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Aim To evaluate the efficacy and safety of liquid nitrogen cryotherapy as a primary or rescue treatment for BE, with and without dysplasia, or intramucosal adenocarcinoma (IMC). Methods This was a retrospective, single-center study carried out in a tertiary care center including 45 patients with BE who was treatment-naive or who had persistent intestinal metaplasia (IM), dysplasia, or IMC despite prior therapy. Barrett's mucosa was resected via EMR when clinically appropriate, then patients underwent cryotherapy until eradication or until deemed to have failed treatment. Surveillance biopsies were taken at standard intervals. Results From 2010 through 2014, 33 patients were studied regarding the efficacy of cryotherapy. Overall, 29 patients (88%) responded to cryotherapy, with 84% having complete regression of all dysplasia and cancer. Complete eradication of cancer and dysplasia was seen in 75% of subjects with IMC; the remaining two subjects did not respond to cryotherapy. Following cryotherapy, 15 patients with high-grade dysplasia (HGD) had 30% complete regression, 50% IM, and 7% low-grade dysplasia (LGD); one subject had persistent HGD. Complete eradication of dysplasia occurred in all 5 patients with LGD. In 5 patients with IM, complete regression occurred in 4, and IM persisted in one. In 136 cryotherapy sessions amongst 45 patients, adverse events included chest pain (1%), stricture (4%), and one gastrointestinal bleed in a patient on dual antiplatelet therapy who had previously undergone EMR. Conclusion Cryotherapy is an efficacious and safe treatment modality for Barrett's esophagus with and without dysplasia or intramucosal adenocarcinoma.

Background & Aims Endoscopic ultrasound (EUS)−guided chemoablation with ethanol lavage followed by infusion of paclitaxel is effective for the treatment of mucinous pancreatic cysts. However, complications arise in 3%−10% of patients, presumably linked to the inflammatory effects of ethanol. We aimed to determine whether alcohol is required for effective pancreatic cyst ablation, if removing alcohol from the ablation process would improve complication rates, and whether a multi-agent chemotherapeutic cocktail could increase the rate of complete cyst resolution compared with findings reported from previous trials using alcohol followed by paclitaxel alone. Methods Between November 2011 and December 2016, we conducted a single-center, prospective, double-blind trial of 39 patients with mucinous-type pancreatic cysts. Patients were randomly assigned to 1 of 2 groups that underwent EUS-guided pancreatic cyst lavage with either 80% ethanol (control) or normal saline (alcohol-free group). Cysts in both groups were then infused with an admixture of paclitaxel and gemcitabine. Primary outcomes were the rates of complete ablation 12 months after the procedure, and rates of serious and minor adverse events within 30 days of the procedure. Results At 12 months, 67% of patients who underwent alcohol-free EUS-guided cyst chemoablation had complete ablation of cysts compared with 61% of patients in the control group. Serious adverse events occurred in 6% of patients in the control group vs none of the patients in the alcohol-free group. Minor adverse events occurred in 22% of patients in the control group and none of the patients in the alcohol-free group. The overall rate of complete ablation was 64%. Conclusions In this prospective, randomized, controlled trial, we found that alcohol is not required for effective EUS-guided pancreatic cyst ablation, and when alcohol is removed from the ablation process, there is a significant reduction in associated adverse events. A multi-agent chemotherapeutic ablation admixture did not appear to significantly improve rates of complete ablation compared with the current standard of alcohol lavage followed by paclitaxel alone. ClinicalTrials.gov ID: NCT01475331.

Background A disparity in colorectal cancer (CRC) incidence and mortality has been reported for black men and women in the United States.

The original article unfortunately contained a mistake. On page 8, Table 2, the row with “POLE POLD1” has been shifted right so all the columns are not correct.

