Radical Resection in Entero-Pancreatic Neuroendocrine Tumors: Recurrence-Free Survival Rate and Definition of a Risk Score for Recurrence.

BACKGROUND: Surgery with radical intent is the only potentially curative option for entero-pancreatic neuroendocrine tumors (EP-NETs) but many patients develop recurrence even after many years. The subset of patients at high risk of disease recurrence has not been clearly defined to date. OBJECTIVE: The aim of this retrospective study was to define, in a series of completely resected EP-NETs, the recurrence-free survival (RFS) rate and a risk score for disease recurrence. PATIENTS AND METHODS: This was a multicenter retrospective analysis of sporadic pancreatic NETs (PanNETs) or small intestine NETs (SiNETs) [G1/G2] that underwent R0/R1 surgery (years 2000-2016) with at least a 24-month follow-up. Survival analysis was performed using the Kaplan-Meier method and risk factor analysis was performed using the Cox regression model. RESULTS: Overall, 441 patients (224 PanNETs and 217 SiNETs) were included, with a median Ki67 of 2% in tumor tissue and 8.2% stage IV disease. Median RFS was 101 months (5-year rate 67.9%). The derived prognostic score defined by multivariable analysis included prognostic parameters, such as TNM stage, lymph node ratio, margin status, and grading. The score distinguished three risk categories with a significantly different RFS (p < 0.01). CONCLUSIONS: Approximately 30% of patients with EP-NETs recurred within 5 years after radical surgery. Risk factors for recurrence were disease stage, lymph node ratio, margin status, and grading. The definition of risk categories may help in selecting patients who might benefit from adjuvant treatments and more intensive follow-up programs.

Intermittent treatment with mesalazine in the prevention of diverticulitis recurrence: a randomised multicentre pilot double-blind placebo-controlled study of 24-month duration.

BACKGROUND AND AIM: Recurrence of diverticulitis is frequent within 5 years from the uncomplicated first attack, and its prophylaxis is still unclear. We have undertaken a multicentre, randomised, double-blind, placebo-controlled pilot study in order to evaluate the role of mesalazine in preventing diverticulitis recurrence as well as its effects on symptoms associated to diverticular disease. METHODS: Ninety-six patients with the recent first episode of uncomplicated diverticulitis were randomised to receive mesalazine 800 mg twice daily for 10 days every month or placebo for 24 months. The primary efficacy end point was the diverticulitis recurrence at intention to treat analysis. Clinical evaluations were performed using the Therapy Impact Questionnaire (TIQ) for physical condition and quality of life at admission and at 3-month intervals. Treatment tolerability and routine biochemistry parameters as well as the use of additional drugs were also evaluated. RESULTS: Ninety-two patients (mean age, 61.5) completed the study, 45 of whom received mesalazine, and 47, placebo. Diverticulitis relapse incidence in mesalazine-treated group was 5/45 (11%) at the 12th month and 6/45 (13%) at the 24th month; in the placebo-treated group, the correspondent rates were 13% (6/47) and 28% (13/47), respectively. Mean values of TIQ at 24 months were significantly better in mesalazine-treated group than in placebo-treated group (p = 0.02); in addition, average additional drug consumption was significantly lower (-20.4%, p < 0.03) in mesalazine than in placebo. CONCLUSIONS: Diverticulitis recurrence occurred in as many as 28% of patients under placebo within 24 months from the initial episode. Intermittent prophylaxis with mesalazine did not significantly reduce the risk of relapse but induced a significant improvement of patients' physical conditions and significantly lowered the additional consumption of other gastrointestinal drugs.

Pre-Endoscopy real-time PCR testing for SARS-CoV2 does not reduce health care workers infection and is associated with a higher reduction of endoscopic activity in an outpatient setting.

