Biological treatment approach to inflammatory bowel disease is similar in academic and nonacademic centres - prime time for decentralisation of inflammatory bowel disease care?

BACKGROUND: With the increasing number of inflammatory bowel disease (IBD) patients, it is difficult to manage them within specialised IBD teams in academic medical centres: many are therefore treated in nonacademic IBD centres. It is unclear whether the time to introducing biologics is the same in both settings. AIM: We aimed to compare treatment approach with biologics in academic vs. nonacademic centres. METHODS: We analysed Slovenian national IBD registry data (UR-CARE Registry, supported by the European Crohn's and Colitis Organisation), which included 2 academic (2319 patients) and 4 nonacademic IBD (429 patients) centres. RESULTS: The disease phenotype was similar in both settings. In total, 1687 patients received 2782 treatment episodes with biologics. We observed no differences in treatment episodes with TNF-alpha inhibitors (60% vs. 61%), vedolizumab (24% vs. 23%), or ustekinumab (17% vs. 16%) in academic compared to nonacademic centres ( P  = 0.949). However, TNF inhibitors were less often the first biologic in academic centres (TNF inhibitors: 67.5% vs. 74.0%, vedolizumab: 20.3% vs. 17.9%, ustekinumab: 12.1% vs. 8.1%; P = 0.0096). Consequently, more patients received ustekinumab (29.8% vs. 18.3%) and vedolizumab (17.4% vs. 13.5%) and fewer TNF inhibitors (52.7% vs. 68.2%) for Crohn's disease in academic compared to nonacademic centres, with no such differences for ulcerative colitis. The time to initiation of the first biologic from diagnosis was short and similar in both settings (11.3 vs. 10.4 months, P  = 0.2). CONCLUSION: In this nationwide registry analysis, we observed that biological treatment choice was similar in academic and nonacademic settings. These findings support the decentralisation of IBD care.

Possible use of 2D shear wave liver elastography in new-onset ascites evaluation.

BACKGROUND: No data on the use of 2D shear wave elastography exists regarding the evaluation of the new-onset ascites causality. AIMS: To determine whether 2D shear wave elastography can help in the non-invasive assessment of the new-onset ascites cause. To assess the applicability of liver stiffness measured by 2D shear wave elastography using Esaote MyLab Nine apparatus in patients with ascites. METHODS: In 52 consecutive patients with new-onset ascites (January 2020 to October 2021), liver stiffness using 2D shear wave elastography was prospectively measured. The reliable measurements were used for further analysis. Relevant clinical and laboratory data was collected. RESULTS: The calculated liver stiffness measurement cut-off value of 14.4 kPa held 94% accuracy, 100% sensitivity, and 83% specificity when determining ascites with serum ascites albumin gradient ≥11 g/L. Reliable 2D shear wave elastography success rate was 84%. CONCLUSIONS: 2D shear wave elastography may potentially be used to differentiate transudative from exudative ascites, especially in patients with portal hypertension and peritoneal carcinomatosis.

Performance of European and American Societies of Gastrointestinal Endoscopy Guidelines for Prediction of Choledocholithiasis in Patients with Acute Biliary Pancreatitis.

