Molecular heterogeneity and prognostic implications of synchronous advanced colorectal neoplasia.

BACKGROUND: It is uncertain whether synchronous colorectal cancers (S-CRCs) preferentially develop through widespread DNA methylation and whether they have a prognosis worse than solitary CRC. As tumours with microsatellite instability (MSI) may confound the effect of S-CRC methylation on outcome, we addressed this issue in a series of CRC characterised by BRAF and MS status. METHODS: Demographics, clinicopathological records and disease-specific survival (DSS) were assessed in 881 consecutively resected CRC undergoing complete colonoscopy. All tumours were typed for BRAF(c.1799T>A) mutation and MS status, followed by search of germ-line mutation in patients with MSI CRC. RESULTS: Synchronous colorectal cancers (50/881, 5.7%) were associated with stage IV microsatellite-stable (MSS) CRC (19/205, 9.3%, P=0.001) and with HNPCC (9/32, 28%, P<0.001). BRAF mutation (60/881, 6.8%) was associated with sporadic MSI CRC (37/62, 60%, P<0.001) but not with S-CRC (3/50, 6.0%, P=0.96). Synchronous colorectal cancer (HR 1.82; 95% CI 1.15-2.87; P=0.01), synchronous advanced adenoma (HR 1.81; 95% CI 1.27-2.58; P=0.001), and BRAF(c.1799T>A) mutation (HR 2.16; 95% CI 1.25-3.73; P=0.01) were stage-independent predictors of death from MSS CRC. Disease-specific survival of MSI CRC patients was not affected by S-CRC (HR 0.74; 95% CI 0.09-5.75; P=0.77). CONCLUSION: Microsatellite-stable CRCs have a worse prognosis if S-CRC or synchronous advanced adenoma are diagnosed. The occurrence and the enhanced aggressiveness of synchronous MSS advanced neoplasia are not associated with BRAF mutation.

Early expression of the fractalkine receptor CX3CR1 in pancreatic carcinogenesis.

BACKGROUND: In pancreatic ductal adenocarcinoma (PDAC), fractalkine receptor CX3CR1 contributes to perineural invasion (PNI). We investigated whether CX3CR1 expression occurs early in PDAC and correlates with tumour features other than PNI. METHODS: We studied CX3CR1 and CX3CL1 expression by immunohistochemistry in 104 human PDAC and coexisting Pancreatic Intraepithelial Neoplasia (PanIN), and in PdxCre/LSL-Kras(G12D) mouse model of PDAC. CX3CR1 expression in vitro was studied by a spheroid model, and in vivo by syngenic mouse graft of tumour cells. RESULTS: In total, 56 (53.9%) PDAC expressed CX3CR1, 70 (67.3%) CX3CL1, and 45 (43.3%) both. CX3CR1 expression was independently associated with tumour glandular differentiation (P=0.005) and PNI (P=0.01). Pancreatic Intraepithelial Neoplasias were more frequently CX3CR1+ (80.3%, P<0.001) and CX3CL1+ (86.8%, P=0.002) than matched cancers. The survival of PDAC patients was better in those with CX3CR1+ tumour (P=0.05). Mouse PanINs were also CX3CR1(+) and -CL1(+). In vitro, cytokines significantly increased CX3CL1 but not CX3CR1 expression. Differently, CX3CR1 was upregulated in tumour spheroids, and in vivo only in well-differentiated tumours. CONCLUSION: Tumour differentiation, rather than inflammatory signalling, modulates CX3CR1 expression in PanINs and PDAC. CX3CR1 expression pattern suggests its early involvement in PDAC progression, outlining a potential target for interfering with the PanIN transition to invasive cancer.

Safety of cold polypectomy for <10mm polyps at colonoscopy: a prospective multicenter study.

