APC, MYH, and the correlation genotype-phenotype in colorectal polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) has been divided into two entities: classical (CFAP) and attenuated (AFAP). With the discovery of MYH associated polyposis (MAP) syndrome, the clinical differences have become unclear. The aim of our study was to investigate patients with polyposis treated in our institution for a correlation between genotype and phenotype. METHODS: Between 1978 and 2007, 515 patients were followed. Four groups were identified: AFAP, CFAP, MAP, and no-mutation patients. Clinical, surgical, histological, and genetic data of patients were collected and compared. Two ranges of mutations responsible for AFAP were used. RESULTS: Patient breakdown was CFAP patients (n = 322/294), AFAP patients (n = 13/41), MYH patients (n = 17) and no-mut patients (n = 32). Patients not tested for APC mutation (n = 131) were excluded. Genotype/phenotype evaluation showed no difference in the number or location of polyps, age at colectomy, presence of cancer, or duodenal polyps. Major differences were found for MYH patients: later age at diagnosis, more cancers, fewer polyps, and more located in the right part of the colon. For phenotype/genotype correlation, patients aged more than 35 years at the time of colectomy and with fewer than 100 polyps had significantly more mutation found on MYH. CONCLUSIONS: This two-way analysis did not show any correlation that might help to identify a subgroup of patients with APC mutation that may be considered attenuated. It is more likely that the MAP syndrome is the real AFAP.

Results of an aggressive surgical approach in the management of postoperative peritonitis.

BACKGROUND: Treatment of postoperative peritonitis (POP) necessitates adequate control of the source of peritoneal contamination. For most patients, a surgical approach to this requires reoperation to restore intestinal continuity. The aim of this study was to audit our results for the surgical treatment of POP. METHODS: Medical records of patients treated for POP using a standardized surgical protocol in a dedicated intensive care unit at the Saint-Antoine Hospital between 1995 and 2003 were reviewed. The aim of the study was to consider the effectiveness of our surgical protocol in the eradication of all sources of peritoneal contamination in patients presenting with POP. RESULTS: There were 87 patients (34 women, mean age of 58.4 +/- 14.7) with a mean Acute Physiology and Chronic Health Evaluation II score of 17.2 +/- 4.7 (median 16.5, range 9-28). Eight patients died and there were complications in 60 patients. Nine patients of the 79 survivors either did not require or could not have an operation to restore intestinal continuity. Intestinal continuity was re-established through a parastomal incision for 26 patients, whereas 44 patients required a further laparotomy. Two patients of the latter group died and 11 patients had a complication. It was not possible to restore intestinal continuity at laparotomy for one patient. CONCLUSION: An aggressive surgical approach, as reported in this series, including stoma formation whenever possible, diversion or intubation, provides effective control of the source of peritoneal contamination. Restoration of intestinal continuity is possible in most patients. The overall mortality rate for this treatment is 11.5%.

Lumboaortic and iliac lymphadenectomy for lymph node recurrence of colorectal cancer: prognostic value of the MSI phenotype.

BACKGROUND: Some patients have isolated lumboaortic and/or iliac lymph node recurrences (ILNR) of colorectal cancer. Current guidelines recommend the use of chemotherapy. The aim of our study was to assess the carcinological results of lymphadenectomy for ILNR and to identify prognostic factors that may be used to select patients for this aggressive surgical approach. METHODS: Medical notes, pathological findings, and surgical procedure of patients who underwent lymphadenectomy for ILNR of colorectal cancer between 1998 and 2005 were reviewed. RESULTS: Ten patients (four women) underwent lymphadenectomy for ILNR. Lymphadenectomy was performed after a mean of 37 +/- 16.6 months after colon or rectal resection. Two patients developed a postoperative complication. Mean number of lymph nodes removed was 5.7 +/- 3.3. After a median follow-up of 30.7 months, four patients were alive, including two patients without recurrence at 95 and 96 months after colectomy and two with local and distant recurrences at 114 and 70 months. Among the three patients with microsatellite-unstable (MSI) tumors, two were free of disease at 61 and 81 months, respectively, and one died of recurrent disease 20 months after lymphadenectomy. CONCLUSION: Lymphadenectomy for ILNR of colorectal cancer is a feasible therapeutic option for selected patients. These preliminary results suggest that resection should be proposed for MSI patients because cure is possible, but to be confirmed, the findings require larger studies.

