Clinical and molecular detection of inherited colorectal cancers in northeast Italy: a first prospective study of incidence of Lynch syndrome and MUTYH-related colorectal cancer in Italy.

The reported incidence of hereditary colorectal cancers (CRCs) is widely variable. The principal aim of the study was to prospectively evaluate the incidence of familial CRCs in a region of northern Italy using a standardized method. Consecutive CRC patients were prospectively enrolled from October 2002 to December 2003. Patients underwent a structured family history, the microsatellite instability (MSI) test and a screen for MUTYH mutations. Following family history patients were classified as belonging to high, moderate and mild risk families. Immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 proteins and investigation for MLH1/MSH2 mutations, for MLH1 promoter methylation and for the V600E hotspot BRAF mutation were performed in high MSI (MSI-H) cases. Of the 430 patients enrolled, 17 (4%) were high risk [4 hereditary non-polyposis colorectal cancer (HNPCC), 12 suspected HNPCC and 1 MUTYH-associated adenomatous polyposis coli (MAP)], 53 moderate risk and 360 mild risk cases. The MSI test was performed on 393 tumours, and 46 (12%) of them showed MSI-H. In these patients, one MLH1 pathogenetic mutations and two MSH2 pathogenetic mutations were found. Thirty-two (70%) MSI-H cases demonstrated MLH1 methylation and/or BRAF mutation: None of them showed MLH1/MSH2 mutation. Two biallelic germline MUTYH mutations were found, one with clinical features of MAP. A strong family history of CRC was present in 4% of the enrolled cases; incidence of MLH1/MSH2 or MUTHY mutations was 1.3% and of MSI-H phenotype was 12%. MLH1 methylation and BRAF mutation can exclude 70% of MSI-H cases from gene sequencing.

Cost-effectiveness analysis of postoperative surveillance protocols following radical surgery for colorectal cancer.

INTRODUCTION: Up to 30-50% of patients who undergo radical surgery for colorectal cancer (CRC) develop tumor relapse. The aim of this study was to assess various surveillance protocols utilized in a tertiary referral hospital in Northern Italy. METHODS: Data concerning 373 consecutive patients who underwent radical surgery for CRC between 1990 and 2006 and whose data had been entered into a prospective database were considered eligible for this study. The overall costs and the percentages of recurrence following the various surveillance protocols were calculated. RESULTS: One hundred two (27.35%) of the patients suffered a recurrence after a mean of 17.6 (95% CI 13.9-21.1) months. The combination of physical examination, colonoscopy, thorax-abdominal computed tomography (CT) scan, and serum carcinoembryonic antigen (CEA) dosage was found to be the most cost/effective one to monitor stages I and II colon cancer; while physical examination, rigid sigmoidoscopy, thorax-abdominal CT scan, and serum CEA dosage were found to be the most cost/effective surveillance to monitor stages III and IV of colon cancer and rectal cancer. CONCLUSIONS: Adherence to follow-up guidelines and early detection are vital factors affecting the curability of relapsed cancer in CRC patients who undergo surgery. The first five years after surgery was found to be the most risky period for recurrence. Cost/effectiveness analysis indicate that follow-up protocols should be tailored to the risk of recurrence with the aim of identifying relapse when the disease is at an asymptomatic, presumably more curable stage.

Endoscopic treatment of bile duct complications after orthotopic liver transplantation.