Background and Objectives: Up to one-third of patients with acute biliary pancreatitis also present with choledocholithiasis. Guidelines from the European Society of Gastrointestinal Endoscopy (ESGE) and the American Society for Gastrointestinal Endoscopy (ASGE) for investigating suspected choledocholithiasis suggest endoscopic retrograde cholangiopancreatography in patients with high-likelihood (ESGE)/high-probability (ASGE) predictors and endoscopic ultrasound in those with intermediate-likelihood (ESGE)/intermediate-probability (ASGE) predictors. Although both guidelines are similar, they are not identical. Furthermore, these algorithms were mainly developed from cohorts of patients without pancreatitis and are therefore poorly validated in a subset of patients with acute pancreatitis. We aimed to assess the performance of the ESGE and ASGE algorithms for the prediction of choledocholithiasis in patients with acute biliary pancreatitis. Materials and Methods: This was a retrospective analysis of 86 consecutive patients admitted to a tertiary referral centre in the year 2020 due to acute biliary pancreatitis. Results: Choledocholithiasis was confirmed in 29/86 (33.7%) of patients (13 with endoscopic retrograde cholangiopancreatography and 16 with endoscopic ultrasound). All 10/10 (100%) ESGE high-likelihood and 14/19 (73.7%) ASGE high-probability patients had choledocholithiasis. Only 19/71 (26.8%) patients with ESGE intermediate likelihood and 15/67 (22.4%) with ASGE intermediate probability had choledocholithiasis. Only 8/13 (61.5%) patients with the ASGE high-probability predictor of dilated common bile duct plus bilirubin > 68.4 µmol/mL had choledocholithiasis. Since this predictor is not considered high likelihood by ESGE, this resulted in a superior specificity of the European compared to the American guideline (100% vs. 91.2%). Following the American instead of the European guidelines would have resulted in five unnecessary endoscopic retrograde cholangiopancreatographies and five unnecessary endoscopic ultrasound examinations. Conclusions: This retrospective analysis suggests that the European guidelines may perform better than the American guidelines at predicting choledocholithiasis in the setting of acute pancreatitis. This was because dilated common bile duct plus bilirubin > 68.4 µmol/mL was not a reliable predictor for persistent bile duct stones.

Abbreviated 13C-mixed triglyceride breath test for detection of pancreatic exocrine insufficiency performs equally as standard 5-hour test in patients after gastrectomy performed for gastric cancer.

BACKGROUND: 13C-mixed triglyceride breath test (13C-MTGT) is a non-invasive test for the detection of moderate and severe pancreatic exocrine insufficiency (PEI), but it requires prolonged breath sampling. The aim of this study was to determine the diagnostic power of abbreviated 13C-MTGT in detecting PEI in patients after subtotal and total gastrectomy performed due to gastric cancer. SUBJECTS AND METHODS: This cross-sectional observational study included 3 groups of subjects; healthy controls, patients with subtotal and patients with total gastrectomy. Demographic and clinical data of patients were collected. Stool samples to determine faecal elastase (Fe-1) and chymotrypsin were collected and measured by ELISA. All subjects performed 5-hour 13C-MTGT breath test. The concentration and relative content of 13C in exhaled air was measured by isotope ratio mass spectrometer (IRMS). PEI was confirmed as values of 13C-exhalation < 26.8% after 5 hours. RESULTS: Overall, 65 participants were included into analysis, 22 having PEI (n = 11 after subtotal and n = 11 after total gastrectomy, both performed for gastric cancer). 13C-MTGT breath test showed difference in percent of exhaled 13C between PEI and non-PEI patients already after 60 minutes (p = 0.034). Receiver operating characteristic (ROC) curve analysis showed that cut-off value of 13.74% after 150 minutes is showing equivalent diagnostic power to the longer test with sensitivity and specificity both above 90% for the exclusion of PEI in patients after subtotal and/or total gastrectomy. CONCLUSIONS: In this study abbreviated 13C-MTGT test could be shortened from 5 to 2.5 hours without decrease in its diagnostic accuracy for detection of PEI in patients with subtotal or total gastrectomy performed for gastric cancer. This allows significant time savings in the diagnostics of PEI in this subgroup of patients.

Quality Control in the Slovenian National Colorectal Cancer Screening Program.