Multiple stomas for recurrent life-threatening gastrointestinal bleeding: report of a case.

Acute lower gastrointestinal hemorrhage is an uncommon and severe symptom. The overall mortality rate ranges from 5 to 12 percent and can approach 40 percent for persistent or recurring bleedings. We report a case of a patient with severe recurrent lower bleeding in whom, despite several repeated explorations and a blind subtotal colectomy, no lesion could be found. Multiple (n = 4) leveled stomas of the small bowel with succus entericus reinfusion were required to localize and treat the cause of the bleeding. This case report is followed by a review of the literature of the management of lower gastrointestinal bleeding.

Long-term results of intersphincteric resection for low rectal cancer.

INTRODUCTION: In the treatment of very low rectal cancer, a distal resection margin of more than 1 cm can be obtained by partial internal sphincteric resection, allowing a sphincter preserving surgery. Thus, intersphincteric resection (ISR) has been proposed as an alternative to abdominoperineal resection for selected low rectal cancer. OBJECTIVE: The aim of our study was to assess the morbidity, mortality, and the long-term oncologic and functional results of ISR. METHODS: Charts of patients who had ISR between 1992 and 2004 were reviewed. Cancer-related survival and locoregional recurrence rates were calculated using the Kaplan-Meier method. Functional outcome was assessed by using a standardized gastrointestinal functional questionnaire. Incontinence was assessed by the continence score of Wexner. RESULTS: Ninety patients (59 males, 31 females) with a tumor at a median distance of 35 mm (range, 22-52) from the anal verge had an ISR. Thirty-seven patients (41%) had preoperative radiotherapy. Histologically complete remission after neoadjuvant radiotherapy (ypT0) was observed in 7 patients (8%), 12 patients (13%) were pT1, 35 patients (39%) pT2, 32 patients (36%) pT3, and 4 patients (4%) pT4. Five patients (5.5%) had synchronous liver metastases. R0 resection was obtained in 85 patients (94.4%). The median distal resection margin on the fixed specimen was 12 mm (range, 5-35) and was positive in 1 case. The circumferential margin was positive (< or =1 mm) in 4 patients (4.4%). There was no mortality. Complication rate was 18.8%: anastomotic leakage occurred in 8 patients (8.8%) and 1 patient had an anovaginal fistula. Five patients (5.6%) underwent secondary abdominoperineal resection: 1 for positive distal margin, 1 for colonic J-pouch necrosis, and 3 for local recurrence. ONCOLOGIC RESULTS: After a median follow-up of 56.2 months (range, 13.3-168.4), local, distant, and combined recurrence occurred in 6 (6.6%), 8 (8.8%), and 2 patients, respectively. Thirteen patients (14.4%) died of cancer recurrence. Five-year overall and disease-free survival was 82% (80-97) and 75% (64-86), respectively. In univariate analysis, overall survival was significantly influenced by pTNM stage and T stage (pT 1-2 vs. 3-4: P = 0.008 and stage I-II vs. III-IV: P = 0.03). In multivariate analysis, we did not find any impact on local recurrence-free survival for the investigated prognostic variables. FUNCTIONAL RESULTS: For a total of 83 patients the mean stool frequency was 2.3 +/- 1.3 per 24 hours. Forty-one percent of patients had stool fragmentation, one-third nocturnal defecation, 19% fecal urgency, and 36% followed low fiber diet. Thirty-four patients (41%) were fully continent, 29 patients (35%) had minor continence problems, and 20 patients (24%) were incontinent. After adjustment for age, gender, tumor level, and pTNM stage, preoperative radiotherapy was the only factor associated with a risk of fecal incontinence [OR (IC 95%) = 3.1 (1.0-9.0), P = 0.04]. CONCLUSION: In selected patients, ISR is a safe operation with good oncologic results. It achieves good functional results in 76% of patients. Functional results are significantly altered by preoperative radiotherapy.