AIM: To assess the indications and results of endoscopic retrograde cholangio-pancreatography (ERCP) in patients who have undergone ortotopic liver transplantation (OLT). METHODS: We reviewed data from 42 consecutive patients who underwent ERCP for biliary complications after OLT over an 8-year period, in particular recording indications and success of the treatment after a mean of 17 months follow-up. RESULTS: Cholangiograms performed in 33/42 patients (79%) displayed anastomotic strictures in 17 patients (52%), bile duct stones in 8 (24%), both bile duct stones and an anastomotic stricture in 2 (6%), papillary stenosis in 1 (3%), and anastomotic biliary leakage in 1 (3%). In contrast, the contrastogram was normal in four patients (12%). Stone extraction was completed in 9/10 patients (90%) with a mean of 1.2 sessions, while stricture dilation was achieved in 12/19 patients (63%) after a mean of 1.7 sessions, by stent positioning (n = 7), balloon dilation (n = 4), or Soehendra dilator (n = 1). Both biliary leakage and papillary stenosis were cured by ERCP. Only one procedure-related complication -- severe pancreatitis (2.4%) -- was observed and no mortality. CONCLUSION: ERCP is a safe and effective mode of management of bile duct complications after OLT. It should be attempted before a surgical approach. Better results are obtained for treatment of biliary stones than of anastomotic strictures.

Laser photoablation of colorectal adenomas: a 12-year experience.

BACKGROUND: We analyze laser photoablation as an alternative treatment of large sessile polyps in inoperable patients. METHODS: Ninety-four colorectal polyps (mean diameter 3.09 +/- 2.7 cm, range 1-15 cm) were treated using high-energy lasers (Nd:YAG and diode). Grade of dysplasia was low in 51, high in 35, with focally invasive cancer in eight. RESULTS: After 405 laser sessions (4.3 per polyp) five procedure-related complications were observed: two strictures, two bleedings, and one perforation. The last needed a surgical resection; the others were successfully treated by endoscopic therapy. Fifty-seven polyps (61%) were completely eradicated and the growth was controlled in all but two (98%). No degeneration was found after 28-month follow-up of treated adenomas with low- or high-grade dysplasia. Outcome of treatment was dependent on the dimension and grade of the dysplasia (p < 0.05), but not on the polyps' position (rectum or colon). Relief of rectal bleeding was obtained in 90%, of mucus discharge in 77%, and of tenesmus in 100% of cases. CONCLUSIONS: Laser photoablation of colonic adenomas can be considered a valid procedure not only to relieve symptoms, but also to control the risk of degeneration in patients unfit for surgery or when surgical treatment is considered excessively invalidating.

Yttrium-aluminum-garnet laser therapy of esophageal granular cell tumor.

BACKGROUND: Granular cell tumor (GCT) is a rare lesion. Approximately 4% to 6% of these tumors occur in the gastrointestinal tract, one-third of them affecting the esophagus. Almost all GCTs are benign lesions. Approximately 1% to 3% are malignant. Endoscopic ultrasonography (EUS) is a diagnostic support. The best treatment for esophageal GCT is not yet clear, whether surgical excision, periodic observation, endoscopic excision, or yttrium-aluminum-garnet (YAG) laser therapy. METHODS: From November 1992 to December 2000, four patients with GCTs of the esophagus were observed. All the patients underwent EUS evaluation and endoscopic YAG laser therapy of the esophageal neoplasm. At each session, a biopsy at the tumor site was obtained. The treatment was continued until endoscopic and histologic evidence of the tumor disappeared. RESULTS: After the YAG laser therapy, no evidence of the tumor was found in any of the four patients with esophageal GCT. At this writing, the patients remain disease free after a mean follow-up period of 66 months. No complication has been observed. Only four sessions for each patient were necessary to eliminate the tumor. CONCLUSIONS: Therapy with YAG laser was effective in all four patients with esophageal GCT, and complete necrosis of the submucosal neoplastic cells was achieved. Endoscopic YAG laser therapy appears to be a good compromise between esophageal dissection and long-term observation without tumor excision. Esophageal laser therapy is safe if correctly used, and previous EUS evaluation increases treatment safety.

Relationship between ras oncogene expression and clinical and pathological features of colonic carcinoma.