OBJECTIVES: The objective of the study was to assess the impact of an internal quality indicator (QI) audit on the quality level of colonoscopies in the National Colorectal Cancer Screening Program (NCCSP). DESIGN: Sixty-eight colonoscopists from 29 endoscopic centres participated in the NCCSP from April 2009 to January 2015. Controlled QIs were the percentage of total colonoscopies, adenoma detection rate (ADR), mean adenoma per procedure (MAP), mean adenoma per positive procedure (MAP+), right-sided ADR, sessile serrated lesion (SSL) detection rate, and patient responses to post-procedural questionnaires. A group of 3 expert endoscopists from the NCCSP Council performed 91 inspections and provided education. RESULTS: A total of 891.364 (58.2%) Slovenian citizens participated in the first 3 screening rounds of the NCCSP. Among 46.552 (6%) positive individuals, 42.866 (92.1%) underwent first colonoscopies. Total colonoscopies were performed in 98% of endoscopies (p = 0.459 between cycles), mean ADR was 51.8% (p = 0.872 between cycles), mean percentage of adenoma in the right colon was 37.5% (p = 0.227 between cycles), mean MAP was 1.1 (p = 0.981 between cycles), mean MAP+ was 2.0 (p = 0.824 between cycles), and mean SSL detection rate was 3% (p < 0.001). We observed great difference in QIs between endoscopists and a significant increase in MAP, ADR in the right colon, and SSL per endoscopist during the 6-year period. Due to quality underperformance, 3 endoscopic centres (10.3%) and 13 endoscopists (19.1%) were excluded from the program. CONCLUSIONS: The success of the NCCSP is related to the quality of colonoscopies performed. To ensure the proper quality level, regular audit and permanent education are needed.

Practice Guidelines of the Central European Hepatologic Collaboration (CEHC) on the Use of Thrombopoietin Receptor Agonists in Patients with Chronic Liver Disease Undergoing Invasive Procedures.

BACKGROUND: Second-generation thrombopoietin receptor agonists (TPO-RAs) are emerging as the new standard for managing thrombocytopenia (TCP) in patients with chronic liver diseases (CLDs) undergoing scheduled procedures. However, practical guidance for their routine use in CLD patients undergoing specific invasive procedures is lacking. METHODS: These practice guidelines were developed by the Initiative Group for Central European Hepatologic Collaboration (CEHC), composed of nine hepatologist/gastroenterologist experts from Central Europe. Using an adapted Delphi process, the CEHC group selected ten invasive procedures most relevant to the hepatology/gastroenterology setting in the region. Consensus recommendations for each invasive procedure are reported as a final percentage of expert panel responses. RESULTS: A consensus was agreed that TPO-RAs should be considered for raising platelet count in CLD patients undergoing scheduled abdominal surgery, high-bleeding risk dentistry, endoscopic polypectomy, endoscopic variceal ligation, liver biopsy, liver surgery, liver transplantation and percutaneous ablation, but it was also agreed that they are less beneficial or not necessary for endoscopy without intervention and paracentesis. CONCLUSIONS: Using a modified Delphi method, experts reached an agreement for TCP management in CLD patients undergoing ten invasive procedures. These practice guidelines may help with decision making and patient management in areas where clinical evidence is absent or limited.

Ustekinumab concentrations shortly after escalation to monthly dosing may identify endoscopic remission in refractory Crohn's disease.

OBJECTIVES: Some patients with Crohn's disease do not achieve remission with the approved maintenance dosing of ustekinumab every 8 weeks, possibly due to insufficient drug exposure. We aimed to study the exposure-response relationship for endoscopic remission and biomarker normalization with ustekinumab dose escalation to every 4 weeks. METHODS: Out of 135 consecutive patients, 44 with active Crohn's disease despite standard maintenance dosing [at least one of C-reactive protein (CRP) >5 mg/L, fecal calprotectin >100 mg/kg, simple endoscopic score (SES) for Crohn's disease >3] underwent dose escalation to every 4 weeks. Subsequent endoscopic remission (SES-CD ≤3 without ulceration) and biomarker normalization were compared against ustekinumab concentrations. RESULTS: Dose escalation led to endoscopic remission in 28.6% (8/28), CRP normalization 29.2% (7/24) and fecal calprotectin normalization 51.7% (15/29) of patients. Ustekinumab concentrations after escalation were higher in patients with endoscopic remission (6.90 vs. 4.29 mg/L; P = 0.025) and fecal calprotectin normalization (6.65 vs. 3.74 mg/L; P = 0.001). A threshold of 6.00 mg/L identified endoscopic remission [area under the receiver operating curve (AUROC): 0.775; 95% confidence interval (CI), 0.551-0.999), a threshold of 4.40 mg/L (AUROC 0.755; 95% CI, 0.545-0.964) two months after escalation identified patients with fecal calprotectin normalization at the end of follow-up. Concentrations <3.5 mg/L after escalation precluded endoscopic remission or biomarker normalization. CONCLUSION: Endoscopic remission was associated with higher ustekinumab concentrations after dose escalation. Patients with concentrations <3.5 mg/L after dose escalation are unlikely to achieve endoscopic remission or biomarker normalization.