BACKGROUND: Cold polypectomy techniques (without electrocautery) by means of biopsy forceps or snare are widely adopted for the removal of subcentimetric polyps. However, few data are available on the safety of this approach. The aim of this study was to assess the safety of cold polypectomy for subcentimetric polyps, as well as the rate of advanced neoplasia in these lesions. PATIENTS AND METHODS: In a prospective multicenter trial, consecutive patients with at least one < 10-mm polyp at colonoscopy were prospectively included. All of the < 10-mm polyps detected within the study period were removed by cold polypectomy. The rates of immediate or delayed bleeding and other complications were assessed at 7 and 30 days after cold polypectomy by telephone calls. The rate of advanced histology was also assessed. Predictive variables of postpolypectomy bleeding or advanced neoplasia were identified by multivariate analysis. RESULTS: A total of 1015 < 10-mm polyps in 823 patients (15.5 % on antiplatelet agents) were removed. Of these, 822 (81 %) were ≤ 5 mm and 193 (19 %) were 6 - 9 mm. Immediate postpolypectomy bleeding occurred in 18 patients, corresponding to a per-patient and per-polyp bleeding rate of 2.2 % (95 % confidence interval [CI] 1.2 % - 3.2 %) and 1.8 % (95 %CI 1 % - 2.6 %), respectively. Therapy with antiplatelet agents (odds ratio [OR] 4; 95 %CI 1.5 - 10.6) and larger polyp size (OR 2; 95 %CI 1.1 - 6.9) were independent predictors of bleeding. Bleeding was successfully treated by endoscopic hemostasis in all cases and required no further medical intervention. Advanced neoplasia prevalence in polyps ≤ 5 mm was as high as 8.7 %. CONCLUSIONS: The results from this study showed the high safety of a cold polypectomy approach for subcentimetric polyps. This was due to the low rate of postpolypectomy bleeding and to the high efficacy of endoscopic hemostasis in its treatment. The high rate of advanced neoplasia in polyps ≤ 5 mm should prompt some caution on the management of these lesions following detection at computed tomography colonography or colon capsule endoscopy.

Canonical and uncanonical pathogenic germline variants in colorectal cancer patients by next-generation sequencing in a European referral center.

BACKGROUND: Despite increasing use of next-generation sequencing (NGS), data concerning the gain in germline pathogenic variants (PVs) remain scanty, especially with respect to uncanonical ones. We aimed to verify the impact of different cancer predisposition genes (CPGs) on colorectal cancer (CRC) in patients referred for genetic evaluation. MATERIALS AND METHODS: We enrolled for NGS, by Illumina TruSight Cancer panel comprising 94 CPGs, 190 consecutive subjects referred for microsatellite instability (MSI) CRC, polyposis, and/or family history. RESULTS: Overall, 51 (26.8%) subjects carried 64 PVs; PVs coexisted in 4 (7.8%) carriers. PVs in mismatch repair (MMR) genes accounted for one-third of variant burden (31.3%). Four Lynch syndrome patients (20%) harbored additional PVs (HOXB13, CHEK2, BRCA1, NF1 plus BRIP1); such multiple PVs occurred only in subjects with PVs in mismatch syndrome genes (4/20 versus 0/31; P = 0.02). Five of 22 (22.7%) patients with MSI cancers but wild-type MMR genes harbored PVs in unconventional genes (FANCL, FANCA, ATM, PTCH1, BAP1). In 10/63 patients (15.9%) with microsatellite stable CRC, 6 had MUTYH PVs (2 being homozygous) and 4 exhibited uncanonical PVs (BRCA2, BRIP1, MC1R, ATM). In polyposis, we detected PVs in 13 (25.5%) cases: 5 (9.8%) in APC, 6 (11.8%) with biallelic PVs in MUTYH, and 2 (3.9%) in uncanonical genes (FANCM, XPC). In subjects tested for family history only, we detected two carriers (18.2%) with PVs (ATM, MUTYH). CONCLUSION: Uncanonical variants may account for up to one-third of PVs, underlining the urgent need of consensus on clinical advice for incidental findings in cancer-predisposing genes not related to patient phenotype.

Transoral treatment of Zenker diverticulum: flexible endoscopy versus endoscopic stapling. A retrospective comparison of outcomes.

