorded, as well as their accuracy for the detection of anastomotic fistula. RESULTS The incidence of fistula was 13% and the overall mortality rate was 2%. Both CRP and PCT were significantly higher in patients with leakage. Areas under the receiver-operating characteristics (ROC) for CRP were higher than those for PCT each day. The best accuracy was obtained for CRP on postoperative day 4 (areas under the ROC curve were 0.869 for CRP and 0.750 for PCT). CONCLUSION Procalcitonin is neither earlier nor more accurate than CRP for the detection of anastomotic leakage after elective colorectal surgery.

Diagnostic Accuracy of Inflammatory Markers As Early Predictors of Infection After Elective Colorectal Surgery: Results From the IMACORS Study.

Background:Intra-abdominal infections are frequent and life-threatening complications after colorectal surgery. An early detection could diminish their clinical impact and permit safe early discharge. Objective:This study aimed to find the most accurate marker for the detection of postoperative intra-abdominal infection and the appropriate moment to measure it. Methods:A prospective, observational study was conducted in 3 centers. Consecutive patients undergoing elective colorectal surgery with anastomosis were included. C-reactive protein and procalcitonin were measured daily until the fourth postoperative day. Postoperative infections were recorded according to the definitions of the Centres for Diseases Control. The areas under the receiver operating characteristic curve were analyzed and compared to assess the diagnostic accuracy of each marker. Results: :Five-hundred and one patients were analyzed. The incidence of intra-abdominal infection was 11.8%, with 24.6% of patients presenting at least one infectious complication. Overall mortality was 1.2%. At the fourth postoperative day, C-reactive protein was more discriminating than procalcitonin for the detection of intra-abdominal infection (areas under the ROC curve: 0.775 vs 0.689, respectively, P = 0.03). Procalcitonin levels showed wide dispersion. For the detection of all infectious complications, C-reactive protein was also significantly more accurate than procalcitonin on the fourth postoperative day (areas under the ROC curve: 0.783 vs 0.671, P = 0.0002). Conclusions:C-reactive protein is more accurate than procalcitonin for the detection of infectious complications and should be systematically measured at the fourth postoperative day. It is a useful tool to ensure a safe early discharge after elective colorectal surgery.

Improvement of Operative Mortality after Curative Resection for Gastric Cancer: Population-based Study

It is not well known if the improvement in operative mortality after surgery for gastric cancer reported in hospital series can be extrapolated to the whole population. The aim of this study was to determine trends in operative mortality over a 20-year period in a nonselected community-based series of patients. A database of 648 patients with gastric cancer resected with curative intent between 1976 and 1995 in a region with a half-million population was divided into two periods: 1976–1983 and 1984–1995. Nonconditional logistic regression was performed to estimate the independent effects of the studied factors. Operative mortality was higher during the 1976–1983 period than during the 1984–1995 period (17.1% vs. 7.1%; p < 0.0001). When comparing the two study periods, operative mortality decreased dramatically from 26.2% to 10.0% in patients over age 70, from 31.8% to 7.9% after total gastrectomy, and from 30.7% to 6.3% after proximal esophagogastrectomy. Operative mortality after total gastrectomy was nearly the same as that after distal gastrectomy (7.9% vs 5.9%) during the second study period. During the first study period, operative mortality was independently associated with age at diagnosis, type of gastrectomy, and to a lesser degree stage at diagnosis; during the second study period, only age and stage at diagnosis were associated with the risk of operative mortality. This study indicates that in this well defined population operative mortality after curative resection for gastric cancer has decreased during the last 20 years. The results should encourage aggressive management of patients with gastric cancer, even in patients over 70 years of age.

High pressure enhances the effect of hyperthermia in intraperitoneal chemotherapy with oxaliplatin: an experimental study.

Background:Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) achieve good results in selected patients with peritoneal carcinomatosis. High intra-abdominal pressure could enhance the penetration of chemotherapy drugs. The aim of this study was to compare the effects of high pressure and hyperthermia when used separately and when combined in terms of blood and tissue absorption of oxaliplatin in a swine model of intraperitoneal chemotherapy. Methods:Four groups of 5 pigs each underwent laparotomy and open intraperitoneal chemotherapy with oxaliplatin at a constant concentration (150 mg/L) for 30 minutes in normothermia and atmospheric pressure (group 1), or hyperthermia (42°C) and atmospheric pressure (group 2), or normothermia and high pressure (25 cm H2O) (group 3), or hyperthermia and high pressure (group 4). High pressure was achieved thorough a water column over the abdomen. Systemic absorption and abdominal tissue mapping of the penetration of oxaliplatin in each group were studied. Results:Blood concentrations of oxaliplatin were similar in the different groups. Hyperthermia achieved higher concentrations in visceral surfaces (P = 0.0014), but not in parietal surfaces. High pressure enhanced diffusion of the drug in both the visceral and parietal peritoneum (P = 0.0058 and P = 0.0044, respectively). The combination of hyperthermia and high pressure significantly increased the penetration of oxaliplatin and achieved the highest tissue concentrations (10.39 mg/kg vs 5.48 mg/kg; P = 0.00001 in the visceral peritoneum, and 66.16 mg/kg vs 35.62 mg/kg; P = 0.0003 in the parietal peritoneum). Conclusions:Open high-pressure HIPEC with oxaliplatin is feasible in the pig. Hyperthermia enhances diffusion in the visceral peritoneum, whereas high pressure is effective in the visceral and parietal peritoneum. The combination of the two achieves the highest tissue concentrations of oxaliplatin.

Closed hyperthermic intraperitoneal chemotherapy with open abdomen: a novel technique to reduce exposure of the surgical team to chemotherapy drugs

BackgroundExposure of the surgical team to toxic drugs during hyperthermic intraperitoneal chemotherapy (HIPEC) remains a matter of great concern. During closed-abdomen HIPEC, operating room staff are not exposed to drugs, but the distribution of the heated liquid within the abdomen is not optimal. With open-abdomen HIPEC, the opposite is true. Although the open-abdomen method is potentially more effective, it has not become a standard procedure because of the risk of exposure of members of the team to drugs.MethodsWe present a new technique (closed HIPEC with open abdomen) which ensures protection against potentially contaminating exposure to liquids, vapours and aerosols, and allows permanent access to the whole abdominal cavity. Its principle is to extend the abdominal surgical wound upwards with a sort of “glove-box”. The cutaneous edges of the laparotomy are stapled to a latex “wall expander”. The expander is draped over a special L-section metal frame placed above the abdomen. A transparent cover containing a “hand-access” port, like those used in laparoscopic surgery, is fixed inside the frame.ResultsIn 10 patients, this device proved to be hermetic for both liquids and vapours. Intra-abdominal temperature was maintained between 42 and 43°C during most of the procedure. The whole abdominal cavity was accessible to the surgeon, allowing optimal exposure of all peritoneal surfaces.ConclusionThis technique allows optimal HIPEC, while limiting the potential toxic effects for the surgical, medical and paramedical teams.