Background & Aims EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon–alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients. Methods Of 2312 patients enrolled, 1459 had an available baseline FT, biopsy, and complete data. Uni- (UV) and multi-variable (MV) analyses were performed using FT and biopsy. Results Baseline characteristics were similar as in the overall population; METAVIR stage: 28% F2, 29% F3, and 43% F4, previous relapsers 29%, previous PEG-IFN regimen 41%, high baseline viral load (BVL) 64%. 506 patients (35%) had undetectable HCV-RNA at TW12 (TW12neg), with 58% achieving SVR. The accuracy of FT was similar to that in naive patients: AUROC curve for the diagnosis of F4 vs F2=0.80 ( p p p ⩽0.001) with EVR. Among patients TW12neg, two independent factors remained highly predictive of SVR by MV analysis ( p ⩽0.001): genotype 2/3 (odds ratio=2.9), fibrosis estimated with FT (4.3) or by biopsy (1.5). Conclusions FibroTest at baseline is a possible non-invasive alternative to biopsy for the prediction of EVR at 12weeks and SVR, in patients with previous failures and advanced fibrosis, retreated with PEG-IFN alfa-2b and ribavirin.

Background and study aims: Direct percutaneous endoscopic necrosectomy has been described as a minimally invasive intervention for the debridement of walled-off pancreatic necrosis (WOPN). In this retrospective cohort study, we aimed to confirm these findings in a US referral center and evaluate the clinical value of this modality in the treatment of pancreatic necrosis as well as other types of intra-abdominal fluid collections and necrosis. Patients and methods: Twelve consecutive patients with WOPN or other abdominal abscess requiring debridement and washout underwent computed tomography (CT)-guided drainage catheter placement. Each patient then underwent direct percutaneous endoscopic necrosectomy and washout with repeat debridement performed until complete. Drains were then removed once output fell below 30 mL/day and imaging confirmed resolution. The primary endpoints were time to clinical resolution and sustained resolution at 1-year follow up. Results: Ten patients were treated for WOPN, one for necrotic hepatic abscesses, and one for omental necrosis. The median time to intervention was 85 days with an average of 2.3 necrosectomies performed. Complete removal of drains was accomplished in 11 patients (92 %). The median time to resolution was 57 days. No serious adverse events occurred; however, one patient developed pancreaticocutaneous fistulas. Ten patients completed 1-year surveillance of which none required drain replacement. No patients required surgery or repeat endoscopy. Conclusions: This series supports the premise that direct percutaneous endoscopic necrosectomy is a safe and effective intervention for intra-abdominal fluid collections and necrosis in appropriately selected patients. Our study demonstrates a high clinical success rate with minimal adverse events. This modality offers several potential advantages over surgical and transgastric approaches including use of improved accessibility, an excellent safety profile, and requirement for only deep or moderate sedation.

Background and aims: Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder often caused by mutations in STK11. Time to onset of symptoms was characterised for a large collection of individuals with PJS who had been tested for STK11 mutations and genotype–phenotype correlations were evaluated. Methods: We characterised mutations in 42 independent probands and also used a historical cohort design to study 51 individuals with Peutz-Jeghers syndrome who had completed self-administered questionnaires. Results: Mutations were detected in 22/32 (69%) probands with PJS and 0/10 probands referred to rule out PJS. Real-time PCR analysis to quantitate DNA failed to detect any large deletions in PJS participants without STK11 mutations. The median time to onset for gastrointestinal symptoms or polypectomy was 13 years of age but showed a wide variability. Gastric polyps were frequent in PJS participants, with a median age at onset of 16 years. Individuals with missense mutations had a significantly later time to onset of first polypectomy (p = 0.04) and of other symptoms compared with those participants either with truncating mutations or no detectable mutation. Conclusion: STK11 mutation analysis should be restricted to individuals who meet PJS criteria or their close relatives. Direct sequencing of STK11 yields a high rate of point mutations in individuals who meet phenotypic PJS criteria. Individuals with missense mutations of STK11 typically had a later time to onset for PJS symptoms. The common occurrence of gastric polyps may facilitate chemopreventive studies for this disorder.

