Granulocyte and monocyte apheresis (GMA) has shown therapeutic efficacy in active ulcerative colitis (UC). We thought that in patients with pouchitis after proctocolectomy for UC, GMA might produce immunological effects in the intestinal mucosa, and improve clinical symptoms. This prospective study was to evaluate the efficacy of GMA for antibiotic-refractory pouchitis after proctocolectomy for UC.
A total of 13 patients with pouchitis disease activity index (PDAI) > 7 unresponsive to 2 weeks of antibiotic therapy were included. All patients received 10 GMA sessions at 2 sessions/week over 5 consecutive weeks. The primary endpoints were response (a decrease of >=3 points in the PDAI) and remission (PDAI < 4). Secondary endpoints included reduction of white blood cells (WBCs), C-reactive protein (CRP), faecal markers (calprotectin and lactoferrin), reduction of the PDAI endoscopic subscore, and GMA safety.
The median PDAI score was significantly decreased from 11 (range, 9–15) at entry to 9 (range, 6–13) after the GMA therapy (p = 0.02). A total of six patients (46%) responded to the treatment, but none achieved remission. The median endoscopic subscore (maximum: 6) was 5 (range, 4–6) at entry and 5 (range, 1–6) after the treatment (p = 0.10). None of the laboratory markers (WBCs, CRP, faecal calprotectin and lactoferrin) significantly changed during the treatment. Transient adverse events (AEs) were observed in two patients (15%), dyspnoea in one and headache in one. The AEs were not serious, and all patients completed the 10 GMA sessions.
GMA has a good safety profile, but its efficacy appears to be limited in the management of chronic refractory pouchitis. However, a large controlled study should be conducted to evaluate the efficacy of GMA therapy in patients with pouchitis at an earlier clinical stage, before the disease has become refractory to conventional medical therapy.
Colon capsule endoscopy (CCE) is a procedure in which capsule swallowing facilitates observation of the lumen of the entire digestive tract. It does not require an air supply, and is a noninvasive procedure with a markedly low risk of adverse events in comparison with conventional colonoscopy (CS). It reduces patient stress, and may be acceptable to patients. A limitation of this procedure is that the entire colon observation rate (CCE excretion rate, completed CCE rate) is not 100%. In this study, we prospectively investigated clinical factors important to achieve observation of the entire colon on CCE.
The participants were 70 patients for whom CCE was scheduled, and from whom written informed consent regarding participation in this study was obtained. We selected patient background/examination factors, and analyzed all factors involved in observation of the entire colon and factors for completion of the CCE within 4 h after the start of examination using multivariate analysis.
Of the 70 enrolled patients, 64 were analyzed, excluding 6. On multiple logistic analysis, only a water intake of >=12.0 ml/min during examination [p = 0.025, odds ratio (OR): 46.753, 95% confidence interval (CI): 1.630–1341.248] was identified as an independent predictive factor involved in observation of the entire colon. With respect to factors involved in the completion of CCE within 4 h, multiple logistic analysis showed that a body mass index (BMI) of >=25 (p = 0.039, OR: 13.723, 95% CI: 1.135–165.913), the absence of constipation (p = 0.030, OR: 13.988, 95% CI: 1.287–152.047), and a water intake of >=12.0 ml/min during examination (p = 0.004, OR: 12.028, 95% CI: 2.225–65.029) were independent predictive factors.
Completion of a CCE was most closely related to water intake per hour. In addition to water intake, CCE-promoting factors included a high BMI and the absence of constipation.
Bile duct stones after hepaticojejunostomy are considered a troublesome adverse event. Although percutaneous transhepatic procedures using a cholangioscopy is performed to treat these bile duct stones, a peroral endoscopic procedure using a short, double-balloon enteroscope (sDBE) is an alternative. This study aimed to compare the immediate and long-term outcomes of both treatments for bile duct stones in patients who underwent prior hepaticojejunostomy.
Between October 2001 and May 2013, 40 consecutive patients were treated for bile duct stones after hepaticojejunostomy at a tertiary care hospital. Initial success with biliary access, biliary intervention-related technical success, clinical success, adverse events, hospitalization duration, and stone-free survival were retrospectively evaluated.
The initial success rates for biliary access were 100% (8/8) with percutaneous transhepatic cholangioscopy (PTCS) and 91% (29/32) with sDBE. In three patients in whom biliary access during initial sDBE failed, successful access with subsequent PTCS was achieved, and biliary intervention-related technical success and clinical success were eventually achieved in all 40 patients. The rate of adverse events was significantly lower with sDBE than with PTCS (10% versus 45%; p = 0.025). The median hospitalization duration for complete stone clearance was significantly shorter with sDBE than with PTCS (10 versus 35 days; p < 0.001). During the median 7.2 year or 3.1 year follow up, the probabilities of being stone-free at 1, 2, and 3 years were 100%, 73%, and 64% for PTCS and 85%, 65%, and 59% for sDBE, respectively (p = 0.919).
sDBE was useful, with few adverse events and short hospitalization; therefore, experienced endoscopists can consider it as first-line treatment for bile duct stones in patients with prior hepaticojejunostomy.
Transjugular intrahepatic portosystemic shunt (TIPS) is a standard treatment option for the management of portal hypertension in liver cirrhosis. Since the introduction of covered stents, shunt patency has been greatly improved. However, it remains uncertain about whether covered stents could improve survival. A meta-analysis of randomized controlled trials has been performed to compare the outcomes of covered versus bare stents for TIPS.
PubMed, EMBASE, and Cochrane Library databases were searched to identify the relevant randomized controlled trials. Overall survival, shunt patency, and hepatic encephalopathy were the major endpoints. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Heterogeneity was calculated. Cochrane risk of bias tool was employed.
Overall, 119 papers were identified. Among them, four randomized controlled trials were eligible. Viatorr covered stents alone, Fluency covered stents alone, and Viatorr plus Fluency covered stents were employed in one, two, and one randomized controlled trials, respectively. Risk of bias was relatively low. Meta-analyses demonstrated that the covered-stents group had significantly higher probabilities of overall survival (HR = 0.67, 95% CI = 0.50–0.90, p = 0.008) and shunt patency (HR = 0.42, 95% CI = 0.29–0.62, p < 0.0001) than the bare-stents group. Additionally, the covered-stents group might have a lower risk of hepatic encephalopathy than the bare-stents group (HR = 0.70, 95% CI = 0.49–1.00, p = 0.05). The heterogeneity among studies was not statistically significant in the meta-analyses.
Compared with bare stents, covered stents for TIPS may improve the overall survival. In the era of covered stents, the indications for TIPS may be further expanded.
Although endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) with transmural stenting has increased for biliary decompression in patients with an inaccessible papilla, the optimal biliary access point and the learning curve of EUS-HGS have not been studied. We evaluated the optimal biliary access point and learning curve for technically successful EUS-HGS.
129 consecutive patients (male n = 81, 62.3%; malignant n = 113, 87.6%) who underwent EUS-HGS due to an inaccessible papilla were enrolled. EUS finding and procedure times according to each needle puncture attempt in EUS-HGS were prospectively measured. Learning curves of EUS-HGS were calculated for two main outcome measurements (procedure time and adverse events) by using the moving average method and cumulative sum (CUSUM) analysis, respectively.
A total of 174 EUS-HGS attempts were performed in 129 patients. The mean number of needle punctures was 1.35 ± 0.57. Using the logistic regression model, bile duct diameter of the puncture site <= 5 mm [odds ratio (OR) 3.7, 95% confidence interval (CI): 1.71–8.1, p < 0.01] and hepatic portion length [linear distance from the mural wall to the punctured bile duct wall on EUS; mean hepatic portion length was 27 mm (range 10–47 mm)] > 3 cm (OR 5.7, 95% CI: 2.7–12, p < 0.01) were associated with low technical success. Procedure time and adverse events were shorter after 24 cases, and stabilized at 33 cases of EUS-HGS, respectively.
Our data suggest that a bile duct diameter > 5 mm and hepatic portion length 1 cm to <= 3 cm on EUS may be suitable for successful EUS-HGS. In our learning curve analysis, over 33 cases might be required to achieve the plateau phase for successful EUS-HGS.
Some chronic hepatitis C virus (HCV), genotype 1 infected patients treated with direct antiviral agents (DAAs) remain viremic at end of treatment (EOT+), yet go on to achieve sustained virological response 12 weeks after completion of therapy (SVR12). The incidence of EOT+/SVR in patients with genotype 1 and other genotypes, as well as whether such patients achieve SVR24 remain in question. The aims of this study were to evaluate the frequency and durability of EOT+/SVR12&24 and other response categories in HCV genotype 1, 2, or 3 infected patients treated with DAA in clinical practice.
