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.

Association between breast and colorectal cancer in a sample of surgical patients.

The frequency of adenomatous polyps and adenocarcinomas of the large bowel in 95 patients mastectomized for breast cancer, and the prevalence of breast cancer in 77 women previously operated on for colorectal cancer were evaluated by means of a case-control study. The mastectomized patients as well as the control group, underwent a left-sided colonoscopy. The latter had been selected among women spontaneously referring to our gastroenterological out-patients clinic. The choice of this self selected control group could produce a under-estimation of the relative for colon cancer in mastectomized patients. Among mastectomized patients the frequency of adenomatous polyps and colorectal cancer was 10.5% and 5.3% respectively; while the control group showed 8.5% frequency for adenomatous polyps and 3.9% frequency for cancer. These figures are not statistically different. Patients operated on for colorectal cancer and the control group underwent clinical and mammographic examination. The prevalence of breast cancer among colorectal cancer patients and the control group women was 5.2% and 0.3% respectively (10 times higher): the difference was statistically significant (P less than 0.006). In spite of the relatively small number of studied cases, our finding are consistent with the hypothesis of a correlation between breast cancer and colorectal cancer.

Long-term postoperative results in 54 cases of early gastric cancer: the choice of surgical procedure.

Surgical experience on the management of early gastric carcinoma (EGC) related to a series of 54 subjects was observed from 1974 to 1984. Thirty-four patients were male, 20 were female; median age was 61.84 (range 22-79) years. Malignancy always occurred in the middle or distal third of the stomach. A partial subtotal gastrectomy (two-thirds of the stomach) with Roux en Y or Billroth II reconstruction was performed. Omentectomy and lymph node dissection of the primary and secondary groups of nodes, according to General Rules, was always performed. Age-corrected 5- and 10-year survival rates were 95.7% and 84.3%, respectively. Based on their experience, the authors discuss the surgical approach to EGC stressing the need for an accurate lymph node dissection and pointing out that results of subtotal gastrectomy are similar to that reported in the literature for total gastrectomy. The only absolute need for a total gastrectomy may be the presence of an EGC in the proximal third of the stomach. To this end the authors compare their results with 5- and 10-year series from Japanese and western countries reported in the literature.

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.

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.

CA 19-9 assay in patients with extrahepatic cholestatic jaundice.

Serum concentrations of the CA 19-9 tumour marker were determined in 35 patients with histologically proven bilio-pancreatic malignancies associated with obstructive jaundice and in 35 patients with benign extrahepatic jaundice due to choledocholithiasis. At a cut-off level of 37 U/ml the sensitivity of this assay was 82.8%, but the specificity was very low (45.7%). Thus CA 19-9 can not be employed to differentiate between malignant and benign extrahepatic jaundice. Serial samples of CA 19-9 were achieved in 7 patients with benign and in 6 patients with malignant biliary obstruction, before and after the disappearance of jaundice. Serum concentrations of this tumour-antigen returned to normal concurrently with the bilirubin values only in patients with benign obstruction, remaining unchanged in all cases of malignancies. The data suggest that patients with extrahepatic jaundice should be evaluated by other examinations or by collecting serial samples for this assay.

Effect of sulglycotide in the prevention of duodenal ulcer relapse.

OBJECTIVE: To evaluate the effectiveness of sulglycotide, a gastroprotective drug, as maintenance treatment for patients with duodenal ulcer. DESIGN: A randomized double-blind study. METHODS: A total of 119 patients with recently healed duodenal ulcers were randomly allocated, in a double-blind fashion, to receive sulglycotide 200 mg twice daily (60 patients) or placebo (59 patients) for 1 year. Patients underwent clinical assessment every third month and endoscopy at 6 and 12 months, or earlier if relapse was suspected. RESULTS: The cumulative endoscopic relapse rates, compared using the log rank test, were 37 and 52% after 6 and 12 months, respectively, in the sulglycotide group and 62 and 71% (P = 0.03), respectively, in the placebo group. CONCLUSIONS: Sulglycotide is moderately effective as a maintenance treatment for duodenal ulcer disease.