Germline mutations of the LKB1 gene lead to Peutz-Jeghers syndrome (PJS), which is associated with a predisposition to gastrointestinal polyposis and cancer. In this study we tested for germline mutations of LKB1 in 11 patients with PJS from nine families and analyzed the expression patterns of the LKB1 and cyclo-oxygenase-2 (COX-2) proteins in 28 Peutz-Jeghers polyps (PJPs) and five carcinomas from these patients by immunohistochemical (IHC) analysis. In eight of those families we identified seven different mutations, which consisted of two splice site mutations, two nonsense mutations, one small in-frame deletion, one frame-shift mutation, and one silent mutation. Immunostaining revealed nuclear and cytoplasmic expression of LKB1 protein in 23 PJPs and five carcinomas, nuclear expression alone in one PJP, and loss of LKB1 protein expression in four PJPs, indicating a heterogeneous LKB1 expression pattern in PJPs. Overexpression of COX-2 was detected in 23 (82%) of 28 PJPs and in all carcinomas. Despite heterogeneity in staining of LKB1 among individuals and even among samples from the same individual, we found statistically significant correlations in staining of LKB1 relative to COX-2. These results suggest that COX-2 plays a role in tumorigenesis in PJS and may therefore be considered as a potential target for PJS chemoprevention.

Background Hepatocellular carcinoma is the most common primary liver malignancy, commonly a sequelae of hepatitis C infection, but can complicate cirrhosis of any cause. Whether metabolic syndrome and its components, type II diabetes, hypertension, and hyperlipidemia increase the risk of hepatocellular carcinoma independent of cirrhosis is unknown. Methods A retrospective cohort study was conducted using the MarketScan insurance claims database from 2008-2012. Individuals with hepatocellular carcinoma aged 19-64 years and age and sex-matched controls were included. Multivariate analysis of hepatocellular carcinoma risk factors was performed. Results Hepatitis C (odds ratio [OR] 2.102) was the largest risk factor for hepatocellular carcinoma. Other independent risk factors were type II diabetes (OR 1.353) and hypertension (OR 1.229). Hyperlipidemia was protective against hepatocellular carcinoma (OR 0.885). The largest risk increase occurred with hypertension with type II diabetes and hepatitis C (OR 4.580), although hypertension and type II diabetes without hepatitis C still incurred additional risk (OR 3.399). Type II diabetes and hyperlipidemia had a similar risk if hepatitis C was present (OR 2.319) or not (OR 2.395). Metformin (OR 0.706) and cholesterol medications (OR 0.645) were protective in diabetics. Insulin (OR 1.640) increased the risk of hepatocellular carcinoma compared with the general type II diabetes population. Conclusion In the absence of cirrhosis, type II diabetes and hypertension were independent risk factors for hepatocellular carcinoma. Hyperlipidemia and medical management of type II diabetes with metformin and cholesterol medication appeared to reduce the incidence of hepatocellular carcinoma. In contrast, insulin was associated with a higher risk of hepatocellular carcinoma.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is characterized by intestinal polyposis, mucocutaneous pigmentation and an increased cancer risk, usually caused by mutations of the STK11 gene. This study collected epidemiological, clinical and genetic data from all Uruguayan PJS patients. METHODS: Clinical data were obtained from public and private medical centers and updated annually. Sequencing of the STK11 gene in one member of each family was performed. RESULTS AND DISCUSSION: 25 cases in 11 unrelated families were registered (15 males, 10 females). The average age of diagnosis and death was 18 and 41 years respectively. All patients had characteristic PJS pigmentation and gastrointestinal polyps. 72% required urgent surgery due to intestinal obstruction. 3 families had multiple cases of seizure disorder, representing 20% of cases. 28% developed cancer and two patients had more than one cancer. An STK11 mutation was found in 8 of the 9 families analyzed. A unique M136K missense mutation was noted in one family. Comparing annual live births and PJS birth records from 1970 to 2009 yielded an incidence of 1 in 155,000. CONCLUSION: The Uruguayan Registry for Peutz-Jeghers patients showed a high chance of emergent surgery, epilepsy, cancer and shortened life expectancy. The M136K missense mutation is a newly reported STK 11 mutation.