Data from patients treated with all oral sofosbuvir-based regimens at a university hepatology practice by 1 July 2015 were reviewed retrospectively. Responses were categorized based on virus levels during and post DAA treatment. HCV RNA levels were measured by Abbott RealTime HCV (ART) or by Roche CobasTaqMan v2.0 (RCTM) assays.
The study population included 89 patients. Participants were 62% genotype 1, 19% genotype 2 and 19% genotype 3, 54% cirrhotic and 46% treatment-experienced. A total of 45 received sofosbuvir–simeprevir, 38 sofosbuvir–ribavirin and 6 sofosbuvir–ledipasvir. The SVR12 rate was 82%. A total of 5 patients (6%), all with genotype 1, had EOT+ by ART assay and each achieved SVR12&24.
A total of 9% of genotype 1 patients (6% overall) treated with DAAs were EOT+ by ART and all EOT+ cases achieved SVR24. EOT+/SVR was not observed with genotype 2 or 3 or by the RCTM assay. In patients treated with DAAs, EOT+ by the ART assay does not indicate treatment failure.
Interferon-free regimens combine different second-wave direct-acting antiviral agents (DAAs), which target the main viral proteins involved in the replication cycle of hepatitis C virus (HCV): NS3/4A protease inhibitors (simeprevir or paritaprevir boosted by ritonavir), NS5B nucleos(t)idic (sofosbuvir) and nonnucleos(t)idic (dasabuvir) polymerase inhibitors, NS5A replication complex inhibitors (daclatasvir, ledipasvir, elbasvir, velpatasvir). Combinations of two or three DAAs, given for 8–24 weeks reach sustained virology response (SVR) rates greater than 90% with good tolerance. SVR rates and safety are similar in clinical trials and in real life, usually higher than 95% in the per-protocol analysis. Next-generation DAAs are now expected. To be competitive, these new combinations need to prove their added value regarding the pill burden, the reduced duration of treatment, the drug–drug interaction profile and safety. Zepatier is a fixed-dose combination product coformulating MK-5172 [grazoprevir (GZR), 100 mg QD] and MK-8742 [elbasvir or (EBR) 50 mg QD]: it combines highly potent inhibitors of the HCV NS3/4A protease and NS5A replication complex, respectively. This review provides a summary of the main evidence available for the use of GZR/EBR and highlights the strength of this combination.
We determined the feasibility of, and tissue response to silicone-covered biodegradable magnesium- and plastic-stent insertion into the esophagus in rabbits.
The mechanical compression–recovery characteristics and degradation behaviors of the magnesium stent were investigated in vitro. A total of 45 rabbits were randomly divided into a magnesium- (n = 15) and a plastic- (n = 15) stent group, and underwent stent insertion into the lower third of the esophagus under fluoroscopic guidance; a control group (n = 15) did not undergo the intervention. Esophagography was performed at 1, 2, and 4 weeks. Five rabbits in each group were euthanized at each time point for histological examination.
Silicone-covered magnesium stents showed similar radial force to plastic stents (p > 0.05). The magnesium stents degraded rapidly in an acidic solution, but 90.2% ± 3.1% of the residual mass was maintained after a 2-week degradation in a solution with a pH of 4.0. All stent insertions were well tolerated. Magnesium stents migrated in six rabbits (one at 1 week, one at 2 weeks and four at 4 weeks), and plastic stents migrated in three rabbits (one at 2 weeks and two at 4 weeks; p > 0.05). Esophageal wall remodeling (thinner epithelial and smooth muscle layers) was similar in both stented groups (p > 0.05), and the esophagus wall was found to be significantly thinner in the stented groups than in the control group (p < 0.05). Esophageal injury and collagen deposition following stent insertion were similar and did not differ from the control group (p > 0.05).
Esophageal silicone-covered magnesium stents provided reliable support for at least 2 weeks, with acceptable migration rates and without causing severe injury or tissue reaction compared with plastic stents.
The pharmacokinetics and pharmacodynamics of a novel orally disintegrating tablet (ODT) formulation of delayed-release dexlansoprazole 30 mg was evaluated versus the dexlansoprazole 30 mg capsule in this phase I, open-label, multiple-dose, randomized, two-period crossover study.
Healthy adults received daily doses of 30 mg dexlansoprazole ODT or 30 mg dexlansoprazole delayed-release capsule for 5 days during two treatment periods, separated by a 7-day washout interval. Blood samples for dexlansoprazole plasma concentrations and intragastric pH measurements were collected through 24 hours postdose on days 1 and 5 of each period.
Bioequivalence between the 30 mg ODT and 30 mg capsule dosage forms was demonstrated by the primary endpoints of dexlansoprazole peak concentration (Cmax) and systemic exposure (AUC) values contained within the prespecified 90% confidence interval (CI) range of 0.80–1.25. Additional primary endpoints of intragastric mean pH values and percentage of time with pH > 4 over the 24-hour postdose interval were equivalent for dexlansoprazole ODT and dexlansoprazole capsule. Treatment-emergent adverse events were reported in 23% and 28% of participants receiving the ODT and capsule formulations, respectively. Headache was the most common adverse event in both treatment regimens (5.8% with ODT and 6.0% with capsule).
Administration of dexlansoprazole 30 mg ODT or 30 mg capsule provided equivalent plasma exposure when either was administered as a single dose or as once daily doses for 5 days. Pharmacodynamic equivalence between the two formulations was demonstrated by similar intragastric pH parameters on both day 1 and day 5. No effect of day on dexlansoprazole pharmacokinetics was observed. Dexlansoprazole ODT and dexlansoprazole capsule were both well tolerated.
Assessment of intestinal activity and severity of Crohn’s disease (CD) is crucial to guide treatment. In this study, we aimed to investigate the accuracy of spectral computed tomography (CT) in this assessment and make a comparison with conventional CT.
A total of 50 patients with ileocolonic CD underwent spectral CT scanning. Conventional CT and spectral CT images were reconstructed. Endoscopic lesions were classified as absent, mild lesions and severe lesions. Qualitative and quantitative findings in CT images were compared in these segments. Logistic regressions were established, based on conventional and spectral CT parameters, to predict intestinal activity and severity. Comparisons were made by receiver operating characteristic (ROC) curve.
The results showed that bowel wall hyperenhancement, ulcers on CT images, comb sign, bowel wall thickness, normalized iodine concentration (NIC) and slope of HU curve (HU) increased significantly (p < 0.01) with endoscopic severity. In predicting intestinal activity, spectral CT demonstrated higher accuracy (99.6% versus 94.7%), sensitivity (99.1% versus 93.4%) and specificity (99.9% versus 94.4%) than conventional CT. In predicting intestinal severity, spectral CT also had higher accuracy (96.5% versus 91.9%), sensitivity (96.5% versus 92.1%) and specificity (95.8% versus 89.8%) than conventional CT. Besides, both NIC and HU correlated significantly with Simple Endoscopic Score for CD (r = 0.833 and r = 0.771; both p < 0.001), but their correlations with C-reactive protein (r = 0.578 and r = 0.513; both p < 0.01) and Harvey–Bradshaw Index (r = 0.545 and r = 0.522; both p < 0.01) were moderate.
Compared with conventional CT, spectral CT had higher accuracy in detecting intestinal activity and severity of CD, which could be an alternative choice in evaluation of CD.
Dual delayed-release dexlansoprazole is approved for use in adults as a 30 mg orally disintegrating tablet (ODT) or as 30 mg and 60 mg capsules. The pharmacokinetics, pharmacodynamics, and safety profile of two dexlansoprazole 30 mg ODTs were compared with one dexlansoprazole 60 mg capsule in this randomized, phase I, open-label, single-center, multiple-dose, two-period crossover study.
Participants were randomized in one of two treatment sequences, each comprised two 5-day treatment periods during which two dexlansoprazole 30 mg ODTs or one 60 mg capsule was administered once daily. Pharmacokinetic parameters and the mean intragastric pH profile for the 24-hour period after dosing on days 1 and 5 were described. Adverse events were monitored during study duration and followed up with a phone call 5–10 days after the last dose of study drug.
On day 1, peak observed plasma concentration (Cmax) values were similar between two 30 mg ODTs (1047 ng/ml) and one 60 mg capsule (1164 ng/ml). Systemic exposure, measured by the area under the plasma concentration–time curve (AUC), was approximately 25% lower after ODT administration. On day 5, mean pH after daily doses of two 30 mg ODT or one 60 mg capsule was 4.33 and 4.36, respectively; both regimens maintained intragastric pH above 4.0 for 60% of the 24-hour period. Headache was the most commonly reported adverse event (observed in 19.2% of participants); no adverse events leading to study withdrawal occurred.
