Abdominal inflammatory myofibroblastic tumour: Clinicopathological and molecular analysis of 20 cases, highlighting potential therapeutic targets.

AIMS: Inflammatory myofibroblastic tumour (IMT) is a rare mesenchymal neoplasm of intermediate malignant potential, occurring at any age and at multiple sites. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive subtype of IMT, typically involving the abdomen. Most IMTs harbour kinase gene fusions, especially involving ALK and ROS1, but 20-30% of IMTs show no detectable translocations. The aim of this study is to further delineate clinicopathological and molecular characteristics of abdominal IMT and discover potential new therapeutic targets. METHODS AND RESULTS: In 20 IMTs, including four EIMS, RNA fusion analysis was performed, followed by multiplex DNA analysis if no ALK or ROS1 fusion was detected. Fourteen IMTs (70.0%) had an ALK translocation and the fusion partner was identified in 11, including a RRBP1::ALK fusion, not previously described in classical (non-EIMS) IMT. RANBP2::ALK fusion was demonstrated in all EIMS. One IMT had a ROS1 fusion. In all ALK/ROS1 translocation-negative IMTs mutations or fusions - as yet unreported in primary IMT - were found in genes related to the receptor tyrosine kinase (RTK)/PI3K/AKT pathway. Three of four patients with EIMS died of disease [mean survival 8 months (4-15 months)], whereas only one of 14 classical IMT patients succumbed to disease [mean follow-up time 52 months (2-204 months); P < 0.01]. CONCLUSION: This study shows the wide clinical spectrum of abdominal IMTs and affirms the poor prognosis of EIMS, raising discussion about its status as IMT subtype. Furthermore, the newly detected alterations of the RTK/PI3K/AKT pathway expand the molecular landscape of IMTs and provide potential therapeutic targets.

Clinical impact of five large-scale screening projects for chronic hepatitis B in Chinese migrants in the Netherlands.

BACKGROUND & AIMS: In low-endemic countries it is debated whether first-generation migrants should be screened for chronic hepatitis B infection. We describe the clinical impact of five large-scale Dutch screening projects for hepatitis B in first-generation Chinese migrants. METHODS: Between 2009 and 2013 five independent outreach screening projects for hepatitis B targeting first-generation Chinese migrants were conducted in five main Dutch regions. To explore the relevance of our screening we defined clinical impact as the presence of an indication for: (i) antiviral therapy, (ii) strict follow-up because of high hepatitis B DNA levels and/or (iii) surveillance for hepatocellular carcinoma. RESULTS: In total, 4423 persons participated in the projects of whom 6.0% (n = 264) were HBsAg positive. One hundred and twenty-nine newly diagnosed HBsAg-positive patients were analysed in specialist care. Among these patients prevalence of cirrhosis was 6.9% and antiviral therapy for hepatitis B was started in 32 patients (25%). In patients without a treatment indication, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma was considered indicated in 64 patients (50%). CONCLUSIONS: In our screening project in first-generation Chinese migrants, antiviral treatment, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma were considered indicated in three of four analysed HBsAg-positive patients. These data show that detection of hepatitis B in Chinese migrants can have considerable impact on patient care.

A Fatal Outcome after Cessation of Nucleotide Analogue Therapy in a Patient with Chronic Hepatitis B: A Case Report.

Introduction: Emerging evidence suggests that long-term nucleos(t)ide analogue (NA) therapy can be ceased in a selective group of chronic hepatitis B (CHB). This is being gradually implemented in clinical practice. Case Presentation: A 68-year-old man known with a chronic hepatitis B e antigen-positive hepatitis B infection without signs of advanced liver fibrosis or cirrhosis was admitted with acute liver failure. Two months prior to his admission, he ceased his NA therapy. During the admission, NA therapy was restarted, but the liver function worsened. The patient was put on the high-urgency liver transplantation waiting list, and the next day, he was successfully transplanted. However, the patient died 17 days later due to hemorrhagic shock that resulted from intra-abdominal bleeding and acute pancreatitis. Conclusion: Current guidelines suggest that NA therapy can be discontinued in a selective group of CHB patients. However, these guidelines suggest different stopping and follow-up criteria. This case illustrates that NA withdrawal is not without risks and that these differences in recommendations may lead to inadequate management and eventually a fatal outcome.