BACKGROUND: While it is clear that luminal epidermal growth factor (EGF) stimulates repair of the damaged bowel, its significance in maintaining normal gut growth remains uncertain. If EGF is important in maintaining normal gut growth, the EGF receptor (EGF-R) should be present on the apical (luminal) surface in addition to the basolateral surface. AIMS/SUBJECTS/METHODS: This study examined the distribution of the EGF-R in the epithelium throughout the human gastro-intestinal tract using immunohistochemistry, electron microscopy, and western blotting of brush border preparations. RESULTS: Immunostaining of the oesophagus showed circumferential EGF-R positivity in the cells of the basal portions of the stratified squamous epithelium but surface cells were EGF-R negative. In the normal stomach, small intestine, and colon, immunostaining localised the receptor to the basolateral surface with the apical membranes being consistently negative. EGF-R positivity within the small intestine appeared to be almost entirely restricted to the proliferative (crypt) region. Western blotting demonstrated a 170 kDa protein in whole tissue homogenates but not in the brush border vesicle preparations. CONCLUSIONS: As the EGF-R is located only on the basolateral surfaces in the normal adult gastrointestinal tract, the major role of luminal EGF is probably to stimulate repair rather than to maintain normal gut growth.

The incidence of esophageal adenocarcinoma (EAC) has increased exponentially in the last 3 decades. Barrett’s esophagus (BE) is the only known precursor of EAC. Patients with BE have a greater than 40 folds higher risk of EAC compared with the general population. Recent years have witnessed a revolution in the clinical and molecular research related to BE. However, several aspects of this condition remain controversial. Data regarding the true prevalence of BE have varied widely. Recent studies have suggested a lower incidence of EAC in nondysplastic BE (NDBE) than previously reported. There is paucity of prospective data showing a survival benefit of screening or surveillance for BE. Furthermore, the ever-increasing emphasis on healthcare cost containment has called for reexamination of the screening and surveillance strategies for BE. There is a need for identification of reliable clinical predictors or molecular biomarkers to risk-stratify patients who might benefit the most from screening or surveillance for BE. Finally, new therapies have emerged for the management of dysplastic BE. In this paper, we highlight the key areas of controversy and uncertainty surrounding BE. The paper discusses, in detail, the current literature about the molecular pathogenesis, biomarkers, histopathological diagnosis, and management strategies for BE.

Purpose. We evaluated a questionnaire to aid in the recognition of CRC risk, as well as patient interest in their risk status within an open-access endoscopy center. Methods. A questionnaire was administered to new patients presenting for colonoscopy from May 2007 to February 2008. 287 patients were enrolled. Family history was evaluated using Amsterdam 1, II, and Revised Bethesda criteria. Recognition of risk and referral for counseling was assessed. Patients' interest to be contacted by a genetic counselor was also assessed. Results. 13.2 % (38/287) of patients met Revised Bethesda criteria. Of these, 18 (47.4 %) were previously told about their increased risk for CRC. Only 1 patient who met Revised Bethesda criteria (2.6 %) was previously referred for genetics, whereas none of the 3 patients who met Amsterdam I or II criteria were referred. 23.7 % of high-risk patients did not want to be contacted if found to be at increased risk for cancer. Conclusion. In our open-access endoscopy system, a significant number of high-risk patients remain unidentified and underreferred for genetic counseling due to numerous barriers. Our findings lend support to taking a public health approach to identifying those at risk for Lynch syndrome by implementing universal screening of all CRC specimens.