While systemic exposure (AUC) was 25% lower with ODT, peak concentrations (Cmax) after administration of two dexlansoprazole 30 mg ODTs and one 60 mg capsule were similar. The 24-hour intragastric pH control after administration of two dexlansoprazole 30 mg ODTs was equivalent to one dexlansoprazole 60 mg capsule. Both ODT and capsule were well tolerated.
Ornithine phenylacetate (OP) has been proven effective in lowering ammonia plasma levels in animals, and to be well tolerated in cirrhotic patients. A trial to assess OP efficacy in lowering plasma ammonia levels versus placebo in cirrhotic patients after an upper gastrointestinal bleeding was performed. The primary outcome was a decrease in venous plasma ammonia at 24 hours.
A total of 38 consecutive cirrhotic patients were enrolled within 24 hours of an upper gastrointestinal bleed. Patients were randomized (1:1) to receive OP (10 g/day) or glucosaline for 5 days.
The primary outcome was not achieved. A progressive decrease in ammonia was observed in both groups, being slightly greater in the OP group, with significant differences only at 120 hours. The subanalysis according to Child–Pugh score showed a statistically significant ammonia decrease in Child–Pugh C-treated patients at 36 hours, as well as in the time-normalized area under the curve (TN-AUC) 0–120 hours in the OP group [40.16 μmol/l (37.7–42.6); median (interquartile range) (IQR)] versus placebo group [65.5 μmol/l (54–126);p = 0.036]. A decrease in plasma glutamine levels was observed in the treated group compared with the placebo group, and was associated with the appearance of phenylacetylglutamine in urine. Adverse-event frequency was similar in both groups. No differences in hepatic encephalopathy incidence were observed.
OP failed to significantly decrease plasma ammonia at the given doses (10 g/day). Higher doses of OP might be required in Child–Pugh A and B patients. OP appeared well tolerated.
There is scant information on the accuracy of different assays used to measure anti-infliximab antibodies (ADAs), especially in the presence of detectable infliximab (IFX). We thus aimed to evaluate and compare three different assays for the detection of IFX and ADAs and to clarify the impact of the presence of circulating IFX on the accuracy of the ADA assays.
Blood samples from 79 ulcerative colitis (UC) patients treated with infliximab were assessed for IFX levels and ADAs using three different assays: an in-house assay and two commercial kits, Immundiagnostik and Theradiag. Sera samples with ADAs and undetectable levels of IFX were spiked with exogenous IFX and analyzed for ADAs.
The three assays showed 81–96% agreement for the measured IFX level. However, the in-house assay and Immundiagnostik assays detected ADAs in 34 out of 79 samples, whereas Theradiag only detected ADAs in 24 samples. Samples negative for ADAs with Theradiag, but ADA-positive in both the in-house and Immundiagnostik assays, were positive for IFX or IgG4 ADAs. In spiking experiments, a low concentration of exogenous IFX (5 µg/ml) hampered ADA detection with Theradiag in sera samples with ADA levels of between 3 and 10 µg/ml. In the Immundiagnostik assay detection interference was only observed at concentrations of exogenous IFX higher than 30 µg/ml. However, in samples with high levels of ADAs (>25 µg/ml) interference was only observed at IFX concentrations higher than 100 µg/ml in all three assays. Binary (IFX/ADA) stratification of the results showed that IFX+/ADA- and IFX-/ADAs+ were less influenced by the assay results than the double-positive (IFX+/ADAs+) and double-negative (IFX-/ADAs-) combination.
All three methodologies are equally suitable for measuring IFX levels. However, erroneous therapeutic decisions may occur when patients show double-negative (IFX-/ADAs-) or double-positive (IFX+/ADAs+) status, since agreement between assays is significantly lower in these circumstances.
Esophageal cancer remains associated with poor outcomes, yet little is known regarding factors that influence survival. Aspirin use prior to cancer diagnosis may influence outcomes. We aimed to assess the effects of prediagnosis aspirin use in patients with esophageal cancer.
We conducted a prospective cohort study of newly-diagnosed esophageal cancer patients at two tertiary care centers. We assessed history of prediagnosis aspirin use, and prospectively followed patients and assessed mortality, cause of death, and development of metastases.
We enrolled 130 patients, the majority of whom were male (81.5%) and had adenocarcinoma (80.8%). Overall, 57 patients (43.9%) were regular aspirin users. In unadjusted analyses, we found no difference in all-cause mortality between aspirin users and nonusers. In multivariate analyses, prediagnosis aspirin use was not associated with all-cause mortality [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.48–1.57] or esophageal cancer-specific mortality (HR 1.07, 95% CI 0.52–2.21). Prediagnosis aspirin use was associated with a significantly increased risk of interval metastasis (HR 3.59, 95% CI 1.08–11.96).
In our cohort of esophageal cancer patients, prediagnosis aspirin use was not associated with all-cause or cancer-specific mortality. However, risk of interval metastatic disease was increased among those who took aspirin regularly prediagnosis. Future studies are warranted to assess whether aspirin influences the molecular characteristics of esophageal tumors, with potential prognostic and therapeutic implications.
Gastric outlet obstruction (GOO) can occur with locally invasive or metastatic cancer involving the upper gastrointestinal tract at the pylorus or the duodenum. Endoscopic management with self-expanding metal stents (SEMSs) is often the preferred palliative approach. Stent occlusion is a common reason for failure and reintervention. We set out to determine whether the location of the malignant obstruction is associated with the angulation of the stent and can predict stent occlusion.
We performed a retrospective review of consecutive patients who underwent successful duodenal stenting with SEMS for malignant GOO between 2006 and 2015 at a large advanced endoscopy referral center. We determined the location of obstruction, the stent angle, and the rate of technical and clinical success of stent placement. We then identified cases of subsequent stent occlusion confirmed by endoscopic evaluation.
A total of 100 consecutive patients were included in the study; 91 of these patients had enough data to evaluate SEMS occlusion. A total of 21 patients (23%) developed stent occlusion with a median time of 39 days. The risk of occlusion sequentially increased as the obstruction occurred more distally from the antrum to the third or fourth portion of the duodenum (p = 0.006). This relationship was maintained after controlling for stent angle (p = 0.05).
A distal location of malignant GOO was strongly predictive of stent occlusion, independent of stent angle. This may be due to longer and more complex distal obstructions, along with foreshortening of the stent during placement and tumor infiltration. If replicated, these results will have implications for endoscopic practice and future device development.
Magnetic resonance imaging-estimated proton-density-fat-fraction (MRI-PDFF) has been shown to be a noninvasive, accurate and reproducible imaging-based biomarker for assessing steatosis and treatment response in nonalcoholic steatohepatitis (NASH) clinical trials. However, there are no data on the magnitude of MRI-PDFF reduction corresponding to histologic response in the setting of a NASH clinical trial. The aim of this study was to quantitatively compare the magnitude of MRI-PDFF reduction between histologic responders versus histologic nonresponders in NASH patients.
This study is a secondary analysis of the MOZART trial, which included 50 patients with biopsy-proven NASH randomized to ezetimibe 10 mg/day orally or placebo for 24 weeks. The primary aim was to perform a head-to-head comparative analysis of histologic responders [defined as a >=2-point reduction in the nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) without worsening fibrosis] versus nonresponders, and the corresponding quantitative change in liver fat content measured via MRI-PDFF.
Of the 35 patients who underwent paired liver biopsy and MRI-PDFF assessment at the beginning and end of treatment, 10 demonstrated a histologic response. Compared with histologic nonresponders, histologic responders had a statistically significant reduction in MRI-PDFF of –4.1% ± 4.9 versus –0.6 ± 4.1 (p < 0.04) with a mean relative percent change of –29.3% ± 33.0 versus +2.0% ± 24.0 (p < 0.004), respectively.
Utilizing paired MRI-PDFF and liver histology data, we demonstrate that a relative reduction of 29% in liver fat on MRI-PDFF is associated with a histologic response in NASH. After external validation by independent research groups, these results can be incorporated into designing future NASH clinical trials, especially those utilizing change in hepatic fat quantified by MRI-PDFF, as a treatment endpoint.
Patients with rectal cancer who exhibit a pathologic complete response to preoperative concurrent chemoradiotherapy have excellent oncologic outcomes. In this study, we evaluated the potential advantages of adding oxaliplatin to preoperative fluoropyrimidine-based chemoradiotherapy administered in rectal cancer patients.