Transoral stapled diverticulo-esophagostomy (TSDE) has gained increased popularity in surgical treatment of Zenker diverticulum (ZD). One of the advantages of this approach is early rehabilitation with significant decrease in patient morbidity and time to resumption of oral intake as compared with open treatment. The section of the septum between the diverticulum and the esophagus with a flexible endoscopic (ES) approach has also been proposed since mid-90s as an alternative for treatment of ZD. Both these approaches are a minimally invasive approach to treat ZD. We compared the TSDE management of ZD versus the ES treatment in a retrospective consecutive series of patients who were referred to either the ES or surgical unit of our Institute. Fifty-eight consecutive patients underwent treatment for ZD either by TSDE or ES. The two techniques were evaluated for length of hospital stay, diverticulum size, resumption of oral intake, resolution of dysphagia, and complications. Clinical outcome was evaluated throughout a symptom score from 0 to 3, calculated before and after the procedure. The two groups were compared on the various parameters using a Mann--Whitney test. Twenty-eight patients underwent ES and 30 TSDE for ZD. In both groups, a significant decrease in postoperative versus preoperative dysphagia was reported. The average length of hospital stay wasn't significantly different in the two groups (3.38 days for TSDE vs. 2.42 days for ES). The overall complication rate was similar in the two groups. There were two cases in the ES group and three cases in the TDSE group that required an ES revision to take down a residual diverticular wall that produced a mild but persistent dysphagia. Minimally invasive treatment of ZD both with ES and with TSDE is a valuable option for this disease: both techniques are safe and effective, with similar outcome in terms of hospital stay, symptom reduction, and complication rate. Long-term results have to be evaluated.

Endoscopic flexible treatment of Zenker's diverticulum: a modification of the needle-knife technique.

BACKGROUND AND STUDY AIM: Endoscopic treatment of Zenker's diverticulum has been successfully reported over the last 10 years using different approaches. The hook-knife is a new device originally developed for endoscopic submucosal dissection procedures. This study aimed to investigate the safety and efficacy of endoscopic myotomy performed with the hook-knife. PATIENTS AND METHOD: From July 2005, 32 consecutive patients (23-male, mean age 74.8 years) with dysphagia secondary to the presence of Zenker's diverticulum were prospectively enrolled. Myotomy was performed using a straight-end transparent hood to the tip of the scope and the hook-knife for the incision of the bridge between the Zenker's diverticulum and the esophagus. Clinical outcome was evaluated assigning a dysphagia symptom score from 0 (symptoms absent) to 4 (inability to swallow saliva). RESULTS: General anesthesia was used in 4 patients, deep sedation with propofol in 23 patients, while midazolam was used in 5 patients. The mean procedural time was 28 minutes. Complications occurred in 2 patients (6.25 %). At 1 month follow-up, the mean dysphagia score was significantly improved from 2.9 to 0.6 ( P < 0.001) with 87.5 % of patients free of symptoms and 4 patients with dysphagia that was persistent but milder than before the treatment. Three of these 4 patients underwent a successful second endoscopic treatment with complete relief of dysphagia; one was not re-treated because of advanced age (92 years). During the follow-up period (23.87 +/- 9.6 months), 2 patients developed dysphagia recurrence. The overall success rate was 90.6 %. CONCLUSIONS: Diverticulectomy with a flexible scope and the hook-knife may represent a safe and effective alternative treatment for patients with Zenker's diverticulum.

Colifagina, a novel preparation of 8 lysed bacteria ameliorates experimental colitis.

Immune reactivity towards the bacterial intestinal flora plays an important part in the pathogenesis of inflammatory bowel disease. Administration of probiotic bacteria has beneficial effects on infectious and inflammatory diseases, principally in bowel disorders. However, little is known about the administration of soluble bacterial antigens in intestinal inflammation. We investigated the therapeutic effects of colifagina in experimental colitis. To assess this effect, C57BL/6 mice with dextran sulphate sodium-induced colitis were treated with colifagina, or with a placebo, for a period of 10 days. The mice were monitored, and inflammation was assessed by disease activity index (DAI). Analysis of fecal IgA concentration and measurement of IgA and inflammatory chemokine production in organ colonic culture was performed by ELISA. Clinically and histologically, bacterial-lysate-treated mice revealed significantly fewer DAI and a reduction of colonic histological inflammation. Treatment of healthy mice with colifagina significantly increased the fecal concentration of IgA and IgA production in organ culture. Colifagina administration in DSS-treated mice significantly increased the fecal concentration of IgA and IgA production in organ culture. MIP-1, MIP-2 and RANTES concentrations in colonic organ culture were significantly lower in colifagina-treated mice than in the placebo group. The use of colifagina is effective in amelioration of murine colitis.