Background In 1996, the National Cancer Institute hosted an international workshop to develop criteria to identify patients with colorectal cancer who should be offered microsatellite instability (MSI) testing due to an increased risk for Hereditary Nonpolyposis Colorectal Cancer (HNPCC). These criteria were further modified in 2004 and became known as the revised Bethesda Guidelines. Our study aimed to retrospectively evaluate the percentage of patients diagnosed with HNPCC tumors in 2004 who met revised Bethesda criteria for MSI testing, who were referred for genetic counseling within our institution. Methods All HNPCC tumors diagnosed in 2004 were identified by accessing CoPath, an internal database. Both the Tumor Registry and patients' electronic medical records were accessed to collect all relevant family history information. The list of patients who met at least one of the revised Bethesda criteria, who were candidates for MSI testing, was then cross-referenced with the database of patients referred for genetic counseling within our institution. Results A total of 380 HNPCC-associated tumors were diagnosed at our institution during 2004 of which 41 (10.7%) met at least one of the revised Bethesda criteria. Eight (19.5%) of these patients were referred for cancer genetic counseling of which 2 (25%) were seen by a genetics professional. Ultimately, only 4.9% of patients eligible for MSI testing in 2004 were seen for genetic counseling. Conclusion This retrospective study identified a number of barriers, both internal and external, which hindered the identification of individuals with HNPCC, thus limiting the ability to appropriately manage these high risk families.

Polyamine content (putrescine, spermidine, and spermine) or ornithine decarboxylase (ODC) activity was measured in normal-appearing colonic mucosa from patients undergoing colonoscopy. Comparisons were made between those with and those without adenomatous polyps. Colonic mucosal polyamine content was measured in 44 persons. Mean putrescine content was 1.25 +/- 0.26 (SE) nmol/mg protein in 22 patients with adenomatous polyps compared with 0.53 +/- 0.12 nmol/mg protein in patients without polyps (P less than 0.02). Tissue content of spermidine and spermine did not differ between these two groups. Ornithine decarboxylase activity was measured in tissue from 45 patients. Mean ODC activity was 2.84 +/- 0.73 pmol/hr/mg protein in 23 persons with adenomatous polyps compared with 1.15 +/- 0.18 pmol/hr/mg protein in persons without polyps (P less than 0.05). Mucosal putrescine and ODC activity are elevated in patients with adenomatous polyps compared with patients without polyps. These biochemical markers may prove helpful in improving surveillance methods for colorectal cancer and premalignant adenomatous polyps.

Background: Mucinous pancreatic cystic lesions have the propensity to progress into pancreatic cancer. Currently radiographic surveillance or surgical resection is recommended for this premalignant type of cyst, both of which have significant limitations. Recently, endoscopic ultrasound-guided cyst ablation has emerged as an innovative and promising alternative treatment approach. Previous studies have shown that EUS-guided ethanol lavage of pancreatic cysts is safe and results in complete cyst resolution in 1/3 of patients. Subsequent studies demonstrated marked increases in rates of ablation with infusion of paclitaxel following ethanol lavage, which raises the question of whether alcohol is necessary for effective ablation. This is important, since ethanol extravasation is felt to have caused two complications in previous trials, abdominal pain and pancreatitis. This study hypothesizes that the removal of alcohol lavage prior to chemotherapy infusion will not impair ablation rates and will decrease complication rates. A secondary aim of this study is to assess whether a custom chemoablation cocktail tailored to pancreatic neoplasia (paclitaxel+gemcitabine) will improve ablation rates overall. Gemcitabine was chosen because it dilutes paclitaxel for injection and has been the standard in pancreatic cancer chemotherapy. Recently, the combination of paclitaxel and gemcitabine was shown to improve response rates and progression-free survival when compared with gemcitabine alone. Methods: Patients with mucinous or indeterminate type pancreatic cysts of 1-5cm’s without signs of malignancy were randomized to undergo either EUS-guided lavage with 80% alcohol or normal saline followed by infusion of 3 mg/ml paclitaxel + 19mg/ml gemcitabine (both arms). 9 patients were enrolled in this initial pilot study and evaluated post op, at 72 hours, with two week lab tests and by CT scan at 3, 6, and 12 months to assess response rates and for any complications. Results: The initial 9 patients of this trial (expected to have an N of 78 when complete) were randomized for this pilot study with 8 patients then able to be treated. Pancreatic cysts ranged in maximum diameter from 2.2cm to 3.8 cm (mean 2.9 cm). Location included body (n=4), head (n=2), neck (n=1) and tail (n=1). The overall reduction in cyst surface area was 67% at 3 months and 82% at 6 months. At 6 months size reduction was 81% in the alcohol infusion arm and 83% in the alcohol-free arm. Complications were mild abdominal pain (1) in the alcohol free arm (12.5%), moderate abdominal pain (1), and mild pancreatitis (1) in the alcohol arm (25%). Conclusion: The treatment of mucinous type pancreatic cysts with either alcohol or saline lavage followed by gemicitabine-paclitaxel infusion is feasible and safe in this limited pilot study. Initial results indicate that alcohol-free ablation does not impair ablation efficacy and is associated with fewer complications although the full sample size will be required to prove this hypothesis with any certainty. Citation Format: Matthew T. Moyer, Setareh Sharzehi, Charles E. Dye, Wafik El-Deiry, Thomas J. McGarrity, Abraham Mathew, Niraj Gusani, Raquel E. Davila, Brooke Ancrile. Is ethanol required for cyst ablation in patients with premalignant type pancreatic cysts? [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B95.