A total of 78 patients with rectal cancer were enrolled. Patients were administered chemoradiotherapy, which comprised radiotherapy and chemotherapy involving a 5-fluorouracil, leucovorin, and oxaliplatin regimen every 2 weeks. Surgery was performed 10–12 weeks after radiotherapy completion. Tumor regression, adverse events, surgical complications, and short-term clinical outcomes were recorded.
Two patients were excluded because of incomplete radiotherapy treatment or refusal of surgery. Eventually, 76 patients underwent total mesorectal excision and no perioperative mortality was observed. Of these, 20 patients (25.6%) developed grade 3 or 4 toxicity during concurrent chemoradiotherapy. Among the 76 patients who underwent surgery, 24 (31.6%) patients achieved a pathologic complete response. The sphincter preservation rate was 96.1% (73/76) in all patients and 92.2% (39/42) in patients with tumors located less than 5 cm from the anal verge. The 2-year overall and disease-free survivals were 94% and 87.4%, respectively.
The intensified multimodality therapy was well tolerated in our cohort and resulted in a considerably high pathologic complete response rate. Regardless of favorable short-term clinical outcomes, long-term oncologic outcomes will be closely monitored among the patients with a pathologic complete response.
The Over-The-Scope Clip (OTSC®, Ovesco Endoscopy GmbH, Tübingen, Germany) is an innovative clipping device that provides a strong tissue grasp and compression without provoking ischemia or laceration. In this retrospective study we evaluated immediate and long-term success rates of OTSC deployment in various pathologies of the gastrointestinal (GI) tract.
A total of 45 patients (35 female, 10 male) with an average age of 56 years old (range, 24–90 years) were treated with an OTSC for GI defects resulting from a diagnostic or interventional endoscopic procedure (acute setting group) or for fistula following abdominal surgery (chronic setting group). All procedures were performed with CO2 insufflation.
From January 2012 to December 2015 a total of 51 OTSCs were delivered in 45 patients for different kinds of GI defects. Technical success was always achieved in the acute setting group with an excellent clip adherence and a clinical long-term success rate of 100% (15/15). Meanwhile, considering the chronic setting group, technical success was achieved in 50% of patients with a long-term clinical success of 37% (11/30); two minor complications occurred. A total of three patients died due to causes not directly related to clip deployment. Overall clinical success rate was achieved in 58% cases (26/45 patients). A mean follow-up period of 17 months was accomplished (range, 1–36 months).
OTSC deployment is an effective and minimally-invasive procedure for GI defects in acute settings. It avoids emergency surgical repair and it allows, in most cases, completion of the primary endoscopic procedure. OTSC should be incorporated as an essential technique of today’s modern endoscopic armamentarium in the management of GI defects in acute settings. OTSCs were less effective in cases of chronic defects.
Temporary stent placement is widely performed for pancreatic duct stenosis due to chronic pancreatitis. A fully covered self-expandable metal stent (FCSEMS) has a larger diameter, and therefore longer stent patency, and the effect of expansion of the main pancreatic duct stricture may be obtained. However, if stent migration upstream occurs, stent removal is extremely difficult. In addition, because of the diameter gap between the FCSEMS and the main pancreatic duct, stent-induced ductal change may occur. To prevent these adverse events, the technical feasibility, safety and efficacy of the placement of a novel 6 mm diameter FCSEMS with a long suture, to facilitate its removal in cases of stent migration upstream, were evaluated in a pilot study.
Between December 2014 and August 2015, symptomatic chronic pancreatitis patients with abdominal pain and a main pancreatic head duct stricture were enrolled. Stent placement for main pancreatic duct stricture was performed under endoscopic retrograde cholangiopancreatography (ERCP) guidance and stent removal was performed within 6 months.
A total of 13 patients were retrospectively enrolled in this study. Metal stent insertion was successfully performed in all patients and clinical success was high (12/13, 92%). As adverse events, stent migration upstream was seen in two patients. Another 11 patients successfully underwent stent removal without any adverse events. During follow up (median 258 days), 2 patients still underwent pancreatic duct stenting because of continuing main pancreatic duct stricture.
In conclusion, this novel FCSEMS is acceptable for stent placement in cases of chronic pancreatitis with a main pancreatic duct stricture.
The use of proton-pump inhibitors (PPIs) has increased over the last decade. The objective of this study was to provide detailed utilization data on PPI use over time, with special emphasis on duration of PPI use and concomitant use of ulcerogenic drugs.
Using the nationwide Danish Prescription Registry, we identified all Danish adults filling a PPI between 2002 and 2014. Using descriptive statistics, we reported (i) the distribution of use between single PPI entities, (ii) the development in incidence and prevalence of use over time, (iii) measures of duration and intensity of treatment, and (iv) the prevalence of use of ulcerogenic drugs among users of PPIs.
We identified 1,617,614 adults using PPIs during the study period. The prevalence of PPI use increased fourfold during the study period to 7.4% of all Danish adults in 2014. PPI use showed strong age dependency, reaching more than 20% among those aged at least 80 years. The proportion of users maintaining treatment over time increased with increasing age, with less than10% of those aged 18–39 years using PPIs 2 years after their first prescription, compared with about 40% among those aged at least 80 years. The overall use of ulcerogenic drugs among PPI users increased moderately, from 35% of users of PPI in 2002 to 45% in 2014.
The use of PPIs is extensive and increasing rapidly, especially among the elderly.
Video capsule endoscopy (VCE) and magnetic resonance enterography (MRE) are the prime modalities for the evaluation of small bowel (SB) Crohn’s disease (CD). Mucosal inflammation on VCE is quantified using the Lewis score (LS). Diffusion-weighted (DW) magnetic resonance imaging (MRI) allows for accurate assessment of SB inflammation without administration of intravenous contrast material. The Magnetic Resonance Index of Activity (MaRiA) and the Clermont index are quantitative activity indices validated for contrast-enhanced MRE and DW-MRE, respectively. The aim of this study was to compare the quantification of distal SB inflammation by VCE and MR-related activity indices.
Patients with known quiescent SB CD were prospectively recruited and underwent MRE and VCE. LS, MaRIA and Clermont scores were calculated for the distal SB.
Both MRI-based indices significantly correlated with the LS and the Clermont index (r = 0.50, p = 0.001 and r = 0.53, p = 0.001, respectively). Both MaRIA and Clermont scores were significantly lower in patients with mucosal healing (LS < 135). The area under the curve (AUC) with both MR scores was moderate for prediction of any mucosal inflammation (LS >= 135) and excellent for prediction of moderate-to-severe inflammation (LS >= 790) (0.71 and 0.74 versus 0.93 and 0.91 for MaRIA and Clermont score, respectively).
Modest correlation between VCE- and MRE-based quantitative indices of inflammation in patients with quiescent SB CD was observed. Between-modality correlation was higher in patients with endoscopically severe disease. DW-MRE gauged by Clermont score was at least as accurate as contrast-enhanced MRE for quantification of SB inflammation.
Ipilimumab is an anticytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody used for the treatment of malignant melanoma. It can cause immune-mediated inflammatory adverse events, including diarrhoea and even intestinal perforation or death in clinical trials but there is a dearth of data on postmarketing outcomes.
A total of 546 patients attending for treatment of metastatic melanoma between 1 January 2009 and 31 August 2015 were identified by interrogation of the oncology database. A total of 83 of these patients received ipilimumab. Clinical information was extracted from chart reviews, endoscopy and radiology reports, and prescription data.
A total of 83 patients received ipilimumab. Only 19.3% (n = 16) of patients developed a diarrhoeal illness not attributable to other causes. The median grade of diarrhoea among included patients was 2 (range 1–4). In two cases, diarrhoea settled spontaneously without any specific treatment. A total of 87.5% of patients received antidiarrhoeal agents such as loperamide or codeine. These resolved symptoms in all patients with grade 1 diarrhoea. For other treatment, 50% patients received systemic glucocorticosteroids and 31.3% required infliximab. Infliximab resolved symptoms in 100% of cases compared with 50% for systemic glucocorticosteroids.
The rate of diarrhoea related to ipilimumab in real-world practice is substantial, but below the range observed in data from RCTs. Grade 1 colitis can usually be managed symptomatically, without recourse to stopping ipilimumab. When diarrhoea was grade 2 or above, results from glucocorticosteroids use proved disappointing; but infliximab has been shown to work well. Further research is required into the earlier use of infliximab as an effective treatment for ipilimumab-induced diarrhoea.