[Acinar cell carcinoma of the pancreas with predominant intraductal growth: report of a case]. / Carcinome à cellules acineuses du pancréas, de développement essentiellement intracanalaire: à propos d'un cas.

Acinar cell carcinoma (ACC) of the pancreas accounts for approximately 1% of all exocrine pancreatic tumours. We report a rare form of ACC in a 66-year-old man. This tumour was revealed by epigastric pain and weight loss. Abdominal computed tomography showed a hypodense, well-demarcated, heterogeneous lesion, in the head of the pancreas, measuring 4.2 cm in diameter. There was a marked dilatation of the main pancreatic duct upstream, with tumour spreading within this duct. The diagnosis of ACC was made on the fine needle aspiration cytology performed during endoscopic ultrasound examination. On the pancreaticoduodenectomy specimen, the dilated main pancreatic duct (2.5 cm in diameter) was filled by an exophytic tumour. Histological examination showed an ACC, with predominant intraductal growth (main and accessory pancreatic ducts), with pancreatic parenchymal and duodenal invasion. Neuroendocrine markers were negative. To our knowledge, this is the second report of an ACC with predominant intraductal spread. These rare forms of ACC can be confused with intraductal papillary-mucinous neoplasms. In our report, fine needle aspiration cytology performed during endoscopic ultrasound examination was a valuable tool in the diagnostic assessment.

Implication of MYH in colorectal polyposis.

OBJECTIVE: The aim of this study was to determine the frequency of MYH mutations in one large population of polyposis patients without APC mutation identified. SUMMARY BACKGROUND DATA: Familial adenomatous polyposis (FAP) is the most known inherited colorectal cancer syndrome. In 70% to 80% of polyposis patients, an APC mutation is found. Patients with polyposis but no APC mutation are considered as APC-muted patients and followed as their relatives accordingly. Biallelic mutation of MYH has been found to responsible of colorectal polyposis and cancer in an autosomal recessive pattern of inheritance. METHODS: Between 1978 and 2004, 433 patients were operated for polyposis. A mutation on APC was identified in 322 patients. Among the remaining patients, 44 were identified as possible MYH-muted patients and contacted, and 31 signed informed consent. Clinical data were obtained from the patients' medical notes. Germline mutation of MYH was searched by sequencing the whole gene. To confirm the deleterious effects of biallelic MYH mutation, transversions on K-ras and APC were searched. RESULTS: There were 9 women and 22 men with a mean age of 53.9 years (range, 22-68 years) at the time of diagnosis. The mean number of polyps was 62.8 (range, 11-266). Eighteen patients (58.1%) had a colorectal cancer. We found biallelic MYH mutation in 6 patients (19.3%; 95% confidence interval, 5.2%-33.5%) and 5 (83.3%) had transversions in K-ras and/or APC. CONCLUSION: MYH is a new gene responsible for about 1.4% of all adenomatous polyposis and about 20% of adenomatous polyposis without APC mutation identified. Search for MYH biallelic mutation in these patients should be systematic as it changes their and relatives'surveillance.

Coloanal sleeve anastomosis (Soave procedure): the ultimate treatment option for complex rectourinary fistulas.

PURPOSE: Acquired rectourinary fistulas represent a therapeutic challenge. Multiple previous unsuccessful procedures increase the difficulty of successful repair, leaving many patients with no option other than permanent urinary and/or fecal diversion. We report our experience with coloanal sleeve anastomosis (Soave procedure) as a salvage procedure for complex rectourinary fistulas. METHODS: Between 1994 and 2005, eight males (median age, 60 (range, 33-72) years) had Soave procedure in our institution. Four fistulas were the result of radical prostatectomy and four followed anterior resection for rectal cancer after radiochemotherapy. The location of the fistulas was bladder (n = 5) and urethra (n = 3). Five patients had previous attempts at surgical repair (median, 2 (range, 1-3) operations). The Soave procedure was chosen as first-line treatment because of fistula size (20 mm and 30 mm) in two patients and because of concomitant severe radiation proctitis in one patient. RESULTS: Morbidity was 38 percent. All patients had a temporary ileostomy, which was successfully reversed in seven patients. One patient required ileal pouch-anal anastomosis on postoperative Day 1 because of necrosis of the descended colon. Two patients had recurrent fistulas at two and three months respectively. One patient had moderate problems with this recurrent fistula and had his stoma closed, but the other patient required a permanent ileostomy. CONCLUSIONS: Soave procedure is an effective treatment for complex rectourinary fistula in the setting of high-dose pelvic radiation or after failed previous repair attempts.