In order to investigate the value of ras oncogene expression as a prognostic indicator in colonic adenocarcinoma, we evaluated the level of ras gene protein product (p21) in the available material of 109 surgical specimens resected at our institution between 1978 and 1981. Pathology slides and archived paraffin blocks were retrieved for confirmation of the original diagnosis, determination of stage, and measurement of p21 content. P21 titers were obtained using the RAP-5 monoclonal antibody in a semiquantitative immunohistochemical assay. Titer was expressed as the highest dilution of antibody given definitive staining using the Avidin-Biotin peroxidase method. The analysis indicated that tumors with high (greater than or equal to 1:40,000) p21 titer had a lower five-year survival rate than tumors with low (less than 1:40,000) titers (34.3% vs 60.8%, p less than 0.02). When a logistic regression analysis was used with the dependent variable being five-year survival and the independent variables being age, sex, location of tumor. Dukes' stage, mucin production, p21 titer, differentiation degree and tumor size, the statistically significant relationship of the level of ras gene protein product to long-term survival was negated by the concomitant knowledge of Dukes' stage. On the other hand, when only the variables available in the preoperative period were entered in the multivariate analysis, p21 titers retained a significant relationship with long-term survival (p less than 0.05). We conclude that ras oncogene determination in colonic carcinomas may have clinical importance for the pre-operative identification of a group of colonic tumors with a more aggressive behavior and a poorer prognosis.

[Palliative treatment of esophageal and cardial carcinoma]. / La palliazione del carcinoma esofageo e cardiale.

Recent series reported increasing incidence of esophageal and cardial cancers with prognosis still severe in spite of surgical progress. The late diagnosis reduces the chance of radical surgery; on the other hand about 80-90% of patients develop local or distant recurrence. Therefore the treatment of esophageal and cardial cancer is often palliative: surgical resection is reserved only to selected cases. Endoscopic palliation was the treatment of choice in a total of 265 patients 174 of which received laser therapy and 91 prosthesis intubation. The results it good in about 80% of cases.

[The treatment of advanced gastric cancer: total gastrectomy "extended" as needed]. / Il trattamento del cancro gastrico avanzato: la gastrectomia totale "allargata" di necessità.

Extended resections do play a definite role in the surgical approach to advanced gastric malignancy. Local extension of distant spread of the tumor is no longer to be considered as a contraindication to aggressive surgery based on the evidence that even for palliation, extensive operations, when feasible, have proved to be beneficial in preventing complications related to the natural history of the disease. Over a nine-year period 105 patients with gastric cancer were surgically treated. Out of the 88 patients undergoing tumor excision, 53 were submitted to total gastrectomy (there were 35 males and 18 females, mean age 63 years). This procedure was considered potentially curative in 37 cases and palliative in 16. In 8 of the patients treated with palliation. An extensive procedure, including splenectomy in 7 cases (1 of which with concomitant distal pancreatic resection) and a colonic resection in 1 case, was undertaken. Alimentary continuity following total gastrectomy was restored by jejunal interposition (Mouchet-type reconstruction) in 3 cases, Roux-en-Y esophagojejunostomy in 7 and simple: end-to-side esophagojejunostomy (Sweet and Allen-type) in 6. No postoperative complications have occurred and mean survival time was 8 months with a maximum of 20 months in a patient with a good nutritional status and quality of life (Karnofsky index 78%) who developed no complications related to tumor recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)

[Lithiasic, congenital, choledochal dilatation: problems of diagnosis and therapy]. / Dilatazione coledocica congenita litiasica: problemi di diagnosi e di terapia.