Dual red imaging (DRI), a novel image-enhanced endoscopic technique, is expected to improve visibility of thin vessels, but no reports of the clinical use of DRI in colorectal endoscopic submucosal dissection (ESD) have been published. We aimed to compare the visibility of vessels, demarcation line between the submucosal and muscle layers after injection of hyaluronate sodium with minute indigo carmine, and fibrosis on DRI with that on white light imaging (WLI). We applied the principle of DRI to the image of the submucosal layer during colorectal ESD as a pilot study.
A total of seven physicians compared 17 DRI images to the corresponding WLI images in colorectal ESD. The physicians compared the number of arteries identified on DRI with the actual number of arteries. The physicians rated the visibility of vessels, the demarcation line between the submucosal and muscle layers after injection of hyaluronate sodium with minute indigo carmine, and fibrosis. Inter-observer agreement was also examined using the kappa statistic.
Visibility of vessels and the demarcation line between the submucosal and muscle layers after injection of hyaluronate sodium with minute indigo carmine improved with the use of DRI compared with that using WLI. DRI can discriminate between arteries and veins clearly through the color of the vessels.
DRI improves the visibility of vessels, especially that of arteries, as they appear orange, and the demarcation line of the muscle layer. DRI may help to make colorectal ESD safer and faster.
It is recommended that ileocolonoscopy is performed within 1 year after resection for Crohn’s disease (CD). Nevertheless, optimal monitoring strategies for recurrence after the ileocolonoscopy remain to be elucidated. This prospective study was to evaluate the value of serial monitoring of faecal calprotectin (FC) after ileocolonoscopy for the assessment of endoscopic recurrence in asymptomatic patients.
Patients in clinical remission who had no endoscopic recurrence at ileocolonoscopy 6–12 months after ileocolonic resection were studied. FC levels were measured every 2 months up to 24 months after the ileocolonoscopy. When the FC level was elevated (>=140 µg/g), a second ileocolonoscopy was immediately undertaken. In contrast, patients who maintained low FC levels (<140 µg/g) during the 24-month follow up underwent a second ileocolonoscopy at the end of the study. Endoscopic recurrence was defined as a Rutgeerts score >=i2.
A total of 30 patients were studied. In eight patients, the FC level was raised during the 24-month follow up. Six of the eight patients (75%) had endoscopic recurrence. Of 22 patients who maintained low FC levels, 20 (91%) had no endoscopic recurrence, whereas two showed endoscopic recurrence at the end of the follow up. The incidence of endoscopic recurrence was significantly higher in patients with elevation of FC levels versus those with maintained low FC levels (75% versus 9%). A cut-off value of 140 µg/g for FC had a sensitivity of 75%, a specificity of 91%, a positive predictive value of 75%, a negative predictive value of 91% and a diagnostic accuracy of 87% to detect endoscopic recurrence.
Consecutive monitoring of FC is useful for the assessment of endoscopic recurrence after the initial ileocolonoscopy. Increased FC levels indicate a need for repeat ileocolonoscopy, while sustained low FC levels predict a low risk of endoscopic recurrence. In patients maintaining low FC levels, unnecessary invasive endoscopic examinations can be avoided.
We have investigated the effects of a multispecies probiotic preparation containing a combination of probiotic bacterial genera that included Bifidobacteria, Lactobacilli and a Streptococcus in a mouse model of high-fat diet or obesity-induced liver steatosis.
Three groups of C57B1/6J mice were fed either a standard chow or a high-fat diet for 20 weeks, while a third group was fed a high-fat diet for 10 weeks and then concomitantly administered probiotics for a further 10 weeks. Serum, liver and large bowel samples were collected for analysis.
The expression of the tight-junction proteins ZO-1 and ZO-2 was reduced (p < 0.05) in high-fat diet-fed mice compared to chow-fed mice. Probiotic supplementation helped to maintain tight ZO-1 and ZO-2 expression compared with the high-fat diet group (p < 0.05), but did not restore ZO-1 or ZO-2 expression compared with chow-fed mice. Mice fed a high-fat diet ± probiotics had significant steatosis development compared with chow-fed mice (p < 0.05); steatosis was less severe in the probiotics group compared with the high-fat diet group. Hepatic triglyceride concentration was higher in mice fed a high-fat diet ± probiotics compared with the chow group (p < 0.05), and was lower in the probiotics group compared with the high-fat diet group (p < 0.05). Compared with chow-fed mice, serum glucose, cholesterol concentration and the activity of alanine transaminase were higher (p < 0.05), whereas serum triglyceride concentration was lower (p < 0.05) in mice fed a high-fat diet ± probiotics.
Supplementation with a multispecies probiotic formulation helped to maintain tight-junction proteins ZO-1 and ZO-2, and reduced hepatic triglyceride concentration compared with a high-fat diet alone.
Minimal hepatic encephalopathy (MHE) has a far-reaching impact on quality and function ability in daily life and may progress to overt hepatic encephalopathy. There is a synergistic effect between systemic oxidative stress and ammonia that is implicated in the pathogenesis of hepatic encephalopathy. The aim of this study is to investigate the effectiveness of oral supplementation of antioxidants and zinc gluconate on MHE versus lactulose.
Our study included 58 patients with cirrhosis diagnosed as having MHE by neuropsychometric tests, including number connection test part A (NCT-A), digit symbol test (DST) and block design tests (BDTs). Patients were randomized to receive 175 mg zinc gluconate, 50,000 IU vitamin A, 500 mg vitamin C and 100 mg vitamin E once daily plus lactulose, dose 30–60 ml/day for 3 months [group A (n = 31)] or initiated and maintained on lactulose dose 30–60 ml/day for 3 months [group B (n = 27)]. Neuropsychometric tests and laboratory investigations were repeated after 3 months of therapy.
Compared with the baseline neuropsychometric tests, a significant improvement was reported in patients with MHE after 3 months of antioxidant and zinc therapy (group A) versus patients with lactulose therapy (group B) (NCT-A, p <0.001; DST, p = 0.006; BDT, p < 0.001). Antioxidant and zinc supplementation significantly decreased arterial ammonia level, alanine aminotransferase (ALT), aspartate aminotransferase (AST) (p < 0.001) and improved Child–Pugh score in MHE after 3 months of therapy (p= 0.024).
Antioxidant and zinc supplementation can improve MHE in patients with liver cirrhosis.
Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that occurs most often in a context of acute or chronic liver disease. Despite the seriousness of the pathology, only a few treatments have been developed for improving its management. Rifaximin-α is the first treatment that has been clinically developed for overt HE (OHE) episodes. Recent results of clinical studies demonstrated its significant improvement in the health-related quality of life. The objective of the current study was to estimate the long-term cost-effectiveness of rifaximin-α used in combination with lactulose compared with lactulose monotherapy in cirrhotic patients, who have experienced at least two prior OHE events.
A Markov model was used to estimate rifaximin-α cost-effectiveness, evaluating it from the perspective of all contributors as recommended by French health technology assessment guidelines. Costs were based on current French treatment practices. The transition between health states was based on the reanalysis of the rifaximin-α pivotal clinical trials RFHE3001 and RFHE3002. The main outcome of the model was cost per quality adjusted life year (QALY).
The results indicate that rifaximin-α is a cost-effective treatment option with an incremental cost per QALY gained of 19,187 and 18,517 over two different time horizons (2 and 5 years). The robustness of the model was studied using probabilistic sensitivity analysis.
For the societal willingness to pay threshold of 27,000 per QALY gained, rifaximin-α in combination with lactulose is a cost-effective and affordable treatment for patients who have experienced at least two prior overt HE episodes.
Interventional endoscopic ultrasound (EUS)-guided procedures such as EUS-guided celiac ganglia neurolysis (EUS-CGN) and EUS-guided broad plexus neurolysis (EUS-BPN) were developed to treat abdominal cancer-associated pain; however, these procedures are not always effective. The aim of this study was to explore predictors of pain response in EUS-guided neurolysis for pancreatic cancer-associated pain.
This was a retrospective analysis of prospectively collected data of 112 consecutive patients who underwent EUS-BPN in our institution. EUS-CGN was added in cases of visible celiac ganglia. The neurolytic-spread area was divided into six sections and evaluated by post-procedural computed tomography scanning. Pain intensity was assessed using a visual analog scale (VAS), and a decrease in VAS scores by >=3 points after neurolysis was considered a good pain response. Univariable and multivariable logistic regression analyses were performed to explore predictors of pain response at 1 and 4 weeks, and complications.