The effect on morbidity of mesentery lengthening techniques and the use of a covering stoma after ileoanal pouch surgery.

PURPOSE: A tension-free anastomosis in a restorative proctocolectomy requires sufficient length of small-bowel mesentery. To ensure adequate length, it has been proposed that the superior mesenteric artery be divided and the right colon marginal vascular arcade be preserved. This study was designed to evaluate the influence of mesenteric lengthening techniques on the need for a stoma and on early outcomes after restorative proctocolectomy. METHODS: Records of patients who had a restorative proctocolectomy between January 1998 and October 2003 were reviewed. Patient and disease characteristics, operative techniques and findings, the need for a stoma, and postoperative complications were recorded. RESULTS: In one patient a restorative proctocolectomy was not possible. The remaining 220 patients were divided into two groups: Group A (inflammatory bowel disease; n = 123) and Group B (noninflammatory bowel disease; n = 97). Sixty-nine patients (31.4 percent) had major comorbidities. A lengthening technique was performed in 120 patients (54.5 percent) by dividing the ileocecal artery (n = 37) or the superior mesenteric artery (n = 88); 5 patients had only the marginal vascular arcade preserved. An ileostomy was not required in 116 patients (52.7 percent). In multivariate analysis, in Group B the only surgical variable influencing the need for an ileostomy was preservation of the marginal vascular arcade (50 vs. 14.7 percent; P < 0.0005). Complications occurred in 41 patients (18.6 percent), more frequently for those in Group A and for patients receiving steroids (23.6 vs. 12.4 percent, P = 0.012; 10.4 vs. 6.8 percent, P = 0.0172). CONCLUSIONS: The use of mesentery lengthening techniques allows a restorative proctocolectomy to be performed in almost all patients without increasing morbidity and may reduce the number of covering stomas. Because division of the ileocecal and/or superior mesenteric arteries may be required, preservation of the marginal vascular arcade is essential whenever possible.

Palliative surgery for unresectable pancreatic and periampullary cancer: a reappraisal.

This study aimed to reappraise short-term and long-term results of palliative biliary and gastric bypass surgery in patients with unresectable pancreatic head carcinoma found at explorative laparotomy. We retrospectively analyzed 83 consecutive patients whose pancreatic head carcinoma appeared unresectable at laparotomy (vascular involvement [57%], liver metastases [24%], distant metastatic lymph nodes [11%], peritoneal implants [8%]) and who underwent palliative surgical concomitant biliary and gastric bypass. Postoperative mortality and morbidity rates were 4.8% and 26.5%, respectively. Postoperative-delayed gastric emptying occurred in 9 patients (10%). Antecolic (46%) and retrocolic (54%) gastrojejunostomies did not differ for the duration of nasogastric suction, the delay of oral intake, and the incidence of delayed gastric emptying. Mean hospital stay was 16 +/- 8 days. Median survival was 9 months (range 1-44). Late cholangitis occurred in 2 patients (2.4%) treated medically. One recurrent jaundice required transhepatic stenting 9 months from surgery. Four late gastric outlet obstructions occurred (4.8%) with a mean delay of 8 months from surgery. These data demonstrate that, in patients with unresectable pancreatic head carcinoma at laparotomy, palliative concomitant biliary and gastric bypass in a single procedure is safe and long-term efficient. This strategy remains to be compared to endoscopic palliation in this setting.

Assessment of MRI and MRCP in diagnosis of biliary cystadenoma and cystadenocarcinoma.