Carriage of CARD15 variants and smoking as risk factors for resective surgery in patients with Crohn's ileal disease.

BACKGROUND: It is controversial whether CARD15 variants are truly associated with a more severe form of Crohn's disease. The relative role of CARD15 genotype and smoking in Crohn's disease progression is also debated. AIM: To investigate the association between CARD15 variants and history of resective surgery in patients with Crohn's ileal disease, taking into account smoking as a possible confounding factor. METHODS: We originally assessed CARD15 genotype in 239 north Italian Crohn's disease patients (mean follow-up: 10.1 +/- 8.1 years). We then focused on 193 patients with proven ileal involvement, 70 of whom (36.3%) carried CARD15-mutated alleles (G908R, R702W, L1007fs). RESULTS: Carriage of CARD15 variants was positively associated with family history and ileal-only disease and negatively associated with uncomplicated behaviour at maximal follow-up (P < 0.05). Ileal resection was the only variable independently associated with CARD15 variants at multivariate analysis (OR 3.8; 95% CI 1.6-9.2; P = 0.003). Kaplan-Meier analysis showed that ileal resection was favoured both by CARD15 variant-carriage (P = 0.01) and by smoking (P = 0.05), but smoking did not affect progression to surgery in variant carriers (P = 0.31). Thirteen of 14 (93%) patients being resection-free at 15-year follow-up, had CARD15 wild-type genotype (P = 0.01), whereas only seven (50%) had never smoked (P = 1.0). CONCLUSIONS: In summary, CARD15 variant-associated Crohn's ileitis is virtually committed to stricturing and/or penetrating disease and, eventually, to resective surgery. Smoking accelerates progression to surgery in patients with wild-type CARD15 genotype, but it seems to exert no additional effect in CARD15-variant carriers.

Autonomic nervous system dysregulation in irritable bowel syndrome.

BACKGROUND: Autonomic nervous system (ANS) regulation may be altered in functional diseases, including irritable bowel syndrome (IBS), but published data are not clear to date. The aim of the study was to analyze ANS function in IBS subjects classified by Rome III criteria and healthy controls using standardized technique. METHODS: ANS activity was evaluated by autoregressive spectral analysis of RR interval and systolic arterial pressure variabilities, to obtain indices of sympatho-vagal modulation of the heart and of spontaneous cardiac baroreflex (α index). A symptom list was used to score 18 somatic complaints (score 0-180) (4SQ). Fatigue and stress were assessed through the use of a global scoring index (0-10). KEY RESULTS: We enrolled 41 IBS subjects (29 F, age 40 ± 2 years) and 42 healthy matched controls. Heart rate was higher in IBS than control subjects (69 ± 2 vs 61 ± 1; p < 0.001). The total variance of RR interval variability, and α index, were significantly lower in IBS compared to controls (1983.12 ± 384.64 ms(2) vs 4184.55 ± 649.59 ms(2) ; 18.1 ± 2 ms/mmHg vs 29 ± 3 ms/mmHg; p < 0.01). The α index results showed an inverse correlation with stress scores and somatic symptoms. CONCLUSIONS & INFERENCES: IBS subjects display a significant reduction in α index, an established marker of cardiac baroreflex. ANS dysfunction appears to be involved in the pathophysiology of IBS and its assessment may open new perspectives for clinical management of patients suffering from IBS.

CCK-1 receptor blockade for treatment of biliary colic: a pilot study.

