Pancreatic intraductal sampling during ERCP in patients with chronic pancreatitis and pancreatic cancer: cytologic studies and k-ras-2 codon 12 molecular analysis in 47 cases.

BACKGROUND: A preoperative tissue diagnosis of pancreatic cancer is desirable but difficult to obtain. METHODS: Pancreatic brush cytology, salvage cytology, and collection of pancreatic juice were attempted prospectively during ERCP in 34 patients with pancreatic cancer and 11 with chronic pancreatitis. K-ras-2 codon 12 was analyzed for presence and type of point mutations. RESULTS: Brush cytology coupled with salvage cytology had a sensitivity of 74%. The addition of cytologic analysis of pancreatic juice did not substantially improve sensitivity (76%). K-ras-2 was mutated in both cancer (87%) and pancreatitis (40%). The specificity for cytology was 100% and for K-ras-2 mutations 60%. Combining cytology with mutation analysis increased sensitivity to 93% but reduced the positive predictive value. The negative predictive value never exceeded 75%. None of the patients with chronic pancreatitis had cancer develop (median follow-up 60 months). CONCLUSIONS: Pancreatic ductal brushing with salvage cytology is useful in the diagnosis of cancer, whereas cytologic analysis of pancreatic juice can be abandoned. At present, K-ras-2 mutation is not useful for differentiating pancreatic cancer from chronic pancreatitis or the identification of patients with chronic pancreatitis at risk for malignant transformation.

Do patients with rectosigmoid adenomas 5 mm or less in diameter need total colonoscopy?

BACKGROUND: The need for colonoscopy in the care of patients with rectosigmoid adenoma 5 mm or less in diameter is still debatable. METHODS: We estimated the prevalence of proximal adenomas among 3052 consecutive subjects undergoing total colonoscopy. Rectosigmoid adenoma was classified as diminutive (5 mm), small (6 to 10 mm), or large (>/=11 mm). Advanced proximal adenoma was 10 mm in diameter or larger, or with a villous component, severe dysplasia, or infiltrating adenocarcinoma. RESULTS: Proximal adenoma was found in 212 of 2483 patients (8.5%, 95% CI [7.5, 9.7]) without distal neoplastic polyps, 49 of 214 (22.9%, 95% CI [17.6, 29.2]) with diminutive, 44 of 174 (25.3%, 95% CI [19.1, 32.5] with small, and 70 of 181 (38.7%, 95% CI [31.6, 46.2]) with large distal adenoma. Advanced proximal adenoma was found in 49 (2.0%, 95% CI [1.5, 2.6]), 8 (3.7%, 95% CI [1.7, 7.5]), 17 (9.8%, 95% CI [6.0, 15.4]), and 29 patients (16.0%, 95% [11.2, 22.4]), respectively. In patients with distal adenoma risk for proximal lesions increased with increasing age, size, and number of distal adenomas (p = 0.01). Size of distal adenoma was the strongest predictor of the presence of proximal advanced adenoma (multivariate analyses). CONCLUSIONS: In a clinical setting, the decision to perform colonoscopy should take into account proximal lesions of clinical interest, life expectancy, costs, and risks associated with the procedure. When detection of advanced proximal adenoma is the goal, presence of distal diminutive adenoma alone might not be an indication for total colonoscopy.

Endoscopic Nd:YAG laser therapy for villous adenomas of the right colon.

BACKGROUND: Endoscopic laser therapy is considered an acceptable treatment of benign colorectal adenomas. The aim of our study was to evaluate the efficacy of Nd:YAG laser to ablate right-sided colonic sessile adenomas. METHODS: Between January 1990 and February 1996, 56 patients underwent laser therapy because of high operative risk or refusal of surgery. Lesions were located as follows: cecum (23), ascending, (15), and hepatic flexure (18). Six patients (10.7%) had multiple polyps in the ascending colon. Histologic examination showed a tubulovillous pattern in 20 (35.7%) and a villous pattern in 36 (64.3%). Low-grade dysplasia was detected in 44 patients (78. 5%) and high-grade dysplasia in 12 (21.4%). RESULTS: The number of laser sessions ranged between 1 and 6 (median 3) and complete ablation, histologically confirmed, was achieved in 49 cases (87.5%). Seven patients (12.5%) underwent surgery: 2 for incomplete tumor destruction, 3 because of invasive carcinoma on repeated biopsies. Two patients (3.6%) had complications (one perforation of the cecum and one hemorrhage). Follow-up ranged from 6 to 60 months and no recurrences were observed. CONCLUSION: Laser therapy is an effective method for the destruction of sessile adenomas of the right colon in selected patients.