Magnetic resonance imaging (MRI) and magnetic resonance cholangio-pancreatography (MRCP) features were analyzed in the diagnosis of seven surgically resected hepatobiliary cystic tumors with reference to histopathological data. Homogeneity, size, location, signal intensity, presence or absence of septa and/or nodules and MRCP features of the lesions were studied. Histological evidence demonstrated six biliary cystadenoma (BCA) including four pseudo-ovarian stroma (POS) and one biliary cystadenocarcinoma (BCAC). Cystic lesions (3-15 cm in diameter) were homogeneous in the six BCA, heterogeneous in the one BCAC, and were located in the left and right liver, respectively. On T2-weighted images all lesions were hyperintense. On T1-weighted images hypointensity was found in three BCA (all serous fluid, including one POS), isointensity was found in the three others (two mucinous and one hemorrhagic fluid, including three POS) and in the one BCAC (containing mucinous fluid). Septas were present in all cases and nodules only in the one BCAC. On MRCP a hyperintense cystic lesion was found in all cases and a bile ducts dilatation in two BCA and the one BCAC. Gadolinium-enhanced MRI in combination with MRCP is a valuable tool for the diagnosis of BCA or BCAC. However, no specific information is gained for POS detection.

Lymph node metastases of prostatic adenocarcinoma in the mesorectum in patients with adenocarcinoma or villous tumor of the rectum with collision phenomenon in a single lymph node: report of five cases.

PURPOSE: Lymph node involvement is the most important prognostic factor when staging patients with rectal cancer. Cancer originating from sites other than rectum rarely may metastasize to the mesorectum. We report five patients with metastatic prostatic carcinoma to mesorectal lymph nodes, with the "collision phenomenon" in one lymph node. The diagnosis of prostate cancer was clinically unsuspected in two cases. METHODS: We examined three cases of primary adenocarcinoma and two villous tumors with high-grade dysplasia (patient age range, 52-74 (mean, 63) years) of the middle or lower third of the rectum. All patients underwent low anterior rectal resection with total mesorectal excision and colorectal or coloanal anastomosis. We used a manual technique for lymph node detection after overnight fixation in 10 percent formalin. All lymph nodes identified (range, 15-32; mean, 21 nodes per patient) were examined histologically. RESULTS: Of 106 lymph nodes examined, 20 contained metastases: 9 from rectal adenocarcinoma, 10 from prostatic adenocarcinoma, and 1 with metastatic foci from both tumors. The diagnosis of prostatic carcinoma was readily confirmed by immunostaining for prostatic-specific antigen, and prostatic acid phosphatase. CONCLUSIONS: Mesorectal lymph node dissection provides prognostic information in rectal cancer, but careful examination may reveal other unsuspected pathology. Immunohistochemical staining is an essential tool in distinguishing the origin of a lymph node metastasis, especially when the histology does not look typical for rectal carcinoma. Moreover, these observations highlight the connection that can exist between mesorectal lymph node drainage, and extra mesorectal lymph nodes drainage.

Malignant deciduoid mesothelioma: a diagnostic challenge.

Malignant deciduoid mesothelioma, a rare phenotype of epithelioid mesothelioma, arises more commonly from the peritoneum of young women, but it is also reported in the pleura of elderly people. We report a case of malignant deciduoid mesothelioma that occurred in a 41-year-old woman after cesarean section and was initially misdiagnosed as pseudotumoral deciduosis. Microscopically, the tumor was entirely composed of deciduoid areas, and only scattered tumor cells were positive for calretinin and keratin 5/6. The patient died 14 months after the first operation. This observation confirms the poor prognosis of this entity and the importance of the differential diagnosis of pseudotumoral deciduosis.

Ex vivo sentinel lymph node mapping in colorectal cancer.