TIPS vs. endoscopic treatment for prevention of recurrent variceal bleeding: a long-term follow-up of 126 patients.

BACKGROUND: Recurrent bleeding from gastroesophageal varices is the most common life-threatening complication of portal hypertension. According to guidelines, transjugular intrahepatic portosystemic shunt (TIPS) should not be used as a first-line treatment and should be limited to those bleedings which are refractory to pharmacologic and endoscopic treatment (ET). To our knowledge, long-term studies evaluating the role of elective TIPS in comparison to ET in patients with recurrent variceal bleeding episodes are rare. PATIENTS AND METHODS: This study was designed as a retrospective single-institution analysis of 70 patients treated with TIPS and 56 with ET. Patients were followed-up from inclusion in the study until death, liver transplantation, the last follow-up observation or until the end of our study. RESULTS: Recurrent variceal bleeding was significantly more frequent in ET group compared to patients TIPS group (66.1% vs. 21.4%, p < 0.001; χ2-test). The incidence of death secondary to recurrent bleeding was higher in the ET group (28.6% vs. 10%). Cumulative survival after 1 year, 2 years and 5 years in TIPS group compared to ET group was 85% vs. 83%, 73% vs. 67% and 41% vs. 35%, respectively. The main cause of death in patients with cumulative survival more than 2 years was liver failure. Median observation time was 47 months (range; 2-194 months) in the TIPS group and 40 months (range; 1-168 months) in the ET group. CONCLUSIONS: In present study TIPS was more effective in the prevention of recurrent variceal bleeding and had lower mortality due to recurrent variceal bleeding compared to ET.

Peak Concentrations of Ustekinumab After Intravenous Induction Therapy Identify Patients With Crohn's Disease Likely to Achieve Endoscopic and Biochemical Remission.

BACKGROUND & AIMS: Little is known about the relationship between ustekinumab exposure during the first 2 weeks of treatment and outcomes of patients with Crohn's disease (CD). We investigated the relationship between serum concentrations of ustekinumab during the first 2 weeks of treatment and endoscopic and biochemical remission in patients with CD. METHODS: In a prospective observational study, we measured concentrations of ustekinumab in serum samples from 41 consecutive patients who started treatment with ustekinumab (approximately 6 mg/kg, intravenously, then 90 mg every 8 weeks), due to endoscopic markers of active CD, at a single center from October 2017 through January 2019. We measured ustekinumab exposure parameters during the first 2 weeks (peak concentration measured immediately after intravenous infusion, week 2 concentration, and area under the curve through week 2). We investigated the correlation between these parameters and endoscopic remission (simple endoscopic score for CD scores of 3 or less without ulceration, assessed centrally) and biochemical remission (level of fecal calprotectin below 100 mg/kg) using the Mann-Whitney U test. RESULTS: Endoscopic remission was achieved in 10 patients (24.4%) at week 24; biochemical remission was achieved in 17 patients (41.5%) at week 8, 17 patients (41.5%) at week 16, and 21 patients (51.2%) at week 24. Peak concentrations associated with endoscopic remission (area under the receiver operating characteristic curve, 0.717; 95% CI, 0.517-0.916); 6 of 13 patients (46%) with peak concentrations above 105 µg/mL (upper tercile) achieved endoscopic remission, compared with only 1 of 14 patients (7%) with peak concentrations below 88 µg/mL (lower tercile). All exposure parameters during the first 2 weeks were associated with biochemical remission. There was no significant difference between the associations of peak concentrations, week-2 concentrations, area under the curve through week 2, or later exposure measures (at weeks 4 and 8) with biochemical or endoscopic remission. CONCLUSIONS: In a prospective study, we found that serum concentrations of ustekinumab as early as 1 hour after intravenous infusion might be used to identify patients with CD most likely to achieve endoscopic remission. This early measurement might be used to optimize treatment of CD.

