Paul-Henri Cugnenc

Type, density, and location of immune cells within human colorectal tumors predict clinical outcome

The role of the adaptive immune response in controlling the growth and recurrence of human tumors has been controversial. We characterized the tumor-infiltrating immune cells in large cohorts of human colorectal cancers by gene expression profiling and in situ immunohistochemical staining. Collectively, the immunological data (the type, density, and location of immune cells within the tumor samples) were found to be a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer. The results were validated in two additional patient populations. These data support the hypothesis that the adaptive immune response influences the behavior of human tumors. In situ analysis of tumor-infiltrating immune cells may therefore be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies.

Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease

BACKGROUND & AIMS The mechanism of intraepithelial lymphocyte hyperplasia, a hallmark of celiac disease, is unknown. We have investigated the role of epithelium-derived interleukin (IL)-15 in the alterations of epithelial homeostasis in refractory celiac sprue, a privileged situation to study the first step of lymphoid transformation and the contribution of intraepithelial lymphocytes to villous atrophy in celiac disease. METHODS IL-15 expression was assessed in biopsy specimens and isolated enterocytes by combining immunohistochemistry, flow cytometry, and real-time quantitative polymerase chain reaction. The ability of IL-15 to induce growth and survival of clonal intraepithelial lymphocytes lacking surface CD3 and to induce their cytotoxicity and secretion of interferon gamma was tested using soluble IL-15 and coculture in the presence of epithelial cell lines expressing membrane IL-15. RESULTS IL-15 was massively overexpressed not only in lamina propria but also in the intestinal epithelium of patients with active celiac disease and refractory celiac sprue. IL-15 was not secreted but delivered at the surface of enterocytes. IL-15 specifically induced the expansion and survival of the clonal abnormal intraepithelial lymphocytes that characterize refractory celiac sprue and triggered their secretion of interferon gamma and their cytotoxicity against intestinal epithelial cells. Comparable activating signals could be delivered by IL-15 expressed at the membrane of the T84 enterocyte cell line. CONCLUSIONS These data provide strong evidence that uncontrolled overexpression of IL-15 in refractory celiac sprue perpetuates epithelial damage and promotes the emergence of T-cell clonal proliferations. Blocking IL-15 might prove useful to treat this severe complication of celiac disease.

Complications after laparoscopic adjustable gastric banding for morbid obesity: experience with 1,000 patients over 7 years.

Background: Laparoscopic adjustable gastric banding (LAGB) is considered the least invasive surgical option for morbid obesity. It is less efficient than gastric bypass in weight loss, but has the advantage of being potentially reversible and can improve the quality of life if mortality and morbidity are low. Methods: Between 1996 and 2003, 1,000 patients underwent LAGB. There were 896 women and 104 men with mean age 40.4 years (16.3-66.3). Preoperative mean BMI was 44.3 kg/m2. Results: There were no deaths. Cumulative rate of complications was 192 (19.2%). 12 were life-threatening (1.2%): gastric perforation (n=4), acute respiratory distress (n=2), pulmonary embolism (n=2), migration (n=3), and gastric necrosis (n=1). 111 patients required an abdominal reoperation (11.1%) for perforation (n=2), slippage (n=78), migration (n=3), necrosis (n=1), esophageal dilatation (n=2), incisional hernias (n=4) and port problems (n=21). Before October 2000, we used the perigastric technique, and the slippage rate was 24% (91 / 378 ).Then, we changed to the pars flaccida approach and the slippage rate fell to 2% (13 / 622). The pars flaccida approach demonstrated safety in relation to both risks of perforation and slippage. Conclusion: The cumulative complication rate increased to 3-4 years, and then decreased with experience and technical improvement. Concerns of long-term follow-up should be migration and esophageal dilatation, which seem to be rare at 3 years.

Intraductal papillary and mucinous tumors of the pancreas: accuracy of preoperative computed tomography, endoscopic retrograde pancreatography and endoscopic ultrasonography, and long-term outcome in a large surgical series

BACKGROUND Few data are available on the accuracy of preoperative imaging or on long-term outcome after surgery for intraductal papillary and mucinous tumors of the pancreas. The aims of this study were to assess the following: (1) the accuracy of preoperative computed tomography, endoscopic retrograde pancreatography, and endoscopic ultrasonography for determination of tumor invasion and pancreatic extension as compared with surgical findings; (2) the long-term outcome after surgery. METHODS Forty-seven patients who underwent surgery between 1980 and 1995 for pathologically diagnosed intraductal papillary and mucinous tumors were included in this study. The findings of available computed tomography (n = 25), endoscopic retrograde pancreatography (n = 29), and endoscopic ultrasonography (n = 21) were reviewed by experienced clinicians blinded to pathologic diagnosis to assess tumor invasion and pancreatic extension. Pathologic specimens were reviewed by experienced pathologists. Postoperative follow-up data were analyzed. RESULTS Histologic features of invasive carcinoma were found in 43% of patients, severe dysplasia in 21%, and mild or moderate dysplasia in 36%. The overall accuracy of computed tomography, endoscopic retrograde pancreatography, and endoscopic ultrasonography in distinguishing between invasive and noninvasive tumors were, respectively, 76%, 79%, and 76%. The overall 3-year disease-free survival rate was 63%, but it was 21% among patients with invasive carcinoma at surgery (p < 0.001). CONCLUSIONS This study emphasizes the need for early surgical resection in patients with suspected intraductal papillary and mucinous tumors of the pancreas because of the high frequency of invasive carcinoma and the inadequacy of preoperative imaging for assessing malignancy.