INTRODUCTION: Sentinel lymph node mapping has been used in clinical work in malignant melanoma and breast cancer and shown an advantage over routine regional lymphadenectomy. The technique has been applied to colorectal cancer, but concerns over accuracy and high false-negative rates have restricted its use in the routine clinical setting. Most published series have used the in vivo technique and only three studies have been published in which the ex vivo technique was used. The aim of this study was to report the results of a larger study of ex vivo sentinel node mapping. METHODS: All patients with colorectal cancer were considered for the trial, except patients who received preoperative radiotherapy for rectal cancer. All specimens were examined in the operating room within 30 minutes of resection. After opening the bowel, 0.5 ml of patent blue dye was injected submucosally at four sites immediately adjacent to the tumor (2 ml). The pathologic examination of the sentinel nodes and of an equal number of nonsentinel nodes consisted of standard hematoxylin and eosin sectioning, followed by multiple sectioning for further hematoxylin and eosin staining and immunohistochemistry if initial samples did not show tumor metastases. RESULTS: A total of 58 tumors in 57 patients were studied. One or more sentinel nodes were found in relation to 56 tumors, with one of the two failures being attributed to gross mesenteric metastases obstructing lymphatic flow. A mean of 2.93 (0-8) sentinel nodes were found per patient. There was concordance between the sentinel nodes and nonsentinel nodes in 43 patients (76.8 percent). There were nine false-negative sentinel nodes (16 percent). Two patients were upstaged by detailed pathologic examination of the sentinel nodes (micrometastases), and in a further two patients the sentinel node was the only positive node on simple hematoxylin and eosin sectioning. CONCLUSIONS: The technique of ex vivo sentinel node mapping is feasible and accurate in defining sentinel nodes in colorectal cancer. There is, however, a significant false-negative rate making the sentinel nodes not representative of the lymph node basin. This precludes the use of this technique in routine clinical practice. There may be a role in a research setting to help define the prognostic significance of micrometastases.

Colonic J-pouch-anal anastomosis for rectal cancer: a prospective, randomized study comparing handsewn vs. stapled anastomosis.

PURPOSE: Colonic J-pouch-anal anastomosis performed after complete proctectomy and total mesorectal excision for adenocarcinoma of the rectum can be handsewn or stapled. Stapling the coloanal anastomosis is believed to shorten operating time and reduce morbidity, but there are no randomized trials comparing the techniques. METHODS: Between January 1999 and May 2001, all patients with rectal adenocarcinoma requiring total mesorectal excision were randomized intraoperatively to handsewn or stapled anastomosis. Mortality, intraoperative, and postoperative findings and functional results at 3, 6, and 12 months were analyzed. RESULTS: Thirty-seven patients (12 females; mean age, 60 +/- 10 years) were randomized (stapled group: n = 20; handsewn group: n = 17). The two groups were comparable for age, gender, distance between the tumor and the levator ani, tumor volume, and use of preoperative radiotherapy (3 in each group). Morbidity did not differ between stapled group (3/20) and handsewn group (4/17; P > 0.05). Mean +/- standard deviation operative time was shorter in stapled group (261 +/- 40 minutes) than in handsewn group (314 +/- 46 minutes; P = 0.0008), and median distance between the anastomosis and the anal verge was shorter in handsewn group (19 +/- 9 mm) than in stapled group (27 +/- 8 mm; P = 0.01). Three patients of handsewn group and none of stapled group developed an anastomotic stricture requiring a single digital dilation (not significant). Number of stools per 24 hours, urgency, incidence of fragmented stools, degree of continence, requirement for protective pad, and/or need to take medication at 3, 6, and 12 months were similar in both groups. CONCLUSIONS: Stapled co-loanal anastomosis is significantly faster than handsewn CAA and has similar functional results. It should be the preferred technique when it is feasible.

Intensive systemic chemotherapy combined with surgery for metastatic colorectal cancer: results of a phase II study.