BACKGROUND: Loxiglumide is a potent and selective cholecystokinin-1 (CCK-1) receptor antagonist able to inhibit gall-bladder contraction. AIM: To assess the effect of CCK-1 receptor blockade on the pain of patients with biliary colic. PATIENTS AND METHODS: Fourteen patients with biliary colic but no suspicion for acute cholecystitis, were randomly and blindly assigned to loxiglumide (50 mg i.v.) or hyoscine-N-butyl bromide (20 mg i.v.) treatment. Pain intensity was monitored by a Visual Analogue Scale. Patients with less than 80% response at 30 min, were retreated with a second injection of the same compound. RESULTS: Reduction in pain score (mean +/- S.E.M.) was faster and significantly greater in patients treated with loxiglumide (n = 7) than in controls (n = 7): 88 +/- 7% vs. 47 +/- 12% after 20 min, P < 0.05; 92 +/- 6% vs. 49 +/- 13%, after 30 min, P < 0.05. Only one of seven patients treated with loxiglumide needed a second injection at 30 min (vs. six of seven controls, P < 0.05). No adverse effect was observed after either treatment. CONCLUSIONS: Loxiglumide is highly effective in obtaining pain relief in patients with biliary colic. The analgesic effect of CCK-1 receptor blockade is superior to that of a conventional anticholinergic treatment.

Comparison of 24-h control of gastric acidity by three different dosages of pantoprazole in patients with duodenal ulcer.

BACKGROUND: It is now clear that the extent to which gastric acid secretion must be suppressed varies with the clinical condition being treated. AIM: To assess the 24-h control of gastric acidity and the individual response variability of three different doses of pantoprazole. METHODS: Sixty-four duodenal ulcer patients were recruited for this prospective, randomized, multicentre, double-blind, parallel-group study. They were subdivided into three well-matched groups treated with 20 mg o.m., 40 mg o.m. and 40 mg b.d. of pantoprazole, respectively. Endoscopy and intragastric pH monitoring were performed in each patient before and after 14 days of treatment. RESULTS: Fifty-five patients were eligible for final analysis (17 treated with 20 mg o.m., 18 with 40 mg o.m. and 20 with 40 mg b.d. pantoprazole). The ulcer crater healed in 94, 88 and 95% of cases, respectively. The three dosages of pantoprazole produced significant increases in gastric pH compared to basal levels (P < 0.0001). There was also a clear dose-dependent pharmacodynamic effect, which augmented on moving from the lowest dosage of 20 mg o.m. pantoprazole to the highest dosage of 40 mg b.d. (P < 0.01-0.001). The inter-individual response variability within the three treatment groups was more marked with the dose of 20 mg than with the two higher doses of pantoprazole. CONCLUSIONS: All three doses of pantoprazole we tested are highly effective in decreasing gastric acidity and there is a clear dose-dependent pharmacodynamic effect on moving from the lowest to the highest dosage. The greatest inter individual variation in the degree of acid inhibition was seen with pantoprazole 20 mg o.m., while the majority of patients responded adequately to the two higher doses of the drug.

K-ras and p16(INK4A)alterations in sputum of NSCLC patients and in heavy asymptomatic chronic smokers.

NSCLC rates among the most frequent and lethal neoplasm world-wide and a significant decrease in morbidity and mortality relies only upon effective early diagnostic strategies. We investigated K-ras mutations and p16(INK4A) hypermethylation in tumor tissue and sputum of 50 patients with NSCLC and correlated them with sputum cytology and with tumor staging, grading and location, to ascertain, in sputum, their potential diagnostic impact. The same genetic/epigenetic abnormalities and cytological features were also evaluated in sputum from 100 chronic heavy smokers. Genetic analysis identified molecular abnormalities in 64% tumors (14/50 K-ras mutations and 24/50 p16(INK4A) hypermethylation) and in 48% sputum (11/50 K-ras mutations and 16/50 p16(INK4A) hypermethylation). In tumors K-ras mutations and p16(INK4A) hypermethylation were mostly mutually exclusive, being found in the same patients in 3 cases only. Genetic abnormalities in sputum were detected only in molecular abnormal tumors. Molecular changes in sputum had rates of detection similar to cytology (42%) but the cyto-molecular combination increased the diagnostic yield up to 60%. Interestingly, the rate of detection of genetic changes in sputum of tumors at early stage (T1) was not significantly different from that of tumors at more advanced stage (T2-T4). In fact K-ras point mutations were frequently recognised in tumors at early stage while p16(INK4A) inactivation prevailed in tumors at advanced stage ( P=0.0063). As expected, diagnostic cytological findings were more frequently found in tumors at advanced stage (P=0.004). No correlation was found between tumor grading and location (central versus peripheral) and molecular changes. p16(INK4A) hypermethylation, but not K-ras mutations, was documented in sporadic cases of asymptomatic heavy smokers (4%) where it was uncoupled from cytological abnormalities. In conclusion the cyto-molecular diagnostic strategy adopted in this study was able to detect the majority of tumors but in order to be proposed as effective and early diagnostic tool, this molecular panel needs to be tested in prospective studies with adequate follow-up.