Thymidylate Synthase Gene Polymorphism Predicts Toxicity in Colorectal Cancer Patients Receiving 5-Fluorouracil-based Chemotherapy

Purpose: The target enzyme for 5-fluorouracil (5-FU) is thymidylate synthase (TS). The TYMS gene encoding this enzyme is polymorphic, having either double (2R) or tri-tandem (3R) repeats of a 28-bp sequence in the promoter region and a 6-bp variation in the 3′-untranslated region (3′-UTR). TS expression predicts response to 5-FU-based chemotherapy, and the expression seems to be determined by the TYMS gene promoter. The aim of this study was to investigate the utility of determining these two TYMS gene polymorphisms to predict the toxicity and efficacy of 5-FU treatment in patients with colorectal cancer. Experimental Design: The determination of TYMS genotypes was performed in tumor and normal tissues by PCR amplification from 90 patients with colorectal cancer who were treated with adjuvant or palliative 5-FU-based chemotherapy. Associations between polymorphisms in the TYMS promoter and in the 3′-UTR gene and clinical outcome of these 90 patients treated with 5-FU based chemotherapy were evaluated individually. The linkage between TYMS promoter and TYMS 3′-UTR region polymorphisms was evaluated and a haplotype analysis was performed. Results: Individuals who were homozygous for the double repeat in the TYMS promoter region had more severe side effects to 5-FU. Patients with a 2R/2R, a 2R/3R, or a 3R/3R genotype had a grade 3 or 4 toxicity rate of 43, 18, and 3% respectively (P < 0.01). The TYMS promoter and TYMS 3′-UTR polymorphisms were in linkage disequilibrium, and the haplotype 2R/ins 6-bp was significantly associated with a high risk of severe side effects to 5-FU. The TYMS promoter and TYMS 3′-UTR polymorphisms were not associated with a response to 5-FU and survival of patients who received palliative 5-FU-based chemotherapy. Conclusions: This study demonstrated that TYMS genotyping could be of help in predicting toxicity to 5-FU-based chemotherapy. TYMS genotyping might make it possible to individualize treatment for patients with colorectal cancer.

Small bowel metastases from primary carcinoma of the lung : Clinical findings and outcome

OBJECTIVES:Symptomatic small bowel metastases from primary carcinoma of the lung have been rarely reported. The aim of this study was to describe clinical presentation and outcome in a series of patients.METHODS:Between 1984 and 1996, 1544 patients with lung cancer were referred to our institution for surgery and 1399 were operated on. Seven of them developed a symptomatic small bowel metastasis. Clinical, radiological, and pathology records were reviewed.RESULTS:In 6 of 7 patients, the lung cancer was previously operated on from 0.5 to 24 months before the diagnosis of small bowel metastasis. In 1 patient, the primary tumor was diagnosed after small bowel metastasis resection. Clinical symptoms at presentation were acute peritonitis in 2 patients, progressive digestive obstruction in 3, and gastrointestinal bleeding in 2. The diagnosis was suspected on abdominal ultrasonography in 2 cases, and small bowel radiography in 3 cases. It was confirmed either by computed tomographic scan or by push enteroscopy. All patients underwent operation (intestinal resection in 6 and bypass in 1) with no postoperative death. Small bowel metastases were located in the jejunum in 2 patients, in the ileum in 3, and in both sites in 2. Histological features of the metastases were identical to the primary tumor: squamous cell carcinoma (n = 3), undifferentiated large cell carcinoma (n = 2), adenosquamous carcinoma (n = 1), and adenocarcinoma (n = 1). In 6 patients, small bowel metastases were associated with other metastatic sites. Six patients died within 8 months after metastasis resection. One patient was alive 22 months after bowel resection.CONCLUSIONS:Symptomatic small bowel metastases can occur early in the course of lung cancer. Resection should be considered as the best palliative treatment to prevent bowel obstruction or peritonitis.