Diabetes mellitus at the time of diagnosis of cirrhosis is associated with higher incidence of spontaneous bacterial peritonitis, but not with increased mortality.

DM (diabetes mellitus) is present in 20-40% of patients with liver cirrhosis, but its prognostic impact is unclear. Therefore, in the present study, we investigated whether the presence of DM in patients with cirrhosis was associated with increased mortality, and/or with increased incidence of SBP (spontaneous bacterial peritonitis). We reviewed medical and laboratory data of 230 patients with cirrhosis from the period 2001-2011, for whom data were complete in n=226. Follow-up for the outcomes mortality and SBP was performed until May 2012, with only 13 patients lost to follow-up. DM was present at baseline in 78 patients (35%). Median follow-up was 6.2 (interquartile range, 3.1-9.3) years, during which 118 patients died [47 out of 78 with DM (60%), and 71 out of 148 without DM (48%)]. The presence of DM at baseline was not associated with increased mortality after adjustment for age {HR (hazard ratio), 1.00 [95% CI (confidence interval), 0.67-1.50]}. Further adjustment for sex, aetiology of cirrhosis, platelet count and the Child-Pugh or MELD (model for end-stage liver disease) score did not change this finding. During follow-up, 37 patients developed incident SBP (19 with DM and 18 without DM). DM at baseline was associated with incident SBP, even after adjustment for age, sex, aetiology, platelet count and the Child-Pugh [HR, 2.39 (95% CI, 1.10-5.18)] or MELD score [HR, 2.50 (95% CI, 1.16-5.40)]. In conclusion, the presence of DM at baseline in patients with cirrhosis was associated with an increased risk of SBP, which may represent an increased susceptibility to infections. On the other hand, DM was not clearly associated with increased mortality in these patients.

Effects of intervention with sulindac and inulin/VSL#3 on mucosal and luminal factors in the pouch of patients with familial adenomatous polyposis.

BACKGROUND/AIM: In order to define future chemoprevention strategies for adenomas or carcinomas in the pouch of patients with familial adenomatous polyposis (FAP), a 4-weeks intervention with (1) sulindac, (2) inulin/VSL#3, and (3) sulindac/inulin/VSL#3 was performed on 17 patients with FAP in a single center intervention study. Primary endpoints were the risk parameters cell proliferation and glutathione S-transferase (GST) detoxification capacity in the pouch mucosa; secondary endpoints were the short chain fatty acid (SCFA) contents, pH, and cytotoxicity of fecal water. METHODS: Before the start and at the end of each 4-week intervention period, six biopsies of the pouch were taken and feces was collected during 24 h. Cell proliferation and GST enzyme activity was assessed in the biopsies and pH, SCFA contents, and cytotoxicity were assessed in the fecal water fraction. The three interventions (sulindac, inulin/VSL#3, sulindac/inulin/VSL#3) were compared with the Mann-Whitney U test. RESULTS: Cell proliferation was lower after sulindac or VSL#3/inulin, the combination treatment with sulindac/inulin/VSL#3 showed the opposite. GST enzyme activity was increased after sulindac or VSL#3/inulin, the combination treatment showed the opposite effect. However, no significance was reached in all these measures. Cytotoxicity, pH, and SCFA content of fecal water showed no differences at all among the three treatment groups. CONCLUSION: Our study revealed non-significant decreased cell proliferation and increased detoxification capacity after treatment with sulindac or VSL#3/inulin; however, combining both regimens did not show an additional effect.

Risk of developing adenomas and carcinomas in the ileal pouch in patients with familial adenomatous polyposis.