We report a case of a 30-year old female with congenital lithiasic choledochal dilatation which was not diagnosed at the ultrasonographic examination. Congenital biliary dilatation abnormalities are rare and may clinically present with episodic biliary colics or more rarely with recurrent pancreatis. Ultrasound, CT-scanning and ERCP usually make these anatomic alterations evident but in some cases there may be some doubt despite the vast range of radiological techniques available (PTC, Tc99m-Isida scinti-scan). The best results from a diagnostic point of view are obtained from the ERCP that may in fact visualize an anomalous pancreatico-biliary junction, rule out carcinoma, accurately define the cyst dimensions or show the intrahepatic ductal radicals. Furthermore, the extraction of intracystic stones or the treatment of choledochocele through a papillostomy may be performed. However the ERCP may cause traumatic pancreatitis, above all in youngster as was verified in our patient. During surgical exploration, the definitive diagnosis can be achieved via intraoperative cholangiography. We emphasize that in patients with congenital choledochal dilatation, the dilated choledochus should be excised even in young children to avoid the risk of malignancy which may occur also following cyso-duodeno- or cystojejunostomy treatment. In our patient an hepatiocojejunostomy on a Roux-en-Y limb was performed. This single case has been oresented along with a review of the literature to recall such anomalies in differential diagnosis of biliary colics and to stress that the choice treatment is surgical resection.

Ras oncogene and the acquisition of metastasizing properties by rectal adenocarcinoma.

To gain a better understanding of the biologic development of rectal adenocarcinomas, the authors evaluated the level of ras gene protein product (p21) in the available material of 74 Dukes' B adenocarcinomas, 64 Dukes' C adenocarcinomas, and 60 lymph-node metastases resected at the University of Chicago Medical Center between 1965 and 1981. Pathologic slides and archival paraffin blocks were retrieved for confirmation of the original diagnosis and measurement of p21 content. P21 titers were obtained using the RAP-5 monoclonal antibody in a semiquantitative immunohistochemical assay. Titer was expressed as the highest dilution giving definitive staining using the avidin-biotin peroxidase method. The analysis indicated that a higher percentage of Dukes' stage C rectal adenocarcinomas had high (greater than or equal to 1:40,000) p21 titers than Dukes' B adenocarcinomas (68.8 vs. 51.4 percent, respectively, P less than 0.05). In view of recent data suggesting that ras oncogene expression confers invasive and metastatic capabilities to NIH 3T3 cells, the authors believe this study offers evidence that overexpression of ras oncogene with overproduction of p21 protein product may be an important prerequisite for the acquisition of metastatic capabilities in the early stages of colon cancer.

Chromosome 5 allele loss in human gastric, ampullary and pancreatic carcinomas.

Chromosome 5 allele loss is a genetic alteration occurring during the multistep progression of colon carcinogenesis. To determine whether a similar genetic alteration occurs in other gastrointestinal malignancies, the authors have analyzed DNA extracted from freshly frozen normal and neoplastic tissue from nineteen patients who underwent radical resections for gastric, ampullary and pancreatic adenocarcinomas at the University of Chicago. Loss of heterozygosity for alleles on the long arm of chromosome 5 was detected in tumor DNA compared to normal tissue DNA from the same patient using restriction fragment length polymorphisms (RFLPs). Eleven patients were informative using the restriction endonuclease TaqI to generate RFLPs for chromosome 5 probes C11 P11 and pTP5E. Loss of heterozygosity was found in one of eight informative gastric carcinomas (12.5%) and in one of two informative ampullary carcinomas. The only informative pancreatic adenocarcinoma was heterozygous. It is concluded that chromosome 5 allele loss occurs in a variety of gastrointestinal malignancies and suggest that common genetic origins may underlie these different tumors.

Experience with 647 consecutive tumors of the duodenum, ampulla, head of the pancreas, and distal common bile duct.