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.

DNA flow cytometry of endoscopically examined colorectal adenocarcinomas.

The purpose of the study was to evaluate the correlation of DNA-ploidy of colorectal adenocarcinomas (adk) with histological and clinical parameters including the survival of the patients. Multiple biopsies from 95 adk were taken during colonoscopy prior to surgery. The samples were used to obtain nuclei suspensions for specific staining of DNA content and high resolution flow cytometry. DNA-aneuploidy, i.e. the presence of more than one G0/G1 peak, was detected in 67/95 cases (71%). The individual-specific control mucosa was DNA-diploid in all cases. The mean fraction of S-phase cells was 7.2% in control mucosa and 13.6% in adk. DNA-ploidy did neither correlate with Dukes' stage nor with differentiation degree. Among the patients studied for the correlation of DNA ploidy with survival for a period extending to 30 months (n = 51), the DNA aneuploid group was estimated to be about 5 times as risky as the DNA diploid group with respect to the odds of dying. We conclude that DNA flow cytometry of colorectal adk may predict clinical outcome and be helpful in addition to histopathology.

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.

[Gastric stump carcinoma after resection for benign gastric or duodenal ulcer (author's transl)]. / Il carcinoma del moncone gastrico dopo resezione per ulcera gastrica o duodenale benigna

33 cases of cancer of the gastric stump after gastrectomy for peptic ulcer observed between 1963 and 1972 are reviewed. In 26 patients the average interval between operation and carcinoma detection was over 20 years. No cases of carcinoma occurred in less than 10 years. All patients came too late for surgery, since they had attributed their symptoms to the previous operation. The gradual increase in the gastric-cancer risk of operated patients with time suggests a continuous carcinogenic influence. Regurgitation of duodenal contents through the Billroth II anastomosis seems to be the most important cause of postoperative atrophic gastritis, which is now considered by many authors to be a condition predisposing to gastric cancer. Gastric resection patients should be regarded as a high gastric-cancer risk group. The periodic use of modern procedures for early gastric cancer detection in this group of patients is therefore justified.

Outcome of follow-up programs in patients previously resected for colorectal cancer.

The survival of a group of 115 patients (group A) who entered a follow-up program after apparently "curative" surgery for colorectal cancer was compared with that of 62 similar patients (group B) who did not join such a program. No significant difference was found. Clinical benefits to single patients in group A, in terms of anticipated diagnosis and effective treatment of recurrences and of metachronous neoplasias, appeared to be, if any, extremely limited. In light of the high costs of intensive follow-up programs, it is concluded that their use can be justified only within controlled perspective trials aimed to evaluate their usefulness.

Gastric carcinoma: preliminary data of a cooperative program for early diagnosis.

The results of a program of early gastric cancer detection, carried out in the Oncologic Institutes of Genoa, Forlì and Florence, are evaluated. General practitioners screened subjects, according to possible anamnestic and clinical risk indicators (age, family history, previous gastric lesions, digestive complaints, etc.). The diagnostic consisted of medical examinations, endoscopy with cytology and/or directed biopsy, and possibly air contrast barium X-ray. Of 3,180 subjects examined, 224 had gastric cancers (7 %), 29 of which were early cancers, and 688 had high risk lesions; 1,478 cases of other pathology were detected. The authors stress that the proportion of early cancer is clearly higher than that found in routine diagnosis, yet still lower compared to the results of screening programs carried on the general population. Moreover, the high diagnostic sensitivity of each method in early gastric cancer detection and, on the other hand, the difficulties in the detection of high risk lesions, which require systematic multiple biopsies, are emphasized.

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).

Value of multiple forceps biopsies in assessing the malignant potential of colonic polyps.