BACKGROUND & AIMS: At present, more than half of patients with familial adenomatous polyposis (FAP) are treated with a proctocolectomy and an ileal pouch-anal anastomosis (IPAA). Originally it was thought that this procedure would eliminate the risk of developing rectal cancer. However, an increasing number of studies reported development of adenoma and carcinoma in the pouch. The aim of this study was to evaluate the long-term risk of developing adenomas and carcinomas in the pouch in a large cohort of Dutch FAP patients. METHODS: A total of 254 patients with FAP who underwent an IPAA were selected from the Dutch Polyposis Registry. The results of the surveillance examinations and the pathology reports were analyzed. Surveillance with chromoendoscopy was offered to a subgroup of patients. RESULTS: Full information on follow-up was available in 212 (84%) patients. These patients (56% male) underwent a total of 761 endoscopies. The mean follow-up was 7.9 years (range, 0.4-20.3 years). The cumulative risk of developing an adenoma in the pouch at 10-year follow-up was 45%. Twenty-five patients (11.8%) developed an adenoma with advanced pathology, and 4 (1.9%) developed a carcinoma. The cumulative risk of developing a pouch carcinoma at 10-year follow-up was 1%. A very high prevalence (75.7%) of adenomas was found in a subgroup of patients who were examined with chromoendoscopy. CONCLUSIONS: This study demonstrated that although the risk of developing adenomas in the pouch after an IPAA is high, the risk of malignant degeneration appears to be low. The use of chromoendoscopy improves the detection of small adenomas.

Low detoxification capacity in the ileal pouch mucosa of patients with ulcerative colitis.

BACKGROUND: An ileal pouch-anal anastomosis has become the most widely accepted procedure for surgical treatment of patients with ulcerative colitis (UC). The primary function of the ileum within the pouch changes from absorption to storage. Malignancies have been described in the pouch mucosa. The detoxifying glutathione S-transferase (GST) enzymes are involved in the mucosal protection against toxins and carcinogens. Levels of GSTs are much higher in the ileum as compared with the colon. The adaptation of the ileal pouch mucosa into a more colon-like phenotype possibly influences the activity and levels of GST. This study compares the detoxification capacity of GST of the afferent ileal limb mucosa with the ileal pouch mucosa of patients with UC. METHODS: Biopsies from normal-appearing mucosa from the ileal pouch and the ileal afferent limb were obtained from 18 patients with UC. GST isoforms were quantified by immunoblotting. GST activity was measured spectrophotometrically, and glutathione and cysteine levels were determined by high-performance liquid chromatography. RESULTS: The GST activity and GSTA1+A2 levels were significantly lower in the pouch compared with the afferent ileal limb of patients with UC, whereas the GSTP1 levels were higher in the pouch. No differences were observed in the levels of GSTM1, GSTT1, glutathione, or cysteine. CONCLUSIONS: The lower GST detoxification activity in the pouch mucosa of patients with UC may result in higher levels of toxins and carcinogens and thus partly contribute to the risk of developing malignancies in the pouch.

A Specifically Designed Stent for Anastomotic Leaks after Bariatric Surgery: Experiences in a Tertiary Referral Hospital.

BACKGROUND: The management of anastomotic leakage after either laparoscopic Roux-en-Y gastric bypass (LGBP) or laparoscopic sleeve gastrectomy (LSG) remains a burden. Various options are available for the treatment of these leaks. A newer and less invasive option for the treatment of leaks is the use of endoluminal stents. The main drawback for this treatment is stent migration. The current study describes the outcome of a new, specifically designed stent for the treatment of anastomotic leaks after bariatric surgery. METHODS: For this retrospective observational study, the medical charts of patients undergoing bariatric surgery between October 1, 2010 and July 1, 2013 were reviewed. All patients with anastomotic leakage, treated with the bariatric Hanarostent, were included. RESULTS: Twelve patients were included out of a total of 1702 bariatric patients in the described period. Seven had a leakage after LSG, five after LGBP. An average of 2.4 endoscopic procedures and 1.25 stents were used per patient. Successful treatment was seen in nine out of 12 patients (75 %). Most common complication was dislocation or migration of the stent, occurring in eight patients (66.7 %). CONCLUSIONS: The ECBB Hanarostent®, which was specifically designed for post bariatric leakages, shows equal but not favorable success rates in this small series compared to previous reports on other types of stenting techniques. Despite the stent design, the complication rate is not reduced and the main future goal should be to target the high stent migration rate.

Antibacterial gauzes are effective in preventing infections after percutaneous endoscopic gastrostomy placement: a retrospective analysis.