Peutz-Jeghers syndrome (PJS, OMIM 175200) is an unusual inherited intestinal polyposis syndrome associated with distinct peri-oral blue/black freckling [1–9]. Variable penetrance and clinical heterogeneity make it difficult to determine the exact frequency of PJS [4]. PJS is a cancer predisposition syndrome. Affected individuals are at high risk for intestinal and extra-intestinal cancers. In 1997, linkage studies mapped PJS to chromosome 19p [10, 11], and subsequently a serine/threonine kinase gene defect (LKB1) was noted in a majority of PJS cases [12, 13]. A phenotypically similar syndrome has been produced in an LKB1 mouse knockout model [14–18]. Several PJS kindred without LKB1 mutations have been described, suggesting other PJS loci [19–22]. The management of PJS is complex and evolving. New endoscopic technologies may improve management of intestinal polyposis. Identification of specific genetic mutations and their targets will more accurately assess the clinical course, and help gage the magnitude of cancer risk for affected individuals.

Background In this paper, we report the health related quality of life (HRQOL) data from patients with hepatitis C viral infection (HCV) who were refractory to prior therapy and had re-treatment with a combination of Pegylated interferon alpha-2b and ribavirin. We hypothesized that the HRQOL will improve in those patients who attain sustained viral response similar to naïve patients undergoing treatment for HCV. Methods HRQOL data was obtained from 152 patients enrolled into a randomized study for re-treatment of HCV refractory to prior therapy with interferon alpha-2b in combination with ribavirin. The treatment protocol was for 48 weeks and had a high and low dose arm. The HRQOL data was collected at baseline, weeks 24 and 48 of treatment, and at 24 week follow-up after treatment. A repeated measures statistical model was used for comparing the HRQOL domain scores between the responders and non-responders and the treatment groups. The responders and non-responders were also compared to the age and sex adjusted national mean scores. Results Twenty-five of the 152 (17%) patients achieved a sustained viral response. At baseline, HRQOL is lower in HCV patients compared to national norms. The norm based HRQOL domain scores for the different domains of the SF-36 instrument were as follows: physical functioning = 47.13, role-physical = 46.87, bodily pain = 48.00, general health = 44.01, vitality = 45.39, social functioning = 47.05, role-emotional = 48.88, mental health = 48.76, physical component score 43.26 and mental component score = 46.17. The scores decreased during therapy in those who would be responders and non-responders, but the pattern of change was different. During the treatment, the HRQOL domain scores of responders decrease notably in the domain of vitality. At week 48 vitality scores were worst in responders. 5 of the 8 domain scores were lower compared to baseline in non-responders. At 24 weeks post treatment follow up, HRQOL in those refractory patients who respond to re-treatment tended to be better than the national average in the domains of vitality (p = .06), social functioning (p = .06) and role-emotional (p = .03) while the non-responders improved their scores in domains of physical function and bodily pain. Conclusion We conclude that patients who are to be responders and non-responders behave differently in terms of the HRQOL domain scores when re-treated with a combination of interferon alpha 2b and ribavirin. The responders sustained a significant decrease in the domain score of vitality while 5 of the 8 domain scores decrease in non-responders at the end of treatment. At the end of follow up, in responders, the HRQOL score tended to be better than the national average notably in the domains of role-emotional, vitality and social functioning. On the other hand, in non-responders, the domain scores of physical function improve, while that of role-emotional worsened.