A good pain response was obtained in 77.7% and 67.9% of patients at 1 and 4 weeks, respectively. In the multivariable analysis of these patients, the combination method (EUS-BPN plus CGN) was a significant positive predictive factor at 1 week (odds ratio = 3.69, p = 0.017) and 4 weeks (odds ratio = 6.37, p = 0.043). The numbers of neurolytic/contrast spread areas (mean ± SD) were 4.98 ± 1.08 and 4.15 ± 1.12 in patients treated with the combination method and single method, respectively (p < 0.001). There was no significant predictor of complications.
EUS-BPN in combination with EUS-CGN was a predictor of a good pain response in EUS-guided neurolysis for pancreatic cancer-related pain. The larger number of neurolytic/contrast spread areas may lead to better outcomes in patients receiving combination treatment.
Whether low-dose azathioprine (AZA) is effective in maintaining remission in patients with steroid-dependent ulcerative colitis (UC) remains unclear. We assessed the efficacy and safety of low-dose AZA in a Chinese population with UC.
We identified steroid-dependent UC patients in clinical remission on AZA maintenance therapy from a territory-wide IBD Registry. Standard- and low-dose AZA were defined as at least 2 mg/kg/day and less than 2 mg/kg/day, respectively. Relapse rates were analyzed by Kaplan–Meier analysis and compared using log-rank test.
Among 1226 UC patients, 128 (53% male, median duration on AZA 44 months) were included. Median maintenance AZA dose was 1.3 mg/kg/day. 97.7% of the patients were on concomitant oral 5-aminosalicylic acid. Cumulative relapse-free rates in patients on standard-dose and low-dose AZA were 71.2%, 52.8% and 45.2%, and 71.8%, 55.3% and 46.2% at 12, 24 and 36 months, respectively (p = 0.871). Relapse rate within 12 months was higher in patients who withdrew compared with those who maintained on AZA (52.6% versus 29.4%; p = 0.045). Mean corpuscular volume increased after AZA therapy in both of the low-dose [median (interquartile range, IQR): 88.2 (81.4–92.2) versus 95.1 (90.1–100.9) fl, p < 0.001] and standard-dose subgroups [median (IQR) 86.8 (76.9–89.9) versus 94.7 (85.9–99.7) fl, p < 0.001]. Leukopenia occurred in 21.1% of the patients. Patients on standard dose had a higher risk for leukopenia than those on low-dose AZA [odds ratio (OR) 3.9, 95% CI 1.9–8.2, p < 0.001].
In the Chinese population, low-dose AZA is effective for maintaining remission in steroid-dependent UC patients. Standard-dose AZA was associated with more than threefold increased risk of leukopenia.
There are little data on patient factors that impact diagnosis rates of celiac disease. This study aims to evaluate the association between patient socioeconomic status and the symptoms at diagnosis of celiac disease.
A total of 872 patients with biopsy-proven celiac disease were categorized based on the presence or absence of (1) diarrhea and (2) any gastrointestinal symptoms at diagnosis. Univariate and multivariate analyses were used to assess the association between socioeconomic status and symptoms.
Patients without diarrhea at presentation had a higher mean per capita income (US$34,469 versus US$32,237, p = 0.02), and patients without any gastrointestinal symptoms had a higher mean per capita income (US$36,738 versus US$31,758, p < 0.01) compared with patients having such symptoms. On multivariable analysis adjusting for sex, age, autoimmune or psychiatric comorbidities, and income, per capita income remained a significant predictor of diagnosis without gastrointestinal symptoms (odds ratio: 1.71, 95% confidence interval: 1.17–2.50, p < 0.01), and it showed a trend towards significance in diagnosis without diarrhea (odds ratio: 1.40, 95% confidence interval: 0.98–2.02, p = 0.06).
Patients with nonclassical symptoms of celiac disease are less likely to be diagnosed if they are of lower socioeconomic status. Celiac disease may be under-recognized in this population due to socioeconomic factors that possibly include lower rates of health-seeking behavior and access to healthcare.
Large-volume paracentesis (LVP) can be time and labor intensive depending on the amount of ascites removed and the method of drainage. Wall suction has been adopted as the preferred method of drainage at many centers, though the safety and benefits of this technique have not been formally evaluated. The primary objective of this study was to define the cost and time savings of wall suction over the traditional glass vacuum bottle method for ascites drainage. The secondary objective was to compare the safety profile and patient satisfaction using these two techniques.
We conducted a randomized, controlled pilot study of the wall suction versus vacuum bottle methods for LVP in hospitalized patients. All LVPs were performed under ultrasound guidance by a single proceduralist. Patients with at least 4 liters removed received 25% intravenous albumin, 8 g/liter fluid removed. Demographic, clinical characteristics, and procedure details were recorded. Laboratory and hemodynamic data were recorded for 24 h prior to and 24–48 h post LVP. An electronic chart review was conducted to evaluate procedure-related complications. Data were compared using Fisher’s exact test, t test, or Mann–Whitney U test.
Thirty-four patients were randomized to wall suction at 200 mmHg (n = 17) or glass vacuum bottle drainage (n = 17). Wall suction was significantly faster and less costly than vacuum bottle drainage (7 versus 15 min, p = 0.002; $4.59 versus $12.73, p < 0.001). There were no differences in outcomes at 24 and 48 h post LVP, or at 60-day follow up.
Performing LVP using wall suction resulted in significantly shorter procedure time and supply cost savings. There were no differences in outcomes between the groups, suggesting equivalent safety, though larger studies powered to detect small differences are needed. Given its efficiency, convenience, and cost effectiveness, wall suction may be a superior method of ascites drainage for LVP.
Otilonium bromide (OB) is a spasmolytic compound of the family of quaternary ammonium derivatives and has been successfully used in the treatment of patients with irritable bowel syndrome (IBS) due to its specific pharmacodynamic effects on motility patterns in the human colon and the contractility of colonic smooth muscle cells. This article examines how. OB inhibits the main patterns of human sigmoid motility in vitro, which are spontaneous rhythmic phasic contractions, smooth muscle tone, contractions induced by stimulation of excitatory motor neurons and contractions induced by direct effect of excitatory neurotransmitters. It does this mainly by blocking calcium influx through L-type calcium channels and interfering with mobilization of cellular calcium required for smooth muscle contraction, thereby limiting excessive intestinal contractility and abdominal cramping. OB also inhibits T-type calcium channels and muscarinic responses. Finally, OB inhibits tachykinin receptors on smooth muscle and primary afferent neurons which may have the joint effect of reducing motility and abdominal pain. All these mechanisms mediate the therapeutic effects of OB in patients with IBS and might be useful in patients with other spastic colonic motility disorders such as diverticular disease.
The goal of chronic hepatitis B (CHB) treatment is to improve survival by preventing disease progression to decompensated cirrhosis and hepatocellular carcinoma which is the cause of over 1 million deaths annually. The risk of disease progression is reduced when a sustained reduction of hepatitis B virus (HBV) DNA to undetectable levels and suppression of HBV replication are obtained which can result in regression of liver fibrosis and may even reverse cirrhosis. However, even if HBsAg loss occurs, HBV is not completely eradicated by treatment, and long-term therapy is required in patients who are HBeAg– and HBeAg+ who do not maintain off-treatment virological suppression and in those with advanced liver disease. The recently updated European Association of the Study of the Liver (EASL) clinical practical guidelines for HBV have clarified, first, how to treat HBV (interferon or the most potent oral drugs with optimal resistance profiles, i.e. entecavir and tenofovir disoproxil fumarate, should be used as first-line monotherapies); second, who should be treated (CHB in patients with significant liver disease but also patients who are HBsAg+ and are receiving immunosuppressive treatment, patients coinfected with HBV and human immunodeficiency virus, mothers who are HBsAg+ with high viral load in late pregnancy associated with sero vaccination to reduce the risk of vertical transmission of HBV; and third, when to stop antiviral therapies. The aim of this review was to clarify how to treat HBV and who should be treated, as well as when to stop treatment. Although the answer to these questions is clear for pegylated interferon, it is more debatable for nucleos(t)ide analogues (anti-HBe seroconversion, HBsAg loss or anti-HBs seroconversion with undetectable HBV DNA are clear indications to discontinue treatment but sustained undetectable HBV DNA in patients who are anti-HBe+ without significant fibrosis might be another indication).
Pancreatic neuroendocrine tumors (pNETs) differ in their clinical behavior, presentation and prognosis based on their initial histological features and disease stage. While small resectable tumors can be treated surgically, metastatic and locally advanced disease carries a significant mortality and treatment options have been limited in terms of their efficacy. Streptozocin-based regimens were the only agents available before but recent advances have improved the armamentarium to treat pNETs. Newer chemotherapeutic agents such as temozolomide, somatostatin analogs and targeted therapies including everolimus and sunitinib are now available to treat these tumors. Several combination regimens with targeted therapies and newer agents such as pazopanib are being developed and tested in ongoing trials.