Ganglioside pattern of normal human brain, from samples obtained at surgery. A study especially referred to alkali labile species.

The ganglioside pattern from normal human temporal cortex and cerebellum has been studied in fresh specimens obtained at surgery. The analyses have been performed by two-dimensional thin layer chromatography with an intermediate ammonia treatment which is a methodology particularly suitable for resolving alkali labile gangliosides. Alkali labile gangliosides were detected in all the analyzed specimens and their content contributed to 23% and 11% of total lipid bound sialic acid, in temporal cortex and cerebellum, respectively.

Cytosolic sialidase from the nerve endings of developing rat forebrain.

The developmental profile of cytosolic sialidase from the nerve ending and the nerve ending-free compartments of rat forebrain was studied from birth to 150 days. Soluble extracts containing the cytosol from nerve endings and nerve ending-free tissue were separately prepared; the recovery of cytosol in the two extracts was followed by assaying lactate-dehydrogenase. In both cytosolic extracts the content of sialidase and lactate-dehydrogenase had a marked and progressive enhancement from the 5th to the 20th day of life and then maintained a constant level through adult life. However the rate of lactate-dehydrogenase and sialidase increase in the two cytosolic compartments was different. Lactate-dehydrogenase increased at a very similar rate in the two cytosols. Instead the rate of sialidase increase was greater in the cytosol from nerve endings from the 5th to the 10th day of life, and, inversely, in the cytosol from nerve ending-free tissue from 10 to 20 days. Between the 5th and 10th day of life the nerve ending cytosol underwent an enrichment of sialidase which was several times higher than that of lactate-dehydrogenase; in the other periods of forebrain development sialidase and lactatedehydrogenase moved in parallel. The variations with age of cytosolic sialidase from the nerve ending-free tissue seemed to follow the overall process of brain development. The nerve ending soluble sialidase would more specifically reflect formation of synaptic junctions in some brain regions in a well defined period of brain maturation.

Nervous system ganglioside composition of normothermic and hibernating dormice (Glis glis).

The ganglioside pattern of seven different regions, olfactory bulb, forebrain cortex, midbrain (corpora quadrigemina), cerebellum, brain stem, pons and spinal cord, of nervous system of normothermic and hibernating dormice (Glis glis) were investigated by two dimensional thin layer chromatography and densitometric quantification. Up to thirty different ganglioside spots were resolved, fifteen of which belonging to alkali labile species. Alkali labile gangliosides were present in all the regions obtained from normothermic animals, and their content, expressed as percentage of total ganglioside-bound sialic acid, ranged from a minimum of 10.2% in olfactory bulb, to a maximum of 30.1% in spinal cord. The most abundant alkali labile gangliosides were O-Ac-GT1b, O-Ac-GQ1b and an unidentified one, we coded I3. Alkali labile gangliosides were practically undetectable in hibernating dormice. They could be recognized only in brain stem, 3.3% and olfactory bulb, 0.6%.

Immunological adverse effects of anticonvulsants. What is their clinical relevance?

Long term administration of anticonvulsants is sometimes associated with impairment of the humoral and/or cellular immune response. Furthermore, certain well known adverse reactions to antiepileptics may have an immunotoxicological origin e.g. lymphadenopathy, pseudolymphoma and systemic lupus erythematosus. However, two important questions remain unresolved. First, the possibility that epilepsy per se might be primarily associated with immune alterations makes it difficult to assess the pathogenetic role of a specific drug, especially in a patient population usually on multiple drug therapy. Secondly, the clinical relevance of some of the observed immunological abnormalities is still highly controversial. This review is intended to give an outline of the present state of knowledge on the effects of anticonvulsants on humoral, cellular and nonspecific immunity, with particular regard to some of the major clinical conditions that have been ascribed to drug-induced immune dysregulation, such as pseudolymphoma and systemic autoimmune diseases. The immunotoxic potential of anticonvulsants appears to be low, and immunological monitoring is not usually required except in patients with known immune defects.