The impact of 6 years of the National Colorectal Cancer Screening Program on colorectal cancer incidence and 5-year survival.

We aimed to assess the impact of the first three rounds of the National Colorectal Cancer Screening Program (NCCSP) on CRC incidence and mortality in Slovenia. In NCCSP, we use two fecal immune tests (FITs) and if test is positive patient is referred to colonoscopy. From 2009, we invite Slovenian residents aged 50-69 years, one screening round takes 2 years. The response rate was from 56.9 to 59.9%. FIT was positive in 6.0-6.2% (more in older patients and in men; P < 0.05). The adenoma detection rate was >51.3% (more in men; P < 0.01). In NCCSP, 70.3% of all cancers diagnosed were in stages I and II, while 20.7% of all CRC were found in polyps resected during colonoscopies. Patients with positive first FIT have odds ratio 2.19 [95% confidence interval (CI), 2.06-2.32] for advanced neoplasia and cancer compared to patients with two negative FITs. The incidence rate for CRC has dropped significantly after 6 years in population and in men (P < 0.01) but not in women. Five-year CRC survival was 31.3% higher if cancer was diagnosed in NCCSP (P < 0.05). After 6 years of NCCSP, the incidence rate for CRC has dropped significantly (P < 0.01). Hazard ratio for death from CRC was 3.84 higher (95% CI, 3.36-4.40; P < 0.001) in patients with cancer detected outside the program.

A Prospective Phase II Study Evaluating Intraoperative Electrochemotherapy of Hepatocellular Carcinoma.

The aim of this clinical study was to investigate the effectiveness and long-term safety of electrochemotherapy as an emerging treatment for HCC in patients not suitable for other treatment options. A prospective phase II clinical study was conducted in patients with primary HCC who were not suitable for other treatment options according to the Barcelona Clinic Liver Cancer classification. A total of 24 patients with 32 tumors were treated by electrochemotherapy. The procedure was effective, feasible, and safe with some procedure-related side effects. The responses of the 32 treated nodules were: 84.4% complete response (CR), 12.5% partial response (PR), and 3.1% stable disease (SD). The treatment was equally effective for nodules located centrally and peripherally. Electrochemotherapy provided a durable response with local tumor control over 50 months of observation in 78.0% of nodules. The patient responses were: 79.2% CR and 16.6% PR. The median progression-free survival was 12 months (range 2.7-50), and the overall survival over 5 years of observation was 72.0%. This prospective phase II clinical study showed that electrochemotherapy was an effective, feasible, and safe option for treating HCC in patients not suitable for other treatment options.

Survival outcomes and rate of missed upper gastrointestinal cancers at routine endoscopy: a single centre retrospective cohort study.

OBJECTIVES: Data on the long-term survival outcome of patients with missed upper gastrointestinal cancers (MUGC) is lacking. Retrospective studies have found no difference in 1- and 2-year survival among patients with missed gastric and oesophageal cancers; we thus aimed to assess 3-year survival of patients with MUGC at oesophagogastroduodenoscopy. METHODS: This was a retrospective cohort study conducted at a single tertiary endoscopy centre. All oesophagogastroduodenoscopies performed between January 2007 and December 2015 were included in the study. The endoscopy database was cross-matched with the Slovenian Cancer Registry database. Missed cancers were defined as those diagnosed within 36 months after a negative oesophagogastroduodenoscopy. RESULTS: During the study period, 29 617 oesophagogastroduodenoscopies were performed. In total, 422 upper gastrointestinal cancers were diagnosed and the rate of missed gastric cancers was 7.3% (95% CI, 4.9-10.6%) (26/354), and 4.4% (95% CI, 0.9-12.4%) for oesophageal cancers (3/68). Three-year survival of patients with MUGC was shorter than that of those with non-MUGC, being 12% (95% CI, 1-25%) vs. 31% (95% CI, 26-36%) (P = 0.043) for gastric and 0 vs. 9% (95% CI, 1-17%) (P = 0.121) for oesophageal cancer. CONCLUSION: Missed gastric cancer during oesophagogastroduodenoscopy may be associated with shorter 3-year survival compared to patients whose gastric cancer was diagnosed at index oesophagogastroduodenoscopy.