Background: Peginterferon α-2b plus ribavirin therapy in previously untreated patients with chronic hepatitis C yields the highest sustained virological response rates of any treatment strategy but is expensive. Aims: To estimate the cost effectiveness of treatment with peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of patients with chronic hepatitis C. Methods: Individual patient level data from a randomised clinical trial with peginterferon plus ribavirin were applied to a previously published and validated Markov model to project lifelong clinical outcomes. Quality of life and economic estimates were based on German patient data. We used a societal perspective and applied a 3% annual discount rate. Results: Compared with no antiviral therapy, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 4.2 and 4.7 years, respectively. Compared with standard interferon α-2b plus ribavirin, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 0.5 and by 1.0 years with incremental cost effectiveness ratios of €11 800 and €6600 per quality adjusted life year (QALY), respectively. Subgroup analyses by genotype, viral load, sex, and histology showed that peginterferon plus weight based ribavirin remained cost effective compared with other well accepted medical treatments. Conclusions: Peginterferon α-2b plus ribavirin should reduce the incidence of liver complications, prolong life, improve quality of life, and be cost effective for the initial treatment of chronic hepatitis C.

papers p 1252 In 1950 Barrett wrote a treatise to clarify confusion over oesophagitis which “connote[s] one thing to some people and something quite different to others.”1 He described gastric mucosa extending into the tubular oesophagus as the result of a congenitally shortened oesophagus. The presence of columnar lined epithelium in the oesophagus is now referred to as Barrett's oesophagus. It is associated with chronic gastro-oesophageal reflux disease and an increased risk of oesophageal adenocarcinoma.2 Quantifying this risk, and the best methods for early diagnosis, are still the subjects of considerable debate. Endoscopically the distal end of the pearly white oesophagus is readily distinguished from the salmon red of the proximal stomach: the so called “Z line” or squamocolumnar junction. However, the location of the Z line may be difficult to identify in cases of intense inflammation, hiatal hernia, and stricture patients with oesophagitis. Extension of the Z line proximally—representing columnar replacement of the squamous epithelium of the distal oesophagus (Barrett's oesophagus)—is seen in 5-15% of patients with peptic oesophagitis.2 Historically one point of confusion has been whether a minimal length of columnar metaplasia is needed to qualify for the diagnosis of Barrett's oesophagus: is it >2 cm, >3 cm, or >5 cm? In part, these arbitrary criteria were established to avoid “false positive” biopsies of intestinal metaplasia which often occur in the gastric …

Calmodulin is an ubiquitous cytoplasmic protein which mediates many of the actions of calcium on intestinal tissue including regulation of growth and differentiation of normal and neoplastic cells. Using a biotinylated calmodulin overlay system, we compared the pattern of calmodulin binding proteins throughout the gastrointestinal tract of mice, rats, rabbits, and humans, and in human colonic adenomas and adenocarcinomas. A common calmodulin binding protein of 67 kDa was found in membrane and cytosolic fractions of oesophagus, stomach, proximal and distal small intestine, and colon from all four species. In human tissue this 67 kDa protein was present in greatest concentration in stomach tissue. Furthermore, a 67 kDa binding protein was the major calmodulin binding protein from human stomach and ileum as determined by ion exchange and calmodulin affinity chromatography. A similar pattern of binding proteins was noted between rabbit and human cytosolic fractions; proteins of 60/67 kDa and 105 kDa were present in stomach tissue. A 94 kDa protein was present in samples of rabbit and human ileum but not of mouse or rat. A similar pattern of calmodulin binding proteins was seen in normal and neoplastic large bowel tissue, apart from one of nine adenocarcinomas, where a distinct 54 kDa band was noted in both cytosolic and membrane fractions. The results of this study show interspecies and organ differences between calmodulin binding proteins, but suggest that a 67 kDa protein is the major binding protein present throughout normal gastro-intestinal tract and neoplastic human tissue.

