Long-term oncological outcomes of endoscopic full-thickness resection after previous incomplete resection of low-risk T1 CRC (LOCAL-study): study protocol of a national prospective cohort study.

BACKGROUND: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization. METHODS/DESIGN: In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate. DISCUSSION: Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Trial registration Nederlands Trial Register, NL 7879, 16 July 2019 ( https://trialregister.nl/trial/7879 ).

Endoscopic mucosal resection (EMR) versus endoscopic submucosal dissection (ESD) for resection of large distal non-pedunculated colorectal adenomas (MATILDA-trial): rationale and design of a multicenter randomized clinical trial.

BACKGROUND: Endoscopic mucosal resection (EMR) is currently the most used technique for resection of large distal colorectal polyps. However, in large lesions EMR can often only be performed in a piecemeal fashion resulting in relatively low radical (R0)-resection rates and high recurrence rates. Endoscopic submucosal dissection (ESD) is a newer procedure that is more difficult resulting in a longer procedural time, but is promising due to the high en-bloc resection rates and the very low recurrence rates. We aim to evaluate the (cost-)effectiveness of ESD against EMR on both short (i.e. 6 months) and long-term (i.e. 36 months). We hypothesize that in the short-run ESD is more time consuming resulting in higher healthcare costs, but is (cost-) effective on the long-term due to lower patients burden, a higher number of R0-resections and lower recurrence rates with less need for repeated procedures. METHODS: This is a multicenter randomized clinical trial in patients with a non-pedunculated polyp larger than 20 mm in the rectum, sigmoid, or descending colon suspected to be an adenoma by means of endoscopic assessment. Primary endpoint is recurrence rate at follow-up colonoscopy at 6 months. Secondary endpoints are R0-resection rate, perceived burden and quality of life, healthcare resources utilization and costs, surgical referral rate, complication rate and recurrence rate at 36 months. Quality-adjusted-life-year (QALY) will be estimated taking an area under the curve approach and using EQ-5D-indexes. Healthcare costs will be calculated by multiplying used healthcare services with unit prices. The cost-effectiveness of ESD against EMR will be expressed as incremental cost-effectiveness ratios (ICER) showing additional costs per recurrence free patient and as ICER showing additional costs per QALY. DISCUSSION: If this trial confirms ESD to be favorable on the long-term, the burden of extra colonoscopies and repeated procedures can be prevented for future patients. TRIAL REGISTRATION: NCT02657044 (Clinicaltrials.gov), registered January 8, 2016.

Switching from infliximab innovator to biosimilar in patients with inflammatory bowel disease: a 12-month multicentre observational prospective cohort study.

BACKGROUND: Infliximab biosimilars have become available for treatment of inflammatory bowel disease (IBD). However, data showing long-term safety and effectiveness of biosimilars in IBD patients are limited. AIM: To study prospectively the switch from infliximab innovator to biosimilar in an IBD cohort with 12 months follow-up to evaluate safety and effectiveness. METHODS: Adult IBD patients from two hospitals treated with infliximab innovator (Remicade; Janssen Biotech,  Horsham ,  Pennsylvania, USA) were switched to infliximab biosimilar (Inflectra; Hospira, Lake Forest, Illinois, USA) as part of routine care, but in a controlled setting. Blood samples were taken just before the first, second, fourth and seventh infusion of biosimilar. Infliximab trough levels, antibodies-to-infliximab (ATI), CRP and ESR were measured and disease activity scores were calculated. RESULTS: Our cohort consisted of 133 IBD patients (64% CD, 36% UC). Before switching we found widely varying infliximab levels (median 3.5 µg/mL). ATI were detected in eight patients (6%). Most patients were in remission or had mild disease (CD: 82% UC: 90%). After switching to biosimilar, 35 patients (26%) discontinued therapy within 12 months, mostly due to subjective higher disease activity (9%) and adverse events (AE, 9.8%). AE included general malaise/fatigue (n = 7), arthralgia (n = 2), skin problems (n = 2) and infusion reactions (n = 2). No differences in IFX levels, CRP, and disease activity scores were found between the four time points (P ≥ .0917). CONCLUSIONS: We found no differences in drug levels and disease activity between infliximab innovator and biosimilar in our IBD cohort, indicating that biosimilars are safe and effective. The high proportions of discontinuers were mostly due to elective withdrawal or subjective disease worsening.