Objective: The role of pre-procedure SARS-CoV2 testing in digestive endoscopy is still debated. AGA guidelines recommend against pre-procedure testing considering low prevalence of SARS- CoV2 infection in the general population and low incidence of infection among endoscopy units Health Care Workers (HCWs). However, no studies have compared pre-procedure testing associated to symptom screening vs. symptom screening alone in reducing the risk of infection for HCWs. Main aim of the present study is to compare the risk of infection for HCWs in different Endoscopy Units adopting different pre-endoscopy screening and operating in two nearby hospital of the same region in Northern Italy in pre-vaccination period. For outpatients in the Endoscopy Unit of Trento (Unit 1) only pre-procedure symptom screening was performed, while in the Endoscopy Unit of Bolzano (Unit 2) pre-procedure symptom screening and negative pre-procedure real-time PCR were requested. Secondary aims were to assess the impact of pre-procedure real-time PCR testing on endoscopic activity and diagnostic delay. Design: Retrospective data collection on a prospectively maintained database was performed, including outpatient endoscopy procedures performed between June 1st 2020 and February 28th 2021 in Unit 1 and Unit 2. Results: No differences in terms of infection rate in HCWs have been identified in Unit 1 and Unit 2 (9.0 vs. 19.3% P=0.2) over a nine-month period. Moreover, in the unit performing pre- procedure real-time PCR before endoscopy a significantly higher reduction in endoscopic activity has been recorded (61.9% vs. 53.4%; P<0.01). In patients with positive real-time PCR, endoscopy was performed with a mean delay of 61.7 days (range 9-294) and 22.5% of them were lost at follow-up and did not undergo any endoscopic procedure in the following 12 months. Conclusions: This study supports the AGA recommendation suggesting that pre-endoscopy real-time PCR is an expensive and time-consuming procedure without proven benefits in an outpatient setting.

High uptake of colonoscopy in first-degree relatives of patients with colorectal cancer in a healthcare region: a population-based, prospective study.

BACKGROUND AND STUDY AIMS: A screening program in first-degree relatives (FDRs) of colorectal cancer (CRC) patients (index patients) was started in Trentino, Italy, to analyze factors that influence uptake of CRC screening among invited FDRs (first objective) and to describe colorectal findings among those undergoing colonoscopy (secondary objective). PATIENTS AND METHODS: FDRs aged between 45 and 75 years were invited; exclusion criteria were: colonoscopy or barium enema in the preceding 5 years, a history of familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, inflammatory bowel diseases, and severe comorbidities. FDRs who were eligible but were not invited for screening because consent was not obtained from the index patients were considered as the control group. FDRs were invited by the education campaign targeted at the population at risk (both study and control groups); in the study group, interventions targeting individuals at risk (letters, phone calls, face-to-face counseling) were implemented. RESULTS: Starting from 626 new index cases of diagnosed CRC, 725 FDRs were invited to counseling; 77.6 % of these attended for colonoscopy in the study group vs. 8 % in the control group ( P < 0.0001). Predictors of colonoscopy uptake were FDR age above 60 years [odds ratio (OR) 2.50, 95 %CI 1.72 - 3.62], complex family history (simple family history: one CRC at age above 60 years; complex family history: one CRC at age below 60 or two or more CRC; OR 1.54; 95 %CI 1.04 - 2.33) and living in a rural area (OR 1.64, 95 %CI 1.12 - 2.44). Of the 560 FDRs in the study group, 186 (33.8 %) had adenomas, and 48 (8.8 %) had advanced adenomas or cancer. CONCLUSIONS: Interventions that target FDRs of patients with CRC, especially those younger than 60 years, with a complex family history of CRC and who live in a rural area, may improve uptake of CRC screening via colonoscopy.

Prevalence of gastrointestinal symptoms in coronavirus disease 2019: a meta-analysis.