Outcome after surgical resection of intraductal papillary and mucinous tumors of the pancreas

OBJECTIVE:Treatment of intraductal papillary and mucinous tumors of pancreas (IPMT) usually requires surgery. The objective of this study was to evaluate the risk of recurrence in patients after surgery according to the histological nature of the neoplasm and the type of surgery.METHODS:The outcome of 45 patients who underwent partial pancreatectomy (n = 35) or total pancreatectomy (n = 10) for IPMT was studied according to the nature of the neoplasm (invasive carcinoma or noninvasive neoplasm), type of surgery (partial or total pancreatectomy), and lymph nodes status.RESULTS:The overall 3-yr actuarial survival rate was 83%. Death occurred in seven of 20 (35%) patients with invasive carcinoma and in one of 26 (4%) patients with noninvasive tumors (p < 0.05). There were two recurrences in the seven patients with noninvasive neoplasm who underwent partial pancreatectomy with involved resection margins, and none in the 13 patients with disease-free margins. In patients with invasive carcinoma, there was one recurrence after total pancreatectomy, six after partial pancreatectomy with disease-free margins and six after partial pancreatectomy with involved margins. In patients with invasive carcinoma, total pancreatectomy and the absence of lymph nodes involvement were independently associated with a low risk of recurrence.CONCLUSIONS:IPMT may be managed as follows: 1) in patients with noninvasive neoplasms, partial pancreatic resection should be guided by frozen section examination until disease-free margins are obtained; and 2) in patients with invasive carcinoma, total pancreatectomy seems most likely to cure the patient, but should be discussed according to the general status and the age.

Right colonic involvement is associated with severe forms of ischemic colitis and occurs frequently in patients with chronic renal failure requiring hemodialysis

OBJECTIVE:The aim of this study was to identify factors associated with severe outcome in patients with ischemic colitis.METHODS:The files of 60 consecutive inpatients (34 women, 26 men, mean age 67 yr) with ischemic colitis were reviewed. The following data were analyzed: age, sex, smoking, medications, history of cardiovascular disease, metabolic disease, chronic renal failure and hemodialysis, the time elapsed between the first symptoms and the diagnosis, and the site and extension of their colonic involvement. Patients were divided into two groups according to outcome: those with severe disease, including those who died from ischemic colitis (n = 3) or who required surgical resection (n = 21); and those with mild forms of colitis who were treated successfully without surgery (n = 36). The two groups were compared by means of univariate and multivariate analysis to identify factors associated with unfavorable outcomes. Only patients who had a complete examination of the colon (n = 51) were entered into the statistical analysis.RESULTS:By univariate analysis, chronic renal failure (p = 0.03), hemodialysis (p = 0.01), short delay between symptoms and diagnosis (p = 0.01), and right colonic involvement (p = 0.002) were significantly more common in the patients with severe colitis. By logistic regression, right colonic involvement was the only factor independently associated with severity (p = 0.01). Right-sided lesions were present in 82% of patients on dialysis but in only 26% of patients not on dialysis (p = 0.0005).CONCLUSIONS:Right colonic involvement is associated with severe forms of ischemic colitis and occurs frequently in patients with chronic renal failure requiring hemodialysis.

Intraoperative enteroscopy for diagnosis and management of unexplained gastrointestinal bleeding

BACKGROUND The aim of this study was to evaluate the diagnostic and therapeutic yield of intraoperative enteroscopy in patients with obscure gastrointestinal (GI) bleeding. METHODS Complete intraoperative enteroscopy was performed in 25 patients with GI bleeding (overt hemorrhage 21, occult blood loss 4). The cause of GI bleeding was unknown before intraoperative enteroscopy in 20 patients and presumed in 5 (colon 4, duodenum 1). RESULTS Complete inspection of the small bowel was achieved in all cases. Mucosal-based lesions of the small bowel were identified in 16 of the 20 patients in whom the source of bleeding was unknown preoperatively (angiodysplasia 12, other causes 4). These lesions were treated by segmental small bowel resection (15) or medical therapy (1). With a mean 19-month follow-up, the rebleeding rate was 30% (6 of 20), and 2 of them in whom enteroscopy was negative died of massive hemorrhage. Intraoperative enteroscopy was normal in the 5 patients with bleeding of presumed GI origin preoperatively. CONCLUSIONS Intraoperative enteroscopy remains a valuable tool for exploring obscure GI bleeding in selected patients.

Adjustable Gastric Banding in a Public University Hospital: Prospective Analysis of 400 Patients

Background: Laparoscopic application of an adjustable gastric band (LAGB) is considered the least invasive surgical option for morbid obesity. It has the advantage of being potentially reversible and can improve quality of life. Method: Between April 1997 and January 2001, 400 patients underwent LAGB. There were 352 women and 48 men with mean age 40.2 years (16-66). Preoperative mean body weight was 119 kg (85-195) and mean body mass index (BMI) was 43.8 kg/m2 (35.1-65.8). Results: Mean operative time was 116 minutes (30-380), and mean hospital stay was 4.55 days (3-42). There was no death. There were 12 conversions (3%). 40 complications required an abdominal reoperation (10%), for perforation (n=2), gastric necrosis (n=1), slippage (n=31), incisional hernia (n=2) and reconnection of the tube (n=4). We noticed 7 pulmonary complications (2 ARDS, 5 atelectasis) and 30 minor problems related to the access port. At 2 years, mean BMI had fallen from 43.8 to 32.7 kg/m2 and mean excess weight loss (EWL) was 52.7 % (12-94). Conclusion: LAGB is a very beneficial operation with an acceptable complication rate. EWL is 50% at 2 years if multidisciplinary follow-up remains assiduous. Surveillance for late anterior stomach slippage within the band is essential.