Comparison of two techniques for lower oesophageal sphincter manometry: sleeve and sphinctometer.

We have compared the sphinctometer with the water-perfused sleeve (gold standard) for measurement of lower oesophageal sphincter (LOS) characteristics by simultaneous recording. LOS pressure and transient LOS relaxations (TLOSR) measured by sleeve and sphinctometer in 11 healthy volunteers showed identical patterns. However, output of the sphinctometer was significantly (P < 0.01) lower than output of the sleeve. A total of 249 TLOSR were recorded. Of these, 176 TLOSR were identified by both sleeve and sphinctometer, 50 TLOSR were identified by sleeve alone and 23 TLOSR by sphinctometer alone. Due to the lower pressure output of the sphinctometer, 29 LOS relaxations did not reach criteria to qualify as TLOSRs. When TLOSR criteria were adjusted for sphinctometer pressure measurements, the number of TLOSRs identified by both sleeve and sphinctometer increased from 176 to 205. In conclusion, in healthy volunteers the sphinctometer registers TLOSR with results comparable with sleeve recording. However at low LOS pressures, the number of TLOSR is underscored by the sphinctometer.

The effect of laparoscopic partial fundoplication on dysphagia, esophageal and lower esophageal sphincter motility.

It has been suggested that dysphagia is less common after partial versus complete fundoplication. The mechanisms contributing to postoperative dysphagia remain unclear. The objective of the present prospective study was to investigate esophageal motility and the prevalence of dysphagia in patients who have undergone laparoscopic partial fundoplication. Symptoms, lower esophageal sphincter (LES) characteristics and esophageal body motility were evaluated prospectively in 62 patients before and after laparoscopic partial fundoplication: 33 women and 29 men with a mean age of 44 +/- 1.5 years (range, 21-71). The patients filled in symptom questionnaires and underwent stationary and ambulatory manometry and 24-h pH-metry before and after operation. A small but significant increase in LES pressure from 14.8 +/- 0.9 to 17.8 +/- 0.8 mmHg was seen after laparoscopic partial fundoplication. Further, LES characteristics and esophageal body motility were not different post- versus preoperation. Three months after surgery, dysphagia was present in eight patients. No differences in LES characteristics or body motility were present between patients with and without dysphagia. Six months after the operation dysphagia was present in only three patients (3.2% mild and 1.6% severe dysphagia). Adequate reflux control was obtained in 85% of the patients. Laparoscopic partial fundoplication offers adequate reflux control without affecting esophageal body motility and with a very low incidence of postoperative dysphagia.

Provocation of transient lower esophageal sphincter relaxations during continuous gastric distension.

BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) are triggered by gastric distension. The aim of the study was to investigate TLESRs during controlled prolonged gastric distensions using the barostat technique. METHODS: Twelve healthy volunteers (4 M, 8 F, age range 19-42 years) were studied under fasting conditions with combined esophageal manometry (Dentsleeve) and gastric barostat. Randomized isobaric distensions at 0 (control), 10, 12 and 14 mmHg were performed each period for 30 min with 30-min recovery periods in between. RESULTS: The frequency of TLESR was significantly (P < 0.05) higher during all distension periods compared to control periods (4.0 +/- 0.4 TLESR/30 min versus 2.6 +/- 0.4 TLESR/30 min). The frequency of TLESR in the first 15-min period of distension was significantly (P < 0.001) higher compared to the second 15-min period pointing to adaptation (2.7 +/- 0.3 TLESR/15 min versus 1.3 +/- 0.2 TLESR/15 min, respectively). The frequency of TLESR correlated significantly with intragastric pressure (r = 0.47; P < 0.01) and wall tension (r = 0.48; P < 0.01), but not with intragastric volume. TLESR characteristics such as duration were not related to pressure or wall tension. CONCLUSIONS: Acute gastric distension increases the frequency of TLESR but adaptation occurs rapidly. The frequency of TLESR during distension is related to pressure and wall tension rather than to intragastric volume.