Sorafenib for the treatment of hepatocellular carcinoma: a single-centre real-world study.

Background Sorafenib is an oral multi-kinase inhibitor used for the treatment of hepatocellular carcinoma. Its efficacy in randomised controlled trials was demonstrated in patients with well-preserved liver function and good functional status. In the real-world setting, treatment is often offered to patients outside these criteria. We therefore performed a single-centre real-world cohort study on the efficacy of sorafenib in patients with hepatocellular carcinoma. Patients and methods We identified all patients with hepatocellular carcinoma initiating treatment with sorafenib between January 2015 and January 2018. The primary endpoint was overall survival (OS) since starting sorafenib. Clinical and demographic variables associated with survival were studied. Results The median OS was 13.4 months (95% CI 8.2-18.6). Multivariable Cox's regression identified worse ECOG performance status (HR 2.21; 95% CI 1.56-3.16; P < 0.0001), Child-Pugh class C (HR 52.4; 95% CI 3.20-859; P = 0.005) and absence of prior locoregional treatment (HR 2.30; 95% CI 1.37-3.86; P = 0.002) to be associated with increased mortality. Conclusions Careful selection of patients for treatment with sorafenib is of paramount importance to optimize outcomes.

Intramural Hematoma Causing Hematochezia After Colonoscopy With Polypectomy.

Intramural hematoma of the colon is a rare complication of colonoscopy. We present a case of a 78-year-old woman on warfarin who presented with hematochezia and hypotension due to intramural hematoma of the sigmoid colon after colonoscopy with polypectomy of small polyps in the right colon.

Early vedolizumab trough levels predict combined endoscopic and clinical remission in inflammatory bowel disease.

Background: The relationship between vedolizumab trough levels and combined endoscopic and clinical remission is unknown. Objective: To compare vedolizumab trough levels in patients with and without combined remission within the first year of treatment. Methods: We prospectively collected vedolizumab trough levels in 51 consecutive patients (28 Crohn's disease (CD) and 23 ulcerative colitis (UC)) before all infusions up to week 22, and at weeks 38 and 54, with concentrations measured after study completion. Centrally read endoscopy was performed at a median of 46 weeks. The primary outcome was combined endoscopic (CD: Simple endoscopic score for CD (SES-CD) < 4 without ulceration; UC: Mayo endoscopic subscore ≤ 1) and clinical remission (CD: resolution of abdominal pain; UC: resolution of rectal bleeding; both: resolution of altered bowel habit). Results: Median vedolizumab trough levels at weeks 6 (25.7 vs 15.6 µg/mL; P = 0.015) and 22 (15.1 vs 4.9 µg/mL; P = 0.001) were higher in patients with combined remission. A threshold of 22 µg/mL at week 6 (area under the curve (AUC) 0.733; 95% confidence interval 0.567-0.899) and 8 µg/mL at week 22 (AUC 0.819; 95% confidence interval 0.692-0.946) predicted combined remission. Conclusion: Early vedolizumab trough levels predicted combined endoscopic and clinical remission highlighting their possible use in clinical practice.

Evaluation of optimal biopsy location for assessment of histological activity, transcriptomic and immunohistochemical analyses in patients with active Crohn's disease.