Between 1946 and 1987, 647 patients with periampullary tumors were diagnosed at the University of Chicago Medical Center. These included 549 tumors located in the head of the pancreas, 40 in the distal common bile duct, 29 in the duodenum, and 29 at the ampulla of Vater. Ninety-eight per cent of all tumors were adenocarcinoma, with 93% of the remaining being duodenal carcinoid or sarcoma. Operability rate ranged from 81% to 97%, according to the tumor location and histologic type. A combination of laparotomy, biopsy, and bypass was performed in 433 patients and only one survived 5 years (0.2%). Resectability rate ranged from 16.5% for pancreatic adenocarcinoma to 89.3% for ampullary tumors. Of the 133 resections, 80 were pancreatoduodenectomies, 29 total pancreatectomies, 7 duodenectomies, 2 gastrectomies, 8 common bile duct resections, and 7 local excisions. Overall 19% of patients who underwent radical resection died in the immediate postoperative period, although mortality has decreased to 5% since 1981. Mortality was 20% after a standard pancreatoduodenectomy and 24.1% after a total pancreatectomy. Five-year actuarial survival rates, including perioperative deaths, were 8.8%, 20%, and 32% for pancreatic, duodenal, and ampullary adenocarcinoma, respectively. One half of patients with sarcoma and two-thirds with carcinoid of the duodenum survived 5 years. No patient with distal common bile duct adenocarcinoma achieved a 5-year survival rate. Multivariate analysis on all patients operated on (n = 566) revealed that the 5-year survival rate was significantly related to intent of operation (palliative 0.2%, curative 12%; p less than 0.001), histologic type (adenocarcinoma 2%, carcinoid and sarcoma 31%; p less than 0.0001), and site (ampullary and duodenal 21%, biliary and pancreatic 0.9%; p less than 0.001). A second multivariate analysis, evaluating only those patients with adenocarcinoma who survived the perioperative period of the radical resection (n = 97) analyzed the influence of tumor size and differentiation, lymphatic, capillary, and perineural microinvasion, lymph node status, and type of procedure (pancreatoduodenectomy vs. total pancreatectomy) on 5-year survival. None of these additional variables was significantly associated with long-term survival rates. In addition we evaluated the presence of local or distant recurrence after resection by analyzing the findings from all autopsies performed on these patients (n = 49): 29.4% of patients died with local recurrence alone, 23.5% with distant recurrence alone, and 47.1% had both local and distant recurrences.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence for a common molecular pathogenesis in colorectal, gastric, and pancreatic cancer.

We examined tissue extracted from 19 gastric, 7 pancreatic, and 23 colorectal carcinoma specimens to determine the comparative incidence of allele loss on chromosomes 5, 17, and 18 and that of KRAS2 point mutations. Chromosome 5 allele loss occurred at the same frequency in all three gastrointestinal tumors (approximately 30%), whereas chromosome 17 and 18 allele losses were seen at a significantly lower frequency in gastric (20%) and pancreatic (0%) malignancies than in colorectal cancer (57%). Point mutations in KRAS2 were seen in 83% of pancreatic and 52% of colon cancers, but not in gastric cancer specimens. In pancreatic tumors, these mutations were always found in the second nucleotide of codon 12. In colorectal cancer, the distribution was more variable, involving the second nucleotide of codon 13 and both the first and second nucleotides of codon 12. These results suggest that inactivation of the adenomatous polyposis coli gene on chromosome 5 may be an initiating step for carcinomas of the stomach and pancreas as well as of the colon, but that the genes involved in tumor progression events may be tissue- or tumor-specific.

Endoscopic palliation of esophageal and cardial cancer: neodymium-yttrium aluminum garnet laser therapy.

The aim of this study was to evaluate the impact of laser palliation on symptoms such as dysphagia and bleeding in patients with esophageal and cardial carcinomas. From November 1992 to October 1997, 174 patients with unresectable esophageal and cardial carcinomas were treated with neodymium-yttrium aluminum garnet laser therapy. The indications for palliative treatment were advanced tumor in 96 patients and high surgical risk in 78. The tumor involved the esophagus and cardia in 107 and 67 patients respectively. The mean length of the tumors was 6 cm. Two laser sessions (range 1-4) were necessary for recanalization. During the follow-up, the average interval between the laser sessions was 2 months. Overall, no early and late complications or hospital mortality occurred. The quality of palliation was excellent or good in 82%, of the patients. The mean survival time was 6 months, and mortality was not related to the procedure. Endoscopic laser therapy in patients with vegetant or hemorrhagic carcinomas may represent the best therapy, with acceptable morbidity and mortality rates and satisfactory functional results.