BACKGROUND AND STUDY AIMS: The coronavirus disease 2019 (COVID-19) is a pandemic infection spreading worldwide at an unprecedented rate. Our aim was to assess the frequency of gastrointestinal (GI) involvement in COVID-19. PATIENTS AND METHODS: We performed a systematic review and meta-analysis of all studies reporting clinical data about COVID-19 patients, published until 25th March 2020. The primary endpoint was the pooled prevalence of COVID-19 patients complaining of GI symptoms. Secondary endpoints were the pooled prevalence of cases with COVID-19 positive stool samples, and of asymptomatic COVID-19 patients. We used random-effects model for meta-analysis. RESULTS: Thirty-three studies were included in the meta-analysis. Out of 4434 COVID-19 patients, the pooled prevalence of GI manifestations was 11.51% (95% CI : 8.16 to 15.35). The most frequent GI symptom was diarrhea (7.78% of cases ; 95% CI : 5.05 to 11.04), followed by nausea/vomiting (3.57% ; 95% CI : 1.87 to 5.80), poor appetite (2.39% ; 95%CI : 0.55 ; 5.46) and abdominal pain (0.78% ; 95% CI : 0.26 to 1.57). Positivity for COVID-19 in stool samples was observed in 41.50% (95% CI : 17.70 to 67.65) of cases. 11.85% (95% CI : 3.53 to 24.17) of COVID-19 patients remained asymptomatic. CONCLUSIONS: The present meta-analysis shows that a significant proportion of COVID-19 patients suffer from GI manifestations, as well as COVID-19 positivity in stool samples. Asymptomatic patients need to be considered a further potential route of viral transmission.

Prevalence of liver injury in patients with coronavirus disease 2019 (COVID-19) : a systematic review and meta-analysis.

BACKGROUND AND STUDY AIMS: The coronavirus disease 2019 (COVID-19) represents a public health emergency of international concern, causing thousands of deaths worldwide. We performed a systematic review with meta-analysis in order to investigate the prevalence of COVID-19-induced liver injury. PATIENTS AND METHODS: We searched MEDLINE, Scopus, Web of Science and the Cochrane Library, for studies reporting laboratory data about COVID-19 patients, with last update on 25th March 2020. The primary outcome was the pooled prevalence of COVID- 19-induced liver damage, mainly represented by increase in serum transaminases and bilirubin. The secondary outcome was the description of abnormalities in serum albumin and prothrombin time (PT). We focused on laboratory data only on hospital admission, and adopted random-effects model for meta-analysis. RESULTS: Eleven studies were eligible for meta-analysis. Out of 793 included patients, the pooled prevalence of COVID-19-related liver damage was 22.17% (95% CI 17.64 to 27.07), mostly indicated by hypertransaminasemia. Serum bilirubin was increased in 5.53% (95% CI 3.60 to 7.85) of cases. Abnormal serum albumin was observed in 78.92% (95% CI 39.82 to 99.56), and increased PT value in 19.98% (95% CI 2.49 to 78.23), but these results derived from significantly heterogeneous studies. CONCLUSIONS: COVID-19-induced liver injury must not be ignored, as it is observed in one fifth of infected patients. Prospective studies evaluating liver function during the course of COVID-19 are needed to provide a complete overview of hepatic involvement during this viral infection.

Role of endoscopic retrograde cholangiopancreatography in the diagnosis and treatment of biliary tract complications after orthotopic liver transplantation.

BACKGROUND: Biliary complications are a major drawback of liver transplantation. AIM: To analyse, in a single centre, experience in endoscopic diagnosis and management of biliary complications after liver transplantation. PATIENTS: A total of 147 consecutive liver transplantations performed on 132 patients over a 5-year period. METHODS: Evaluation of the incidence and type of biliary-related complications and analysis of their diagnosis and endoscopic treatment by cholangiopancreatography in terms of success of the endoscopic approach, conversion to surgery and long-term patient and graft survival. RESULTS: Endoscopic retrograde cholangiopancreatography was performed on 30 patients (23%). Overall incidence of biliary complications as confirmed by endoscopic retrograde cholangiopancreatography was 17% (25 cases). Endoscopic retrograde cholangiopancreatography was negative in 5 cases (16%). Biliary complications were successfully treated by endoscopy in 84% of cases (21 out of 25 patients); 4 cases (16%) required a surgical approach (2 choledochojejunostomy, 2 retransplantation) due to failure to correct the problem endoscopically. Stenoses and biliary sludge associated with retained internal stent were almost always successfully managed by endoscopic retrograde cholangiopancreatography, while anastomotic leakage more frequently required a surgical approach. CONCLUSIONS: Endoscopic retrograde cholangiopancreatography is a safe and effective approach for diagnosis and treatment of biliary-related complications after liver transplantation thereby reducing morbidity and mortality related to re-operation which is, however, required in selected cases.