PEG-intron plus ribavirin in chronic hepatitis C patients refractory to prior treatment: end of follow-up report

The binding characteristics of fluorescein isothiocyanate conjugated lectins to normal colonic mucosa, and 43 adenomatous polyps were studied by fluorescence microscopy. The lectin, Dolichos biflorus agglutinin (DBA) stained intensely to upper crypt cells of the sigmoid colon and rectum but to a lesser degree to proximal colonic crypts or lower crypt cells distally. Peanut agglutinin (PNA) and Ulex europaeus agglutinin (UEA) did not bind to the theca of proximal or distal colonic crypts. The lectin Griffonia simplicafolia agglutinin (GSA1) bound intensely to upper and lower crypt cells of both regions. PNA binding was noted in 56% of adenomatous polyps, occurred more often in polyps of the distal colorectum, and increased with polyp size and villous histology. UEA bound to 26% of adenomatous polyps, 42% of proximal polyps, and 17% of distal polyps. DBA staining was noted in 72% of polyps without regional preference. GSA1 stained all polyp specimens. To determine if the lectin binding characteristics of an index (initial) polyp might serve as a predictor of metachronous lesions, 20 patients (29 polyps) without a history of polyps or cancer and who had at least one surveillance colonoscopy 1 to 3 years after the initial polypectomy were studied. The presence or absence of PNA, UEA, or DBA binding in an index polyp did not predict the occurrence of metachronous lesions. Five of the six patients with more than one index polyp had metachronous polyps at follow-up surveillance colonoscopy.

Of the original Peutz-Jeghers families reported by Jeghers, the "Harrisburg Family" has now been followed for 49 yr. Their 12 affected family members comprise the largest Peutz-Jeghers kindred reported. The course of this family illustrates that Peutz-Jeghers syndrome is not a benign disease. One family member developed a duodenal carcinoma in a hamartoma with adenomatous changes; this progression in the duodenum has not previously been reported. Ten patients underwent 75 polypectomies. One patient developed short bowel syndrome. Three patients died in young adulthood. The development of gastrointestinal malignancy in 2 of 12 affected patients suggests that Peutz-Jeghers syndrome may be a premalignant condition. Consequently, even asymptomatic gastric, duodenal, and colonic polyps should be removed endoscopically. If surgical intervention is necessary, intraoperative endoscopy with polypectomy may prevent the development of a short bowel syndrome. Colonoscopic screening of patients and their family members may be beneficial and surveillance for extraintestinal malignancy appears to be warranted.

Sequential changes in proliferative parameters in proximal and distal colonic crypts were studied during 1,2-dimethylhydrazine-induced carcinogenesis using [3H]thymidine autoradiography as a probe. 1,2-dimethylhydrazine (20 mg/kg) and vehicle (ethylenediaminetetraacetic acid) control rats received weekly s.c. injections for 20 wk. All animals received a pulse of [3H]thymidine before death at weeks 2, 6, 10, 16, 22, 26, or 30. In addition, 8 animals unexposed to 1,2-dimethylhydrazine or vehicle served as baseline controls. Dramatic regional differences were noted in the baseline controls. Crypt length, labeling index, and proliferative zone size were all significantly greater distally than proximally (p less than 0.05), whereas the labeling index of the proliferative zone tended to be enhanced proximally. During 1,2-dimethylhydrazine treatment the crypt length, labeling index, and proliferative zone size increased in both regions. As these parameters changed in parallel, the differences between proximal and distal colon did not change significantly during carcinogenesis. Actual tumor formation did differ, however, with tumors appearing earlier and in greater abundance in the distal colon. These findings show similar proliferative changes in both the proximal and distal colon during 1,2-dimethylhydrazine treatment and indicate that the enhanced baseline proliferative state of the distal colon compared with the proximal colon must be considered in the process of tumor formation.