PURPOSE: To evaluate the efficacy and tolerability of the metastatic irinotecan plus oxaliplatin (MIROX) strategy (adjuvant FOLFOX-7 followed by FOLFIRI), in patients with resectable metastatic colorectal cancer. PATIENTS AND METHODS: Forty-seven patients with resectable metastases of colorectal cancer were prospectively enrolled onto this study. Treatment consisted of six cycles of leucovorin 400 mg/m(2), oxaliplatin 130 mg/m(2) in a 120-minute infusion, and fluorouracil (FU) 2,400 mg/m(2) in a 46-hour infusion, every 2 weeks (FOLFOX-7), followed by six cycles of leucovorin 400 mg/m(2), irinotecan 180 mg/m(2) in a 90-minute infusion, bolus FU 400 mg/m(2), and FU 2,400 mg/m(2) as a 46-hour infusion, every 2 weeks (FOLFIRI). Surgery was performed before chemotherapy in 25 patients and after six cycles of FOLFOX-7 in 22 patients (six cycles of FOLFIRI were administered after surgery). RESULTS: All but one of the patients underwent curative surgery. Two patients refused postoperative chemotherapy. Tolerability was generally good. The main toxicities were grade 3 to 4 neutropenia (13%) and thrombocytopenia (11%); no febrile neutropenia or bleeding occurred, and there were no deaths caused by toxicity. Two pathologically confirmed complete responses and 15 partial responses were obtained with FOLFOX-7 in the 22 patients who received this regimen before surgery (overall response rate, 77%; 95% CI, 68 to 86). The median disease-free survival time was 21 months; the median overall survival has not yet been reached. The 2-year overall and disease-free survival rates were 89% and 47%, respectively. CONCLUSION: The MIROX strategy is feasible and well tolerated by patients with resectable metastatic colorectal cancer. Progression-free and overall survival rates are promising, with a median of 38 months of follow-up. This strategy currently is being compared with the leucovorin and FU regimen in a phase III trial.

Cytoplasmic phospholipase A2 alpha overexpression in stromal cells is correlated with angiogenesis in human colorectal cancer.

In colorectal cancer, cyclooxygenase-2 (COX-2) overexpression in stromal cells induces angiogenesis through EP2 prostaglandin E2 receptor signaling. Cytoplasmic phospholipase A2 (PLA2) alpha preferentially hydrolyses arachidonic acid, which is the limiting substrate for prostaglandin production, from membrane phospholipids. We therefore investigated a possible relationship between cytoplasmic PLA2 and COX-2 overexpression in stromal cells, angiogenesis and microsatellite instability in 48 human colorectal adenocarcinomas. Cytoplasmic PLA2 and COX-2 expression in stromal cells and vascular endothelial growth factor (VEGF) expression in tumor cells were evaluated by immunohistochemistry. Microvessel density was assessed in 10 x 400 fields after CD31 staining. Microsatellite instability was evaluated by PCR and immunohistochemistry. A total of 16 tumors had microsatellite instability. We found an overexpression of cytoplasmic PLA2 in superficial stromal cells. These cells corresponded to fibroblasts and myofibroblasts. There was an association between the number of cytoplasmic PLA2 and COX-2-expressing cells (P=0.006). Cytoplasmic PLA2-positive stromal cells usually also expressed COX-2. A high number of cytoplasmic PLA2-positive stromal cells was correlated with a high microvessel density (P=0.002), a strong VEGF (P=0.01) and the absence of microsatellite instability (P=0.001). The coordinate overexpression of cytoplasmic PLA2 and COX-2 in stromal cells could lead to an important prostaglandin production. These results suggest that cytoplasmic PLA2 overexpression in these cells regulates COX-induced angiogenesis probably by providing arachidonic acid, which is the limiting factor for prostaglandin production. The lower number of cytoplasmic PLA2-positive stromal cells in carcinomas with microsatellite instability could be related to their lower microvessel density and VEGF expression.

Viabilidade do fígado bioartificial utilizando hepatócitos humanos imunoprotegidos por macroencapsulação / Assessment of bioartificial liver using human hepatocytes immunoprotected by macroencapsulation