Gastroesophageal reflux disease: relationship between clinical and histological features. GOSPE. Gruppo Operativo per lo Studio delle Precancerosi dell'Esofago.

Our purpose was to evaluate the relationship between the clinical and histological features in a cohort of patients who had gastroesophageal reflux-related lesions diagnosed after upper digestive endoscopy. In all, 589 patients scheduled for elective endoscopy in a multicentric prospective study were evaluated. Multiple biopsies from the distal esophagus showing aspects of esophagitis or metaplastic epithelium were taken. Esophagitis was histologically detected in 25.6%, gastric-type Barrett's esophagus in 36.2%, and specialized columnar epithelium in 33.1%. The frequency of esophagitis was constant across age decades. Patients with specialized columnar epithelium were significantly older (P = 0.01) and had a greater extent of metaplastic epithelium (P<0.0001). Specialized columnar epithelium was observed in 15% of patients with only distal esophagitis. In conclusion, endoscopic esophagitis was constant across age strata. The presence of specialized columnar epithelium was associated with older age and with longer segments of Barrett's esophagus. Short areas of esophagitis should be biopsied in view of their potential for holding areas of specialized columnar epithelium.

Novel germline APC variants in patients with multiple adenomas.

Chain-terminating germline APC mutations are responsible for adenomatous polyposis coli (APC). In the present work, we tested the hypothesis that germline APC mutations may be present in some patients with a milder phenotype, i.e., multiple synchronous colorectal adenomas. Eighteen patients with 3 or more colorectal adenomas at endoscopy (within a 6-month period) were ascertained from a series of subjects undergoing endoscopic examination. Their blood DNAs were analysed for the presence of germline mutations in the APC coding region by single-strand polymorphism analysis. Ten unrelated polyp-free subjects and 101 unrelated APC patients were used as controls in the molecular analyses. Five of the eighteen patients carried novel germline APC variants or rare polymorphisms. These were various in site (from the splice acceptor site of intron 7 to the end of exon 15) and type (splice-site, missense, and chain-terminating mutations). Only one of ten polyp-free individuals carried a silent APC variant and none of these variants was found in the 101 APC controls. A first- or second-degree family history of colorectal cancer was reported by 4 of the 5 patients carrying a germline APC variant. In conclusion, novel APC germline variants were detected in patients with multiple synchronous adenomas. This suggests that the development of sporadic adenomas, in some instances, is associated with the presence of minor germline variants of the APC gene and that the spectrum of germline APC functional mutations may be larger than previously thought.

Incidence of Barrett's adenocarcinoma in an Italian population: an endoscopic surveillance programme. Gruppo Operativo per lo Studio delle Precancerosi Esofagee (GOSPE).

BACKGROUND: Barrett's oesophagus is a premalignant condition leading to adenocarcinoma. The incidence of adenocarcinoma of the oesophagus and the gastrooesophageal junction is rapidly increasing in the USA, northern and central Europe. Data from southern Europe are still unavailable. OBJECTIVE: To evaluate the incidence of oesophageal adenocarcinoma in a large cohort of Italian patients with Barrett's oesophagus. METHODS: A total of 344 patients (253 males and 91 females, age range 19-75 years) with histologically proven Barrett's oesophagus (length of metaplasia > or = 3 cm) were enrolled from November 1987 to June 1995. Endoscopic and histological examinations were scheduled at yearly intervals. RESULTS: One hundred and eighty-seven patients complied with the follow-up. The mean duration of the follow-up period was 36 months (total follow-up 562 patient-years; range 12-90 months). Low grade dysplasia was found in five patients at the initial examination. During the surveillance period, dysplasia increased in frequency as well as in severity and was found exclusively in the intestinal type of Barrett's oesophagus. In all, dysplastic changes were found in seven patients (five low grade and two high grade) and adenocarcinoma developed in three patients during the follow-up. In a single case, both adenocarcinoma and specialized columnar epithelium developed without any evidence of dysplasia or intestinal metaplasia at the previous follow-up examination. This prospective study shows an incidence of adenocarcinoma in Barrett's oesophagus of 1/187 patient-years. When only patients with specialized columnar epithelium were considered, the risk of adenocarcinoma was 1/88 patient-years. CONCLUSION: The present report shows that the incidence of adenocarcinoma in Italian Barrett's oesophagus patients is in the range of that reported from other Western countries.