Prevalence of intestinal metaplasia in the distal oesophagus, oesophagogastric junction and gastric cardia in symptomatic patients in north-east Italy: a prospective, descriptive survey. The Italian Ulcer Study Group "GISU".

BACKGROUND: Incidence of adenocarcinoma of distal oesophagus and gastric cardia, probably arising from areas of intestinal metaplasia, has been increasing rapidly. AIMS: To define prevalence of intestinal metaplasia of distal oesophagus, oesophagogastric junction and gastric cardia and to evaluate potential associated factors, by means of a prospective multicentre study including University and teaching hospitals, and primary and tertiary care centres. PATIENTS: Each of 24 institutions involved in study enrolled 10 consecutive patients undergoing first-time routine endoscopy for dyspeptic symptoms. METHODS: Patients answered symptom questionnaires and underwent gastroscopy Three biopsies were taken from distal oesophagus, oesophago-gastric junction and gastric cardia, and were stained with haematoxylin and eosin. Specimens were also evaluated for Helicobacter pylori infection. RESULTS: A total of 240 patients (124 male, 116 female; median age 56 years, range 20-90) were enrolled in study. Intestinal metaplasia affected distal oesophagus in 5, oesophago-gastric junction in 19 and gastric cardia in 10 patients. Low-grade dysplasia was found at distal oesophagus and/or oesophago-gastric junction of 3/24 patients with intestinal metaplasia vs 2/216 without intestinal metaplasia (p<0.05). A significant association was found between symptoms and presence of intestinal metaplasia, regardless of location, and between Helicobacter pylori infection and intestinal metaplasia at oesophago-gastric junction. CONCLUSIONS: Intestinal metaplasia of distal oesophagus, oesophagogastric-junction and gastric cardia is found in a significant proportion of symptomatic patients undergoing gastroscopy and is associated with dysplasia in many cases. Although prevalence of dysplasia seems to decrease when specialized columnar epithelium is found in short segment, or even focally in oesophago-gastric junction, these small foci of intestinal metaplastic cells may represent source of most adenocarcinomas of cardia.

Endoscopic double-blind controlled trial of ranitidine vs placebo in the short-term treatment of duodenal ulcer.

The aim of the present study was to investigate the effectiveness of ranitidine in the treatment of duodenal ulcer. Fourty patients with endoscopically proven pyloric or duodenal ulcer were treated with ranitidine 40 mg t.d. with meals and 80 mg nocte, or identical placebo tablets under double-blind conditions. Endoscopy after four weeks of treatment revealed complete healing in 15 out of 18 (83.3%) ranitidine-treated patients and in 5 out of 17 (29.4%) of the placebo patients (P less than 0.01). Ulcer symptoms were significantly less in ranitidine-treated patients, while the difference in antacid consumption between the two groups was found to be only arithmetical. No side effects or significant hematological or biochemical abnormalities were found. Four-week treatment with 200 mg of ranitidine daily seems to correspond to that of 6-8 weeks with 1-1, 6 g of cimetidine.

Ranitidine vs cimetidine: short-term treatment of gastric ulcer.

We compared the clinical effectiveness and endoscopic results of ranitidine and cimetidine treatment; 71 outpatients, all affected with benign gastric ulcer, were selected for the study (43 type I, 7 type II and 21 type III, according to Johnson's classification). The patients were treated randomly for 4 weeks with ranitidine (300 mg daily) or cimetidine (1 g daily). An endoscopic examination was repeated within 3 days after the end of the treatment. Clinical checks were performed weekly in order to monitor the clinical course of pain and antacid consumption, according to the patient's needs. The patients who did not demonstrate complete healing on endoscopic examination were treated for an additional 4 week period. At the end of this 4 week period, another endoscopic examination was done. Thirty-six patients treated with ranitidine and 33 with cimetidine completed the first period of therapy. The two groups were homogeneous with regard to sex, age, duration of disease, smoking habits, alcohol consumption, and type and size of ulcer. Ranitidine and cimetidine treatments did not demonstrate any significant difference with regard to ulcer healing after the 4th or the 8th week of therapy. Both ranitidine and cimetidine were less effective in healing type I than type II and III G.U., at the 4th week of treatment. No significant differences between the two groups were noted with regard to pain or weekly antacid consumption. No significant side effects were reported.