Fifty-nine colo-rectal polyps were detected at endoscopy and repeatedly biopsied before removal by endoscopic snare polypectomy. The aim of the present paper was to evaluate the reliability of multiple forceps biopsies in assessing both the malignant potential and the presence or absence of invasive cancer (IC) in colo-rectal adenomas (CRA). In order to achieve the first objective, the histologic types and the degree of dysplasia have been defined. The data obtained by means of multiple biopsies examination, compared with those of polyp in toto study, show that fractional biopsies were of value in the histologic classification of only the smallest 41 polyps (agreement 88.09%), whilst no reliability of biopsies was demonstrated in the 18 largest polyps (agreement 27.68%). In the field of dysplasia grading, the agreement was 55% and 61% for the smallest and the largest CRA respectively. These last figures are hardly acceptable. Biopsies examination gave also under- and overestimation of the histologic severity and of dysplasia as well as a significant incidence of false negative results in IC detection. It is concluded that polypectomy is the only method which provides adequate material for precise diagnosis, no matter how large a polyp. Therefore it should be performed whenever possible. Finally the authors discuss the management of small sessile adenomas.

Cancer of the pancreas: clinical outcome in 76 cases.

A final diagnosis of pancreatic cancer was established in 76 consecutive patients during 4 years. The clinical outcome was evaluated retrospectively, as well as clinical presentation and its impact on the rate of resectability. Even though the diagnostic techniques showed a high sensitivity, only 18.4% of patients had a radical resection performed. In 77.6% of the cases a tissue diagnosis had been obtained. However, in only 1/5 of them was the tissue proof obtained preoperatively. This review confirms that the survival of patients with pancreatic cancer is poor, with slight advantages in the few resectable cases. Therefore, an earlier diagnosis should be attempted in high-risk symptomatic patients, selected by means of nonaggressive tests and evaluated by means of more accurate diagnostic techniques, when suitable.

[Diagnostic and therapeutic problems in angiodysplasias of the digestive tract]. / Problemi diagnostici e terapeutici nelle angiodisplasie dell'apparato digerente.

After a review of recent literature on angiodysplasias of the digestive system, a diagnostic procedure based on personal experience is proposed for haemorrhagic patients. Criteria for the selection of treatment protocols are then proposed for cases where angiodysplasia is recognised as the cause of the bleeding.

[Use of vasopressin in the treatment of acute hemorrhagic lesions of the stomach. Our experience]. / Impiego della vasopressina nel trattamento delle lesioni emorragiche acute dello stomaco. Nostra esperienza.

Since bleeding from acute lesions of the gastric mucosa can cease spontaneously and the mortality rate of emergency surgery is high, conservative treatment is always preferable. Satisfactory results were obtained with continuous infusions of vasopressin in low doses (0.2 U/kg/hr for 8 hours) so that this treatment appears a valid alternative to more recent techniques (somatostatin).

[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.

Prolonged endoscopic and manometric observations of the pylorus.

Functional aspects of the antral-pyloric segment were evaluated in 30 patients without gastroduodenal disorders by means of prolonged endoscopic observations. Patients were examined in standardized conditions. Pressure measurements of the antrum, pylorus and duodenal bulb were assessed by means of water-perfused polyvinyl tubes in 7 patients of the same group a few days after the endoscopy. The pylorus appeared open in above 80% of the total endoscopic observation time. Pyloric closure was observed only for few seconds at the end of 30-40% of antral peristaltic waves. The antrum and pylorus appeared to contract in sequence. Antral peristaltic waves moved at a mean rate of 2.4 per minute and duodenal reflux was observed at a mean rate of 0.96 per minute usually in the form of bubbles. The manometric measurements by means of pull through in 7 patients and immediately after by means of prolonged registration carried out in a fixed position in 4 patients failed to show a high pressure zone in the gastroduodenal junction. In some cases it was possible to observe a peculiar phasic activity in the pyloric tract. The endoscopic and manometric observations suggest that human pylorus does not act as a true physiological sphincter. These findings confirm the functional aspects described by radiology and manometry in other studies. In this way, endoscopy appears to be a useful procedure to evaluate some functional aspect of the gastroduodenal tract.