Pancreatic polypeptide response to food and cerulein in patients with total gastrectomy.

In order to investigate the intestinal phase of pancreatic polypeptide (PP) release, the hormonal response to food and cerulein was measured in 19 patients with truncal vagotomy and total gastrectomy (10 with simple esophagojejunal anastomosis and 9 with an additional duodenojejunal anastomosis) and in 7 healthy subjects. After gastrectomy, the early peak of the physiologic biphasic PP response to food was lost but the late predominant phase was unchanged so that the overall postprandial release of the hormone was not significantly lowered. Gastrectomized patients with duodenal bypass had postprandial serum levels only slightly lower than those of patients with preserved duodenal transit of food. Serum PP response to cerulein stimulation was significantly lower in vagotomized patients than in healthy subjects. However, in operated patients as well as in controls, cerulein infusion did induce a rapid increase of plasma PP, followed by persistently elevated levels. The PP response to cerulein was abolished by atropine pretreatment. Our findings indicate that the intestinal phase of meal-stimulated PP response is not dependent on the integrity of vagal pancreatic innervation and that the preservation of the duodenal transit of food after total gastrectomy is not crucial for the maintenance of the enteroinsular axis.

Fat absorption and gastroenteric pH profile in postsurgical pancreatic insufficiency: role of the association of H2-receptor antagonists with pancreatic enzymes.

The complete control of steatorrhea in post-surgical exocrine pancreatic insufficiency is difficult. The aim of this study was to evaluate the effect of the association of ranitidine with pancrelipase om fecal fat excretion in patients who had undergone a pancreatoduodenectomy with suppression of the exocrine pancreatic secretion by Neoprene injection. Ten patients were studied 1 year after surgery. Steatorrhea was measured as an integrated test of 3-day stools, while patients were kept on a diet of 100 g lipid/day, with their usual enzyme supplementation therapy (16,050 USP units of lipase/meal). A basal 24-h gastroenteric pH profile was also obtained. In the following month, patients had ranitidine (150 mg twice a day) in addition to pancrelipase. Then steatorrhea and gastroenteric pH were reassessed. Mean fecal fat was 26.9 (SD 13.7) g/day without ranitidine and 30.5 (SD 13.9) g/day during combined treatment. Body weight and nutritional parameters did not show any significant variation after ranitidine administration. Even in the absence of ranitidine, postprandial gastroenteric pH values were always > 4; the H2-receptor antagonist only reduced fasting gastric acidity. In conclusion, the gastroenteric pH and fecal fat determinations showed that ranitidine is not useful in patients with total postsurgical exocrine pancreatic insufficiency.

Clinical utility of the serum CA 19-9 test for diagnosing pancreatic carcinoma in symptomatic patients: a prospective study.

The diagnostic accuracy of the serum CA 19-9 determination was prospectively evaluated in patients selected for the presence of signs or symptoms highly suggestive for pancreatic cancer. Of 110 patients included in the study, 54 had a final diagnosis of pancreatic adenocarcinoma (49% prevalence). CA 19-9 values were higher than 40 U/ml in 45 patients with pancreatic carcinoma and in 18 of the 56 patients with other final diagnosis (sensitivity, 0.83; specificity, 0.68; positive predictive value [PPV], 0.71; negative predictive value [NPV], 0.81). The serum CA 19-9 determination was not capable of shortening the diagnostic workup of patients with strong clinical suspicion of pancreatic cancer since adequate imaging of the pancreas was required to confirm or exclude the diagnosis. However, values above 120 U/ml were strongly suggestive for pancreatic carcinoma in the overall population (PPV, 0.85) and they were diagnostic (PPV, 1.0) in the anicteric portion. Combined with pancreatic imaging, the CA 19-9 was an excellent confirmatory test; a normal value in a patient with negative imaging ruled out pancreatic carcinoma as the cause of symptoms (NPV, 1.0), whereas a pathological result in the presence of positive or equivocal pancreatic radiology was highly suggestive for the presence of the disease (PPV, 0.93).