Is ethanol metabolism affected by oral administration of cimetidine and ranitidine at therapeutic doses?

The aim of this study was to compare the ethanol serum concentration curve, the area under the curve and subjective response after acute ingestion of ethanol (red wine, 13 degrees proof, at a dose of 0.8 g/kg of ideal weight in 6 healthy volunteers with a mean habitual alcohol intake of 20 g/day. All the subjects underwent the test a total of three times, after pre-treatment with cimetidine (400 mg X 2/day/7 days) and ranitidine (150 mg X 2/day/7 days), respectively, and after receiving no pre-treatment. The wine was taken orally within the space of 15 min, four hours after taking a standard-weight ham sandwich. Blood samples were drawn at the following times: 0, 30, 60, 90, 120, 180, 240 and 360 minutes. The plasma ethanol curve of the subjects pre-treated with cimetidine lies above that of the subjects pre-treated with ranitidine, and largely coincides with the curve obtained in those who received no pre-treatment, with the exception of the initial hour-and-a-half, when the later show a slightly higher mean plasma concentration. The differences between the three treatment groups are merely arithmetical, but not statistical, with respect to peak plasma ethanol concentrations, time elapsing before peaking, and areas under the curves. These results are at variance with some published data suggesting a significant interaction of cimetidine with the metabolism of alcohol by way of interference either with the hepatic oxidative metabolizing enzymes, or with the activity of alcohol dehydrogenase.

Comparison of pirenzepine and carbenoxolone in the treatment of chronic gastric ulcer. A double-blind endoscopic trial.

The purpose of the present study was to compare the effectiveness of pirenzepine and carbenoxolone in accelerating the healing of chronic gastric ulcer. Sixty-six out-patients with endoscopically proven gastric ulcer, without major systemic diseases, were admitted to the study. Patients were randomly allocated to either pirenzepine, 50 mg three times a day for 6 weeks, or carbenoxolone, 100 mg three times a day for one week followed by 50 mg three times a day for the remaining five weeks. At 6 weeks, the ulcers had healed in 20 out of 34 patients (59%) treated with pirenzepine, and in 15 out of 29 patients (52%) treated with carbenoxolone. Symptomatic improvement was similar with both drugs. Some major side effects (oedema, hypokalaemia and hypertension) occurred in approximately 30% of patients treated with carbenoxolone; of those receiving pirenzepine 25% complained of minor symptoms (e.g. dry mouth, headache, tachycardia). It is concluded that pirenzepine and carbenoxolone are of similar, but rather limited, efficacy in speeding the healing of chronic gastric ulcer, but show important differences with respect to tolerability.

[The medical therapy of chronic pancreatitis. Problems, progress and outlook]. / La terapia medica della pancreatite cronica. Problemi, progressi e prospettive.

The aims of medical therapy in chronic pancreatitis are mainly to relieve the recurrent pain and to correct any malabsorption secondary to digestive insufficiency resulting from deficient exocrine pancreatic function. The treatment of the pain initially involves the use of dietary measures and analgesic drugs. The results of the use of pancreatic extracts and somatostatin reported in the literature are controversial, as are those of coeliac plexus block. Of unquestionable efficacy, at least in the short to medium term, are surgical decompression interventions in patients, with pain refractory to these measures and who present significant dilation of Wirsung's duct at ERCP. Endoscopic decompression constitutes an alternative to surgical decompression. In view of the transitory results of endoscopic decompression, which, in any event, should be implemented only by endoscopists possessing the necessary experience and expertise, the use of this technique may perhaps be targeted at carefully selected patients to be submitted to surgical decompression. As far as maldigestion is concerned, which occurs only when the pancreatic functional deficit reaches 90% or more, replacement therapy with pancreatic extracts must be resorted to. Multi-Unit Dose preparations are to be preferred, consisting in gastro-protected microspheres measuring not more than 2 mm in diameter and containing high doses of lipase, since at least 30,000 I.U. of lipase are required in the post-prandial phase for reasonably satisfactory correction of the steatorrhoea. Should this fail to prove effective, it is good policy to add antisecretory drugs (H2-antagonists, proton-pump inhibitors).