OBJECTIVES: The most common complication after percutaneous endoscopic gastrostomy (PEG) placement is peristomal wound infection (up to 40% without antibiotic prophylaxis). Single-dose parenteral prophylactic antibiotics as advised by current guidelines decrease the infection rate to 9-15%. We assume a prolonged effect of local antibiotic treatment with antibacterial gauzes. This study is the first to describe the effect of antibacterial gauzes in preventing infections in PEG without the use of antibiotics. METHODS: A retrospective data analysis was carried out of all patients with PEG insertion between January 2009 and October 2014 in the Catharina Hospital Eindhoven. Data include placement and the period of the first 2 weeks after PEG placement, and long-term follow-up. All patients received a locally applied antibacterial gauze polyhexamethylene biguanide immediately following PEG insertion for 3 days. No other antibiotics were administered. The main outcomes were wound infection, peritonitis, and necrotizing fasciitis; secondary outcomes included other complications. RESULTS: A total of 331 patients with only antibacterial gauzes were analyzed. The total number of infections 2 weeks after PEG insertion was 9.4%, including 8.2% minor and 1.2% major infections (peritonitis). No wound infection-related mortality or bacterial resistance was found. Costs are five times lower than antibiotics, and gauzes are more practical and patient friendly for use. CONCLUSION: Retrospectively, antibacterial gauzes are at least comparable with literature data on parenteral antibiotics in preventing peristomal wound infection after PEG placement, with an infection rate of 9.4%. Rates of other complications found in this study were comparable with current literature data.

Adherence to ribavirin in chronic hepatitis C patients on antiviral treatment: Results from a randomized controlled trial using real-time medication monitoring.

BACKGROUND AND OBJECTIVE: Adherence is essential in antiviral therapy for chronic hepatitis C. We investigated the effect of real-time medication monitoring on adherence to ribavirin. METHODS: In this randomized controlled trial, patients in the intervention group received a medication dispenser that monitored ribavirin intake real-time during 24 weeks PEG-interferon/ribavirin±boceprevir or telaprevir. Patients in the control group received standard-of-care. Adherence was also measured by pill count. RESULTS: Seventy-two patients were assigned to either intervention (n=35) or control groups (n=37). Median adherence by pill count was 96% (range: 43%-100%) with 30 (94%) of patients exhibiting≥80% adherence. Perfect adherence (i.e. 100%) was similar in intervention and control groups: 22 (85%) vs. 15 (75%) (P=0.47). Adherences by real-time medication monitoring and by pill count did not correlate (R=0.19, P=0.36). No predictors of poor adherence could be identified. Ribavirin trough levels after 8 weeks (median: 2.4 vs. 2.7mg/L, P=0.30) and 24 weeks (median: 3.0 vs. 3.0mg/L, P=0.69), and virological responses did not differ between intervention and control groups. CONCLUSIONS: Adherence to ribavirin during PEG-interferon containing therapy in chronic hepatitis C is high. Real-time medication monitoring did not influence adherence to ribavirin, plasma ribavirin levels or virological responses.

Limited Generalizability of Registration Trials in Hepatitis C: A Nationwide Cohort Study.

BACKGROUND: Approval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness and safety of real world hepatitis C patients eligible and ineligible for registration trials. METHODS: We performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes. RESULTS: In this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45-2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used. CONCLUSIONS: Nearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.

[CT colonography as first-line diagnostic procedure in patients with bowel symptoms]. / CT-colografie als eerstelijnsdiagnosticum bij patiënten met darmklachten.