Distal hyperplastic polyps do not predict proximal adenomas: results from a multicentric study of colorectal adenomas.

BACKGROUND: The association between distal hyperplastic polyps and proximal adenomas is still a matter of debate. We investigated this association while taking into account patient characteristics. METHODS: After exclusion of patients with inflammatory bowel diseases, familial adenomatous polyposis, or any cancer, 3088 eligible consecutive subjects aged 18 to 69 years underwent total colonoscopy in four gastroenterology units. The odds ratios (OR) of having proximal adenomas according to patient characteristics (age, sex, medical center, year of endoscopy, reasons for referral, and distal findings) were estimated in univariate and multivariate analyses. RESULTS: Patients with distal polyps of any type showed an adjusted OR of 2.5 (95% CI [1.9, 3.1] p < .001) of having proximal adenomas as compared with those without distal polyps. When distal adenomas and distal hyperplastic polyps were included in the multivariate model as independent factors, the presence of adenomas significantly increased the risk of proximal adenomas (OR = 2.8: 95% CI [2.2, 3.6] p < .001), whereas the presence of hyperplastic polyps did not (OR = 1.1: 95% CI [0.8, 1.5] p = .64). No association with number, size, or location of distal hyperplastic polyps was seen. CONCLUSIONS: Our data show that the presence of hyperplastic polyps should not be the sole indication for total colonoscopy because they are not associated with proximal adenomas when adjusting for patient characteristics and presence of distal adenomas.

Combined treatment with lasertherapy (Nd:YAG) and endocavitary radiation in the palliation of rectal cancer.

BACKGROUND/AIMS: The ideal treatment for patients with advanced rectal cancer and who cannot undergo a radical therapy is still undefined. The association between lasertherapy (LT) and internal radiotherapy (IRT) could affect both technical results and quality of life. This study was aimed at evaluating the association of LT and IRT in the palliative treatment of rectal cancer. MATERIAL AND METHODS: Between January and April 1994, 9 patients (2 males, 7 females) with rectal cancer underwent a combined treatment modality in order to control their symptoms. All patients were unfit for surgery and EUS showed an invasion of the whole muscular layer. After laser recanalization, brachytherapy was applied at a one week interval from last laser session. Two fractions of 10 Gy were administered at one week intervals. RESULTS: The mean number of laser sessions to obtain a complete recanalization was 3 (range:2-5) and no complications occurred. After IRT, we obtained a good result in 7/9 patients (79%) and 2 patients required further LT. The mean follow-up was 146 days (range:74-240): during this period no laser treatment was performed. Four patients complained of acute perineal pain and tenesmus after brachytherapy: in one patient, a colostomy was performed. CONCLUSION: We deem that the administration of two fractions of 10 Gy is not advisable, particularly for the treatment of non-circumferential lesions, due to the severe side effects we observed.

p53 is frequently mutated in Barrett's metaplasia of the intestinal type.

Barrett's Esophagus (BE) is a complication of gastroesophageal reflux in which the normal squamous epithelium of the lower esophagus is replaced by metaplastic tissue. The clinical significance of this condition is the associated predisposition to adenocarcinomas (ADCs). Three types of BE have been characterized: the gastric fundic (F) type, the gastric cardial (C) type, and the intestinal (I) type. The latter is the most closely associated with the development of ADCs; the causes of this bias remain unknown. To determine whether p53 and/or K-ras gene alterations (a) are present in preneoplastic lesions and (b) are associated with a specific histotype, we performed PCR-based denaturing gradient gel electrophoresis (DGGE) analysis of exon 1 (codons 12-13) of K-ras gene and of exons 5-8 of the p53 gene in biopsies obtained from 30 patients with BE of the I type (9 patients), combined I type (I + C +/- F; 10 patients) and non-I type (C, F, or C + F; 11 patients). None of the cases under study revealed K-ras mutations, whereas biopsies from 12 patients showed at least one p53 DGGE variant. Four patients showed the exact same variants in leukocytes also (polymorphisms), whereas eight cases revealed specific DGGE variants only in biopsies. The molecular characterization of these variants revealed that four of them showed a single base pair substitution, and four showed multiple mutations. Of 17 somatic mutations, all but 1 were base pair substitutions located mainly in exons 7 and 8. The majority of these mutations were GC targeted (13 of 16; 81%), 54% (7 of 13) of which were transitions occurring at CpG sites. All somatic mutations were found in BE with at least one I component. The association with the histotype was statistically significant (P < 0.03; pure I type versus non-I type; P < 0.04, combined I type versus non-I type; Fisher's exact test). Loss of heterozygosity in the vicinity of the p53 locus was evaluated by PCR using a highly polymorphic variable number of tandem repeats marker on 25 out of 30 cases. Ninety-two % of the cases analyzed were informative, and none of them showed LOH. In conclusion, we showed that p53 mutations are frequently observed in specimens from BE patients of the I-type, whereas no involvement of K-ras (exon 1) mutational activation was observed. In light of the key roles that the p53 protein plays in controlling cell cycle and cell diploidy, this result may suggest why this type of metaplasia is the most closely associated to the development of ADCs.