Background: We studied the management of patients with acute upper gastrointestinal (GI) bleeding (AUGIB) at the Royal Free Hospital. The aim was to compare our performance with the national standard and determine ways of improving the delivery of care in accordance with the recently published ‘Scope for improvement’ report.
Methods: We randomly selected patients who presented with haematemesis, melaena, or both, and had an oesophageogastroduodenoscopy (OGD) between April and October 2009. We developed local guidelines and presented our findings in various forums. We collaborated with the British Medical Journal’s Evidence Centre and Cerner Millennium electronic patient record system to create an electronic ‘Action Set’ for the management of patients presenting with AUGIB. We re-audited using the same standard and target.
Results: With the action set, documentation of pre-OGD Rockall scores increased significantly (p ≤ 0.0001). The differences in the calculation and documentation of post-OGD full Rockall scores were also significant between the two audit loops (p = 0.007). Patients who inappropriately received proton-pump inhibitors (PPIs) before endoscopy were reduced from 73.8% to 33% (p = 0.02). Patients receiving PPIs after OGD were also reduced from 66% to 50% (p = 0.01). Discharges of patients whose full Rockall score was less than or equal to two increased from 40% to 100% (p = 0.43).
Conclusion: The use of the Action Set improved calculation and documentation of risk scores and facilitated earlier hospital discharge for low-risk patients. Significant improvements were also seen in inappropriate use of PPIs. Actions sets can improve guideline adherence and can potentially promote cost-cutting and improve health economics.
The past 15 years has seen a marked increase in available therapeutic options for patients with metastatic colorectal cancer resulting in improvements in median survival from 12 to 24 months. One of these new options is panitumumab, which is a fully humanized monoclonal antibody that binds to the epidermal growth factor receptor of tumor cells and inhibits downstream cell signaling with antitumor effects of inhibition of tumor growth, induction of apoptosis and inhibition of angiogenesis. Large randomized clinical trials have demonstrated significant improvements in tumor response rates and progression-free survival when panitumumab is combined with chemotherapy and as monotherapy in chemorefractory metastatic colorectal cancer. Clinical benefit with panitumumab is limited to patients with nonmutated KRAS tumors. Rash is a common toxicity of panitumumab treatment but can potentially be ameliorated with the use of prophylactic strategies. The role of panitumumab in the overall treatment of metastatic colorectal cancer is evolving and future clinical trials will focus on improved patient selection through use of novel predictive biomarkers, and the optimal timing of treatment.
Methods: Suboptimal bowel preparation, present in over 20% of colonoscopies, can severely compromise the effectiveness of the colonoscopy procedure. We surveyed 93 primarily urban minority men and women who underwent asymptomatic ‘screening’ colonoscopy regarding their precolonoscopy bowel-preparation experience.
Results: Print materials alone (39.8%) and in-person verbal instructions alone (35.5%) were reportedly the most common modes of instruction from the gastroenterologists. Liquid-containing laxative (70.6%) was the most common laxative agent; a clear liquid diet (69.6%) the most common dietary restriction. Almost half of the participants mentioned ‘getting the laxative down’ as one of the hardest parts of the preparation; 40.9% mentioned dietary restrictions. The 24.7% who mentioned ‘understanding the instructions’ as one of the hardest parts were more likely to be non-US born and to have lower education and income. There was no relationship between difficulty in understanding instructions and mode of instruction or preparation protocol. One quarter suggested that a smaller volume and/or more palatable liquid would have made the preparation easier. Three quarters agreed that it would have been helpful to have someone to guide them through the preparation process.
Conclusions: These findings suggest a variety of opportunities for both physician- and patient-directed educational interventions to promote higher rates of optimal colonoscopy bowel preparation.
Despite the established efficacy of sorafenib in advanced hepatocellular carcinoma (HCC), a significant number of sorafenib-treated patients experience disease progression. Current guidelines recommend either best supportive care or clinical trial enrollment for this population. As such, there remains an unmet need for tolerable, life-prolonging strategies in the second-line setting. New information regarding the molecular pathogenesis of resistance to antiangiogenic therapy and positive post-progression experience with antiangiogenics in other tumor types has led to trials investigating the effect of continued use of sorafenib, alone or combined with other agents. Trials investigating the effect of switching from sorafenib to alternate antiangiogenic agents, phosphatidylinositol 3 kinase/AKT/mammalian target of rapamycin inhibitors, or cMet inhibitors are also underway. As these data emerge, clinicians may consider a new paradigm for managing advanced HCC. This article briefly reviews the mechanisms of disease resistance to antiangiogenic therapy as a vehicle for discussing clinical strategies to prolong survival in patients with advanced HCC that are currently employed at our institutions or are under investigation. Key ongoing trials investigating the use of molecularly targeted therapies in patients with progressive disease are also highlighted.
Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms with various clinical presentations. More than half of patients present with so-called nonfunctioning tumors with no hormone-related symptoms, whereas other tumors produce symptoms like gastric problems, ulcers, hypoglycemia, skin rash and diarrhea related to hormone production. The traditional treatment for pNETs over the last three decades has been cytotoxic agents, mainly streptozotocin plus 5-fluorouracil or doxorubicin. Most recently two new compounds have been registered worldwide for the treatment of pNETs, the mammalian target of rapamycin (mTOR) inhibitor everolimus and the tyrosine kinase inhibitor sunitinib. This paper concentrates on the use of mTOR inhibitors and the mechanisms of action. The mTOR pathway is altered in a number of pNETs. Everolimus (RAD001) is an orally active rapamycin analog and mTOR inhibitor. It blocks activity of the mTOR pathway by binding with high affinity to the cytoplasmic protein FKBP-12. The efficacy of everolimus in pNETs has been demonstrated in two multicenter studies (RADIANT 1 and 3). The RADIANT 3 study was a randomized controlled study in pNETs of everolimus 10 mg/day versus placebo, showing an increased progression-free survival (11.7 months versus 4.6 months) and hazard ratio of 0.35 ( p < 0.001). Current studies indicate that there is strong evidence to support the antitumor effect of rapalogs in pNETs. However, significant tumor reduction is very rarely obtained, usually in less than 10% of treated patients. Therefore, these drugs may be more effective in combination with other anticancer agents, including chemotherapy, targeted therapies as well as peptide receptor radiotherapy.
Background: Endoscopic balloon dilatation (EBD) is an effective therapy for caustic-induced gastric outlet obstruction (GOO). Gaining access to the stricture site is the most important step. It is sometimes difficult to negotiate a balloon through the stricture with a front-viewing endoscope due to deformed anatomy of stomach. To overcome this technical difficulty, a side-viewing endoscope can be used. There is limited data regarding the use of side-viewing endoscopes in EBD. We here report on the short-term efficacy and safety of EBD in caustic-induced GOO. In technically difficult cases, a side-viewing endoscope was used for EBD and its efficacy and safety were assessed.
Methods: The study included 25 patients with caustic-induced GOO. Patients underwent EBD using a through-the-scope balloon. Initial balloon dilatation was performed with a front-viewing endoscope. A side-viewing endoscope was used where negotiation across the stricture failed with a front-viewing endoscope. Dilatation was started at 8 mm diameter and was performed at 1-week intervals. The end point of dilatation was 15 mm diameter.
Results: In 18 patients successful balloon dilatation was possible with a front-viewing endoscope. A side-viewing endoscope was used in six patients as negotiation across the stricture was not possible with a front-viewing endoscope. In all six patients negotiation across the stricture followed by successful dilatation was successful with a side-viewing endoscope. Of the 25 patients included in this study, 24 (96%) achieved procedural success (18 with a front-viewing endoscope and 6 with a side-viewing endoscope) in 3–9 sessions.
Conclusion: Our results show that EBD is a safe and effective option for caustic-induced GOO and in difficult cases a side-viewing endoscope can be used to achieve technical success.