OBJECTIVE: To investigate in how many patients with bowel or abdominal complaints, referred by the primary care physician (PCP) for exclusion of colorectal carcinoma (CRC), the more invasive colonoscopy could be avoided on the basis of the findings of CT colonography. DESIGN: Retrospective, descriptive. METHODS: All consecutive patients who underwent CT colonography in our centre on the request of their PCP from December 2006 to June 2009 were included. Demographic and referral data were collected. CT colonography results were described according to the 'CT Colonography Reporting and Data System'. We also investigated how many patients had to undergo colonoscopy in the 6 months following CT colonography. RESULTS: 398 patients (154 men and 244 women) with a median age of 61 years (range: 22-91) were included. Follow-up colonoscopy was indicated by CT colonography in 30 patients (7.5%) for suspected colorectal carcinoma, polyps > 10 mm, or 3 or more polyps 6-9 mm in size. In 33 patients (8.3%) follow-up colonoscopy or CT colonography was indicated for 1 or 2 polyps 6-9 mm in size, or suspicious lesions. 11 of these patients (2.8%) underwent colonoscopy. In 335 patients (84.2%) polyps > 6 mm or malignancies could be excluded. 18 of these patients (4.5%) still had a colonoscopy. In total, colonoscopy was spared in 341 patients (85.7%). Significant or potentially significant extra-colonic pathological abnormalities were found in 63 patients (15.8%). CONCLUSION: Our results support the theory that in the vast majority of patients with low or moderate suspicion of CRC referred by their PCP, invasive colonoscopy could be avoided, because CRC and polyps could be excluded by CT colonography. CT colonography could be a valuable additional diagnostic tool in primary care.

Folic acid and vitamin B-12 supplementation does not favorably influence uracil incorporation and promoter methylation in rectal mucosa DNA of subjects with previous colorectal adenomas.

Adequate folate availability is necessary to sustain normal DNA synthesis and normal patterns of DNA methylation and these features of DNA can be modified by methylenetetrahydrofolate reductase (MTHFR) C677T genotype. This study investigated the effect of MTHFR C677T genotype and daily supplementation with 5 mg folic acid and 1.25 mg vitamin B-12 on uracil misincorporation into DNA and promoter methylation. Subjects (n = 86) with a history of colorectal adenoma and MTHFR CC or TT genotype were randomly assigned to receive folic acid plus vitamin B-12 or placebo for 6 mo. Uracil misincorporation and promoter methylation of 6 tumor suppressor and DNA repair genes were assessed in DNA from rectal biopsies at baseline and after the intervention. The biomarkers did not differ between the treated group and the placebo group after 6 mo compared with baseline. The uracil concentration of DNA increased in the treated group (5.37 fmol/microg DNA, P = 0.02), whereas it did not change in the placebo group (P = 0.42). The change from baseline of 4.01 fmol uracil/microg DNA tended to differ between the groups (P = 0.16). An increase in promoter methylation tended to occur more often in the intervention group than in the placebo group (OR = 1.67; P = 0.08). This study suggests that supplementation with high doses of folic acid and vitamin B-12 may not favorably influence uracil incorporation and promoter methylation in subjects with previous colorectal adenomas. Because such alterations may potentially increase the risk of neoplastic transformation, more research is needed to fully define the consequences of these molecular alterations.

Ability of FDG-PET to detect all cancers in patients with familial adenomatous polyposis, and impact on clinical management.

PURPOSE: Familial adenomatous polyposis (FAP) is characterised by colonic and duodenal adenomatous polyps that carry a risk of malignant transformation. Malignant degeneration of duodenal adenomas is difficult to detect. We speculated that 2-((18)F)-fluoro-2-deoxy-D: -glucose positron emission tomography (FDG-PET) might be able to detect early duodenal cancer in FAP. Accordingly, we investigated the role of FDG-PET in the management of FAP patients. METHODS: FDG-PET was performed in 24 FAP patients. Eight had advanced duodenal adenomas (Spigelman IV), including two patients with duodenal cancer. Scans were defined as positive on the basis of focal FDG accumulation. RESULTS: Pathological FDG accumulation was absent in 19 of 24 patients. All six patients with Spigelman IV duodenal adenomas (without cancer) were negative; two of these underwent a duodenectomy and pathological examination did not reveal duodenal cancer. In five patients, FDG-PET revealed significant uptake, in the duodenum (2), lower abdomen (1), lung (1) and multiple sites in the abdomen (1). These hot spots correlated with duodenal cancer (2), abdominal metastasis (1) and sclerosing haemangioma of the lung (1). We failed to make a histopathological diagnosis in the single patient with multiple intra-abdominal sites of FDG uptake. None of the patients from the FDG-PET-negative group developed cancer during follow-up (mean 2.8 years). CONCLUSION: FDG-PET detected all the cancers present, and none of the patients with negative FDG-PET developed cancer. This suggests that positive FDG-PET in FAP patients should lead to further examinations to rule out cancer. In patients with negative FDG-PET a more conservative approach seems justified.