Clinical aspects and management of hereditary non-polyposis colorectal cancer (HNPCC).

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomical dominant trasmitted disease phenotypically defined according to the "Amsterdam criteria" as follows: at least 3 affected relatives, one of whom first degree relative of other two, at least two successive generations affected. Important cardinal features are: 1) prevalent proximal location of cancers (above splenic flexure); 2) multiple synchronous or methachronous large bowel cancers; 3) early age of onset (<50 years); 4) presence of extracolonic cancers (endometrium, stomach, urinary tract, skin). The treatment is essentially surgical and total colectomy with ileo-rectum anastomosis is already proposed as standard procedure with annual endoscopic examination of retained rectum. The screening of individuals at risk, so determined by the analysis of pedigree or the results of molecular tests, must be performed every 1-2 years by colonoscopy starting around the age of 25 years. In this review are described and analysed the spectrum of the disease with particular attention to the frequency and characteristics of extracolonic cancers. Moreover, the guidelines of the surveillance and screening are reported following the data of the literature and as proposed by the International Collaborative Group (ICG-HNPCC).

Correlation between family history of colorectal cancer and pathological and clinical features of the disease.

Familial aggregation of colorectal cancer occurs even among sporadic cases that are not part of defined genetic syndromes. First-degree relatives of patients with "sporadic" colorectal cancer have a three- to fourfold increased risk of the same cancer. The aim of the present study is to investigate the relationship between a first-degree family history of colorectal cancer and the pathological and clinical features of the tumor (site, Dukes' stage, age at diagnosis, sex, and patient survival). Four hundred and sixty-one patients with colorectal cancer were evaluated (250 males and 211 females) and information obtained on their family history of cancer. Sex, age, and stage of disease were the only parameters that correlated significantly with survival. No relationship between family history of colorectal cancer and the prognostic variables was observed.

Genomic PCR-SSCP analysis of the metastasis associated NM23-H1 (NME1) gene: a study on colorectal cancer.

To facilitate further mutational analysis of NM13-H1, a human metastasis suppressor gene, we have established its genomic organization. NM23-H1 is composed of five exons, spanning a genomic DNA fragment of 10 kb. Using oligonucleotide primers flanking each exon, PCR-SSCP analysis was performed on genomic DNAs of healthy individuals. A common polymorphism, a C to T transition, was detected 30 nucleotides upstream from the 5' splice site flanking exon 1. As NM23-H1 allele loss and altered expression have been reported in colorectal cancer, genomic DNAs of 20 colorectal tumors were analyzed for the presence of gene-specific mutations by PCR-SSCP: no abnormal sequences were detected within the coding and splice site regions of the NM23-H1 gene. This finding suggests that NM23-H1 mutations are rare events in human colorectal cancer.

Primary gastric lymphoma.

The records of 30 patients with primary gastric lymphoma and a minimum of 5 years of follow-up were reviewed and clinical and pathologic prognostic factors analyzed. The overall 5-year survival was 40% (median 23 months). No significant relationship between surgical and patient age, sex, duration of symptoms, macroscopic appearance, or size of the primary lesion or degree of serosal infiltration was demonstrated. Stage of disease and site of primary had an impact on prognosis. Survival was improved in patients with stage I-II disease (P < 0.05) and in patients with primary located in the distal third of the stomach (P < 0.05). Although histology in all three classifications did not correlate well with survival, patients with low-grade lymphoma according to Kiel showed improved outcome (P < 0.05). Five-year survival of 11 patients with positive lymph nodes, 6 of whom were treated with cytotoxic therapy, was 54% and comparable to that of 7 patients (56%) with no nodal involvement who did not receive chemotherapy after surgery.