BACKGROUND: The appropriate location for biopsy procurement relative to an ulcer in active Crohn's disease is unknown. AIM: To explore the relationship between biopsy location, histological disease activity, proinflammatory gene expression and the presence of inflammatory cells. METHODS: Fifty-one patients with Crohn's disease and ulcers >0.5 cm diameter in the colon and/or ileum were prospectively enrolled at three centres. Biopsies were obtained from 0 mm, 7 to 8 mm and 21 to 24 mm from the edge of the largest ulcer. Histological activity was blindly assessed with the Global Histological Disease Activity Score, the Robarts Histopathology and Nancy Histological indices. Messenger ribonucleic acid (mRNA) levels for interleukins-6, -8 and -23 (p19 and p40 subunits), CD31 and S100A9 were measured using quantitative polymerase chain reaction. The number of CD3+, CD68+ and myeloperoxidase-positive cells was quantified by immunohistochemistry. Data were analysed using mixed models with location and segment as fixed effects and patients as random effect to account for correlation among segments within a patient. RESULTS: Histological disease activity scores (P < 0.0001), proinflammatory gene expression levels (P < 0.005) and numbers of myeloperoxidase-positive cells (P < 0.0001) were highest in biopsies from the ulcer edge in the colon and ileum, with decreasing gradients observed with distance from the edge (P < 0.05). No differences between colonic and ileal samples were detected for the parameters measured at any location. CONCLUSIONS: Biopsies from the ulcer edge in patients with Crohn's disease yielded the greatest histological disease activity and mRNA levels and had similar readouts in the colon and ileum. Research is needed to confirm this conclusion for other measures.

Clinically important neutralizing anti-drug antibodies detected with an in-house competitive ELISA.

Therapeutic drug monitoring of TNF-alpha inhibitors is crucial for evaluating patients with inflammatory diseases on a personalized level. It has been clinically observed that many patients receiving TNF-alpha inhibitors, with negative drug and anti-drug antibody results from bridging ELISA (bELISA), lose their drug response over time, despite dose optimization. Our aims were to develop innovative in-house competitive ELISAs (cELISAs) for the detection of neutralizing antibodies against infliximab and adalimumab and compare their results to reporter gene assay (RGA) and in-house bELISA. Furthermore, we aimed to evaluate patient anti-drug antibody results in regard to their clinical records and potential benefits of therapeutic drug monitoring with the novel cELISAs. Sera of patients treated with infliximab (n = 46) or adalimumab (n = 31), having undetectable drug levels, were tested with our in-house cELISA. Briefly, samples were incubated with a fixed amount of drug and the neutralizing capacity of the samples was determined. The cELISA results were compared to RGA and bELISA results using Spearman's correlation coefficient. Additionally, patient clinical data were evaluated in line with the results of cELISA, bELISA, and RGA using the Kaplan-Meier analysis and the Log Rank test. Both anti-infliximab and anti-adalimumab cELISAs showed very good correlation to RGA (r = 0.932, p < 0.0001 and r = 0.947, p < 0.0001, respectively). Furthermore, a positive result in anti-infliximab cELISA can predict treatment failure in 100% of patients with negative bELISA, while a positive result in anti-adalimumab cELISA can predict treatment failure in 80% of patients with negative bELISA. Taken together, we developed innovative cELISAs enabling quantification of functional and neutralizing anti-drug antibodies, comparable to RGA. The association between cELISA results and loss of drug response in patients identified clinically important anti-drug antibodies, as measured by cELISA.

The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients.

BACKGROUND: Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin can reduce colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin has also been associated with decreased colon adenoma recurrence in clinical trials and lower CRC incidence and mortality in epidemiological studies in diabetics. While both drugs have been tested as single agents, their combination has not been tested in cancer prevention trials. METHODS/DESIGN: This is a randomized, placebo-controlled, double-blind, 2 × 2 biomarker trial of aspirin and metformin to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC are randomly assigned in a four-arm trial to either aspirin (100 mg day), metformin (850 mg bis in die), their combination, or placebo for one year. The primary endpoint biomarker is the change of IHC expression of nuclear factor kappa-B (NFκB) in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the measurement of circulating IL-6, CRP and VEGF; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of genetic markers with treatment response as assessed by next generation sequencing of primary tumors; 4) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; and 5) the evaluation of adenoma occurrence at 1 year. DISCUSSION: A favorable biomarker modulation by aspirin and metformin may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC. TRIAL REGISTRATION: EudraCT Number: 2015-004824-77; ClinicalTrial.gov Identifier: NCT03047837 . Registered on February 1, 2017.