Oxmetidine in the short term treatment of active duodenal ulcer. A review and commentary.

Oxmetidine is an H2-antagonist like cimetidine containing an imidazole ring in its molecule, but differing from cimetidine in that it contains in the side-chain a substituted isocytosine moiety in place of the cyanoguanidine group. Nine controlled clinical trials are critically analysed in detail. The overall results show that the antiulcer activity of oxmetidine is not significantly different from that of cimetidine with mean healing rates by week 4 of 74.9% and 75.3%, respectively. Healing rates proved to be lower in smokers than in non-smokers in all trials but one. Satisfactory response as regards symptoms was obtained both with oxmetidine and cimetidine. A certain degree of variability with regard to the untoward effects was found, but in all cases failed to prove significant from the clinical point of view. However, a better definition of oxmetidine safety requires a study on a large number of patients and for a longer period.

Comparison of once-daily bedtime administration of famotidine and ranitidine in the short-term treatment of duodenal ulcer. A multicenter, double-blind, controlled study.

A multicenter, double-blind, randomized, controlled study was conducted in 234 duodenal ulcer patients to compare the efficacy and safety of the H2-receptor antagonists famotidine and ranitidine in the treatment of duodenal ulcer. Patients received 40 mg famotidine (119 patients) or 300 mg ranitidine (115 patients) once daily at bedtime for 4 weeks. If ulcer lesions persisted, treatment was extended to 6 weeks. Efficacy was assessed by relief of symptoms and endoscopic findings of ulcer healing. Safety was determined on the basis of reports of side effects, results of laboratory tests, and, in selected patients, changes in plasma levels of hormones. The 4- and 6-week healing rates achieved with famotidine were 76% and 91%, respectively, and with ranitidine they were 76% and 87%, respectively; the differences in healing rates for the two drugs were not statistically significant. Similarly, both drugs provided satisfactory relief of pain and dyspeptic symptoms. However, famotidine produced significantly (P less than 0.05) greater relief of postprandial fullness and heartburn. The incidence of untoward effects was low in both treatment groups, and abnormal results in laboratory tests were observed in only one patient, a chronic alcoholic receiving famotidine, who withdrew from the study because of a slight elevation in serum transaminase levels. One patient in the ranitidine treatment group dropped out of the study because of a generalized urticarial rash; however, a causal relationship between drug and effect could not be established. The authors conclude that famotidine may be regarded as the best alternative to ranitidine in the treatment of duodenal ulcer.

Detection of human papillomavirus DNA and p53 gene mutations in esophageal cancer samples and adjacent normal mucosa.

BACKGROUND/AIM: There is evidence of a possible etiological role of human papillomaviruses (HPVs) in the development of esophageal tumors. Loss of function of the wild-type p53 tumor suppressor gene product by binding to E6 oncoproteins of high-risk HPVs is considered an important event in tumor development. The aim of this study was to verify the prevalence of HPV infection and p53 mutation in esophageal tumor tissue samples and in the adjacent normal mucosa in patients from a high-risk area in Italy. METHODS: DNA from 33 biopsy specimens (17 tumor sample biopsies and 16 samples of adjacent normal mucosa) was screened for HPV DNA using two polymerase chain reaction based procedures. Restriction fragment length polymorphism analysis was used for typing. Screening of p53 mutations was performed with polymerase chain reaction-single strand conformation polymorphism analysis and DNA sequencing. RESULTS: Overall, 8 of 17 patients presented HPV DNA; HPV 16 was detected in 4 of 8 samples. Samples from tumors and adjacent mucosa were positive for mucosal HPVs in 7 of 17 and 4 of 16 cases, respectively. In 1 case, HPV DNA was detected in the normal mucosa only. None of the samples contained HPVs of the epidermodysplasia verruciformis or cutaneous groups. Mutations of p53 were detected in two HPV DNA negative samples. In both cases, the mutation was present in the tumor only. CONCLUSIONS: Our results are in favor of the involvement of both aberrant p53 expression and HPV infection in the development of esophageal tumors. The high HPV infection rate in patients from a high-risk region suggests that subjects harboring HPVs (in particular HPV 16) in the esophagus should be considered at risk of esophageal malignancies.