[Colorectal adenocarcinoma in patients with familial anamnesis positive for malignant neoplasms of the large intestine]. / Adenocarcinoma del colon-retto in pazienti con anamnesi familiare positiva per neoplasie maligne del grosso intestino.

Familial aggregation of colorectal cancer occurs also among sporadic cases that are not part of defined genetic syndromes. First degree relatives of patients with "sporadic" colorectal cancer have a 3-4 fold increased risk of the same cancer. The aim of the present study is to investigate the relationship between a first degree family history of colorectal cancer and pathological and clinical features of the tumor (site, Dukes' stage, age at diagnosis, sex and survival of patients). 461 patients with colorectal cancer were evaluated (250 males and 211 females) after obtaining informations about their family history of cancer. 52 (11.25%) of them reported to have at least one close relative affected by intestinal cancer. Sex, age and stage of the disease are the only parameters that significantly affect survival. No relationship between family history of colorectal cancer and prognostic variables was observed.

Cytosolic and nuclear androgen receptors in colorectal adenomas.

The aim of this study was to verify the presence of androgen receptors (AR) in human colorectal adenomas and in normal adjacent mucosa, and to determine whether there is any difference in AR tissue content between females and males. Our data show higher levels of nuclear AR in normal mucosa than in adenomas (p less than 0.001). A significant difference was also present in males between normal and pathological tissue both in cytosolic (p less than 0.05) and nuclear receptors (p less than 0.01). In female subjects this difference was also evident, but not significant. Our results seem to support the hypothesis of protective effects of androgens in colonic mucosa.

Flow cytometric DNA index in the prognosis of colorectal cancer.

The authors investigated the relationship between flow cytometric DNA index (DI, defined as the ratio of the DNA content of malignant cells to that of normal cells) and other prognostic factors (grade and stage, anatomical site, age and sex) with the survival of 115 patients with colorectal cancer. Multiple biopsy specimens from 62 patients were taken during colonoscopy before surgery. Additional samples from 53 patients were obtained from paraffin-embedded material. All patients were treated with surgery only. Fresh-frozen material gave higher incidence of DNA aneuploidy than paraffin-embedded material (79% versus 41%). The patients with DNA diploid tumors (DI = 1) had a better overall survival than those with DNA aneuploid tumors (DI = 1). Among DNA aneuploid tumors, those with DI greater than 1.2 (excluding DI = 2) were worse than those with DI = 1.2 (excluding DI = 1) and DI = 2. Cox's regression analysis showed that pathologic stage was more important for prognosis than DNA index, whereas age, sex, histologic grade, and anatomic site were removed from the analysis as not relevant for prognosis. Relative risk of death (RR), in reference to patients with DI = 1 and Stages A + B (RR = 1), were RR = 1.8 for patients with carcinomas with Stage C. RR = 2.7 for patients with carcinomas with DNA near-diploid and DNA tetraploid tumors. RR = 3.5 for those with DI greater than 1.2 (excluding DI = 2), and RR = 8.0 for those with Stage D. These data indicate that flow cytometrically evaluated DI values have a relevant independent power for predicting the clinical outcome of colorectal cancer patients.

Palliative bipolar electrocoagulation treatment of malignant gastroesophageal strictures.

Seventeen patients with non-resectable circumferential malignant strictures of the esophagus (n = 13) or the gastroesophageal junction (n = 4) were treated with a bipolar electrocoagulation tumor probe (BICAP). None had received prior radiotherapy or chemotherapy. The mean tumor length was 7.2 cm. After treatment swallowing was improved in 86.7% of the patients. The mean duration of response to the first treatment was 18 days. Three major complications (1 fatal hemorrhage, 2 tracheoesophageal fistulae) and two minor complications (chest pain) were observed. The overall actuarial survival rate after 13 months of follow-up was 20%. The BICAP tumor probe can be considered an efficacious and safe device in selected patients with long, circumferential esophageal cancers.