OBJETIVO: O transplante de hepatócitos xenogênicos encapsulados pode ser utilizado no futuro em situações como a insuficiência hepática fulminante. Porém, observa-se perda precoce da expressão de genes hepatocitários específicos em hepatócitos humanos. O objetivo deste estudo é avaliar a influência da resposta imunológica na perda da expressão genética hepatocitária de hepatócitos humanos encapsulados e transplantados em ratos. MÉTODO: Hepatócitos humanos foram isolados de fragmentos hepáticos, encapsulados em fibras e transplantados em ratos. Nos dias 3, 7 e 14 após o transplante as fibras foram coletadas e avaliadas a morfologia por microscopia óptica e eletrônica, e a expressão dos genes por biologia molecular. O ARNm da albumina humana foi quantificado por RT-PCR e Northern blot. A resposta imunológica contra os hepatócitos foi avaliada através do ADN hepatocitário na busca de apoptose do núcleo celular e pelo aumento da expressão do CMH de classe I. RESULTADOS: Os aspectos morfológicos dos hepatócitos mantiveram-se normais até o sétimo dia após o transplante. Não se observaram células envolvidas com resposta imunológica do receptor nas fibras. Os transcritos da albumina foram detectados até D-14. Entre os dias 3 e 7 estavam em 30 por cento em relação ao dia 0. A análise do ADN mostrou bandas preservadas sem a presença de fenômenos de apoptose nos diferentes dias. Não ocorreu aumento da expressão do CMH de classe I. CONCLUSÕES: Hepatócitos humanos encapsulados e transplantados em ratos permanecem viáveis apesar da diminuição da expressão de determinados genes. Este fenômeno, não se deve à resposta imunológica do receptor, mas ao próprio processo de isolamento celular.

BACKGROUND: Xenogeneic hepatocytes encapsulated in semipermeable membranes could be used in the future; however, encapsulated human hepatocytes presented an early decrease of hepatocyte gene expression. The objective of this study is to investigate the immunological consequences of intraperitoneal implantation of encapsulated xenogeneic hepatocytes on gene expression. METHODS: human hepatocytes were encapsulated in hollow fibers and transplanted in the peritoneal cavity of rats. The fibers were explanted for analysis at days D3, D7 and D14 following transplantation. Morphological features under light and electron microscopies and gene expression were compared to those of non-transplanted encapsulated hepatocytes. Human albumin mRNAs were quantified by RT-PCR and Northern blot. Immunological activity against human hepatocytes was assessed by the analysis of DNA searching for nucleolar apoptosis and also by the rise on MHC class I expression. RESULTS: Transplanted hepatocytes were more than 60 percent viables and exhibited morphological criteria of hepatocytic differentiation up to D7. At no time cells involved with the immunological response were observed inside the fibers. Albumin transcripts were also detected up to D14. At D3 and D7, albumin mRNA levels were of 30 percent, compared to control. The DNA analysis showed well preserved bands with no apoptosis at any time of evaluation. There was no rise on MHC class I expression. CONCLUSION: Human hepatocytes remain viable following encapsulation and intraperitoneal transplantation in rats. Although there is a decrease in gene expression this is not due to a host response against those cells. It seems that this effect is rather related to the process of hepatocyte isolation itself.

Long-term outcome of familial adenomatous polyposis patients after restorative coloproctectomy.

BACKGROUND: Restorative proctocolectomy (RPC) eliminates the risk of colorectal adenocarcinoma in familial adenomatous polyposis (FAP) patients, but desmoid tumors, duodenal, and ileal adenomas can still develop. Our aim was to assess the long-term outcome of FAP patients after RPC. PATIENTS AND METHODS: FAP patients who had RPC between 1983 and 1990 were contacted for interview and upper gastrointestinal (GI) and ileal pouch endoscopy. RESULTS: Sixty-two males and 48 females had undergone hand-sewn RPC during this period. One patient died postoperatively (0.9%). Among 96 patients available for a minimal follow-up of 11 years, 7 patients died: 3 from causes unrelated to FAP, 2 from metastatic colorectal cancer, and 2 from mesenteric desmoid tumor (MDT). Thirteen patients had a symptomatic MDT (13.5%). Of 73 patients who had an upper GI endoscopy, 52 developed duodenal and/or ampullary adenomas. Four patients required surgical treatment of their duodenal lesions. Among 54 patients who underwent ileal pouch endoscopy, pouch adenomas were noted in 29. No invasive duodenal or ileal pouch carcinoma were detected. Functional results of RPC were significantly worse in MDT patients. CONCLUSIONS: RPC eliminates the risk of colorectal cancer, and close upper GI surveillance may help prevent duodenal malignancy. MDTs are the principal cause of death, once colorectal cancer has been prevented, and the main reason for worsening functional results.