Pancreatic neuroendocrine tumors (pNETs) are relatively rare malignancies. With secretory tumors such as insulinomas, vasoactive intestinal peptideomas, and gastrinomas, the hormone produced causes the symptom complex (e.g. hypoglycemia, peptic ulcer disease). With nonsecretory NETs, the clinical condition is determined by tumoral growth and metastasis. The course of metastatic pNETs may be indolent for several years but progression is often more rapid at later stages, leading to significant disability and a markedly negative impact on quality of life. Until recently, there were few effective systemic treatments for pNETs. Standard chemotherapy produces limited responses and has considerable toxicity. Somatostatin analogues control symptoms in some types of pNETs, but have not yet demonstrated antitumor activity. The recent introduction of targeted therapies, including the tyrosine kinase inhibitor sunitinib and the mammalian target of rapamycin inhibitor everolimus, yielded new opportunities for patients with advanced/metastatic pNETs. These drugs, which target key pathways in tumor proliferation and angiogenesis, provided clear clinical benefits in phase III clinical trials, including delayed tumor progression. The pivotal sunitinib phase III trial was discontinued prematurely due to higher rates of death and serious adverse events with placebo and greater progression-free survival (PFS) with sunitinib. In this trial, sunitinib demonstrated encouraging long-term responses as well as PFS and overall survival benefits, and an acceptable safety profile that allowed patients to preserve their quality of life. In every patient subgroup, including secretory and nonsecretory tumors, the hazard ratio for progression or death favored sunitinib. Circulating biomarkers are being investigated for the prediction and monitoring of responses to sunitinib. Although not fully evaluated in pNETs, biomarkers associated with response to sunitinib in several tumor types include soluble vascular endothelial growth factor receptor 2 and 3, interleukin 8, and stromal cell-derived factor 1α. Based on recent data, treatment algorithms have been updated for advanced and metastatic pNETs.
Objectives: A gluten-free diet is the treatment for celiac disease, but pharmaceutical agents are being developed. The level of interest amongst patients in using a medication to treat celiac disease is unknown. This study examined the level of interest amongst patients in medication to treat celiac disease.
Methods: A questionnaire was distributed to celiac disease patients and data were collected on demographics, presentation, and interest in medication. Three validated celiac disease-specific instruments were incorporated: Celiac Disease Associated Quality of Life, the Celiac Symptom Index, and the Celiac Dietary Adherence Test.
Results: Responses were received from 365 individuals with biopsy-proven celiac disease. Respondents were 78% (n = 276) female, 48% (n = 170) over 50 years of age, and experienced a classical (diarrhea predominant) presentation in 44% (n = 154). Of the 339 individuals answering the question regarding use of a medication to treat celiac disease, 66% were interested. Interest was greatest in older individuals (71% >50 years of age versus 60% <50 years of age, p = 0.0415), men (78% men versus 62% women, p = 0.0083), frequent restaurant customers (76% versus 58%, p = 0.0006), those dissatisfied with their weight (73% versus 51%, p = 0.0003) and those concerned with the cost of a gluten-free diet (77% versus 64%, p = 0.0176). Length of time since diagnosis, education, presentation, and symptoms with gluten exposure did not demonstrate any effect. Interest in medication was associated with a worse quality of life (CD-QOL 69.4 versus 80.1, p < 0.0001).
Conclusions: Most individuals with celiac disease are interested in using a medication. Interest was highest among men, older individuals, frequent restaurant customers, individuals dissatisfied with their weight or concerned with the cost of a gluten-free diet, and those with a worse quality of life.
Objectives: Adverse events (AEs) of ischemic colitis (IC) and complications of constipation (CoC) associated with alosetron are rare and have been adjudicated during the first 5.5 years of the risk management program (RMP); however, changes in incidence rates relative to reductions in AE reports and increases in alosetron prescriptions over the 9-year RMP have not been evaluated. The authors aim to evaluate temporal trends in alosetron postmarketing safety over the 9-year RMP.
Methods: The alosetron safety database was searched to identify cases of IC, CoC, and related AEs from 20 November 2002 to 31 December 2011. Adjudication of IC and CoC cases were based on US Food and Drug Administration-defined criteria. Incidence rates were calculated using the number of AEs and alosetron prescriptions (expressed as cases/1000 patient-years exposure).
Results: A total of 29 cases were adjudicated as probable/possible IC and 7 cases were adjudicated as CoC. Cumulative adjudicated incidence rate of IC (1.03 cases/1000 patient-years) is low and stable, while that of CoC (0.25 cases/1000 patient-years) is low, declining progressively over time. Decreases in the incidence rates of potential symptoms of IC (abdominal pain with bloody diarrhea/hematochezia) and CoC (constipation) were also observed.
Conclusions: Over the 9-year RMP period, incidence rates of IC and CoC remain rare. Substantial reductions over time were observed in the incidence of CoC and in symptoms suggestive of IC or CoC, while IC incidence has been stable at approximately 1.0 case/1000 patient-years. Decreases in AEs and serious outcomes associated with IC and CoC since the reintroduction of alosetron are likely attributable to the RMP.
Background: Benign occlusive esophageal strictures create substantial morbidity and have poor surgical outcomes. Various endoscopic techniques have been described to manage these strictures. The challenge remains to maintain adequate long-term esophageal patency and to limit the need for serial endoscopic dilations. Little has been reported regarding the management of these benign occlusive strictures.
Methods: We report a case series describing the management of technically challenging benign occlusive esophageal strictures. Three patients with occlusive esophageal strictures of differing etiologies were treated using a variety of endoscopic methodologies.
Results: The first patient sustained a caustic oropharyngeal injury resulting in a proximal esophageal stricture which was treated by using a combined antegrade retrograde dilation (CARD) with argon plasma coagulation (APC) and needle knife dissection resulting in the successful recanalization and patency of his stricture. A second patient developed an esophageal stricture following radiotherapy, and was treated with a CARD procedure and serial balloon dilations in combination with APC to successfully achieve esophageal luminal patency. The final patient acquired an occlusive esophageal stricture after treatment for thyroid cancer which was treated with endoscopic needle knife dissection followed by serial balloon dilations to successfully manage this stricture.
Conclusions: Occlusive esophageal strictures pose a difficult challenge to gastroenterologists and little has been reported with regards to their endoscopic management. Using the CARD technique, needle knife dissection and APC, individually or in combination, luminal patency of occlusive esophageal strictures can be accomplished safely with good results.
Advances in the treatment of metastatic colorectal cancer have led to an improvement in survival from 12 months with fluorouracil monotherapy to approximately 2 years. This is partly as a result of the addition of irinotecan and oxaliplatin, but is also due to the use of monoclonal antibodies against the epidermal growth factor receptor (EGFR) and antiangiogenic drugs such as bevacizumab. However, there are significant molecular differences between tumours which can affect both prognosis and response to treatment. Personalized medicine aims to tailor treatment according to the characteristics of the individual patient and is now a clinical reality as testing for KRAS mutations to guide treatment with the anti-EGFR monoclonal antibodies cetuximab and panitumumab is now part of routine clinical practice. However, not all patients who are KRAS wild type respond to anti-EGFR therapy and a validated biomarker for antiangiogenic therapy is still lacking. Therefore, other biomarkers are needed to assist with predicting response to both existing drugs as well as to drugs currently under investigation. This review summarizes the molecular biology of colorectal cancer, focusing on the genetic features that are currently most clinically relevant. Current and emerging biomarkers are reviewed along with their roles in selecting patients for targeted treatment with currently licensed therapies and drugs being evaluated in clinical trials. The value of predictive biomarkers of chemosensitivity and potential future treatment strategies are also discussed.
Patients with inflammatory bowel disease (IBD) are at increased risk for colorectal cancer (CRC). Despite weak supporting evidence, important logistic barriers and high cost, colonoscopy is currently the only recommended approach to CRC surveillance in patients with IBD. As such, there is imperative to explore alternative or complementary strategies with potential to improve the efficiency and effectiveness of surveillance in IBD. Given our increasing understanding of tumorigenesis in IBD and the accompanying cascade of molecular alterations, there is a strong rationale to pursue biomarker assays for this application. Stool-based DNA testing with advanced technology has been shown to be highly discriminatory for detection of sporadic colorectal cancer and advanced precancers. In early observations, stool DNA testing also shows promise for the accurate detection of IBD-associated colorectal neoplasms. These findings raise important clinical and translational questions about how to best evaluate and develop this technology, and devise clinical algorithms that will complement colonoscopy to improve patient outcomes.
Prantera, C. and Marconi, S. (2013) Glucocorticosteroids in the treatment of inflammatory bowel disease and approaches to minimising systemic activity. Ther Adv Gastroenterol 6: 137–156. (Original doi: 10.1177/1756283X12473675)
The above article, which appeared in issue 6(2) of Therapeutic Advances in Gastroenterology, was missing the second named author Stefano Marconi from all versions of the publication. The above reference is the correct and full updated version.
The author’s affiliation details are as follows:
Stefano Marconi, PhD
Chiesi Farmaceutici S.p.A., Parma, Italy