Fecal Microbial Transplantation versus Mesalamine Enema for Treatment of Active Left-Sided Ulcerative Colitis—Results of a Randomized Controlled Trial

Background and Aims: Ulcerative colitis (UC) is a chronic inflammatory disease. Fecal microbial transplantation (FMT) is a promising alternative treatment. Methods: This multicenter, open-label, noninferiority trial randomized patients with active left-sided UC (Mayo score 4–10) equally to FMT or 5-aminosalicylic acid (5-ASA) enemas. FMT enemas were administered five times in the first week and then once weekly for 5 weeks. 5-ASA enemas were administered daily for 2 weeks and then every other day. The primary study endpoint was clinical remission, with a total Mayo score ≤2 at week 12 with no subscore >1. Results: Sixty-one patients were screened; 45 were enrolled and randomized to FMT (n = 23) or 5-ASA (n = 22). Twenty-one FMT and 22 5-ASA patients completed at least the week 4 study visit and were included in the mITT analysis. Twelve FMT (57%) and eight 5-ASA patients achieved the primary study endpoint. FMT noninferiority with 10% margin was confirmed (95% CI: −7.6%, 48.9%). Adverse events occurred in 12 FMT (57%) and 13 5-ASA (59%) patients. Increased microbial diversity persisted 3 months after FMT. Conclusion: FMT is an effective treatment for left-sided UC and increased recipient microbiome diversity. Targeted microbiome modification may improve FMT efficacy. Further investigation is needed to guide donor and patient selection.

Feasibility and safety of robotic-assisted total pancreatectomy: a pilot western series

This study was designed to demonstrate non-inferiority of robot-assisted total pancreatectomy (RATP) to open total pancreatectomy (OPT) based on an intention-to-treat analysis, having occurrence of severe post-operative complications (SPC) as primary study endpoint. The two groups were matched (2:1) by propensity scores. Assuming a rate of SPC of 22.5% (non-inferiority margin: 15%; α: 0.05; β: 0.20; power: 80%), a total of 25 patients were required per group. During the study period (October 2008–December 2019), 209 patients received a total pancreatectomy. After application of exclusion and inclusion criteria, matched groups were extracted from an overall cohort of 132 patients (OPT: 107; RATP: 25). Before matching, the two groups were different with respect to prevalence of cardiac disease (24.3% versus 4.0%; p = 0.03), presence of jaundice (45.8% versus 12.0%; p = 0.002), presence of a biliary drainage (23.4% versus 0; p = 0.004), history of weight loss (28.0% versus 8.0%; p = 0.04), and vein involvement (55.1% versus 28.0%) (p = 0.03). After matching, the two groups (OTP: 50; RATP: 25) were well balanced. Regarding primary study endpoint, SPC developed in 13 patients (26.0%) after OTP and in 6 patients (24.0%) after RATP (p = 0.85). Regarding secondary study endpoints, RATP was associated with longer median operating times [475 (408.8–582.5) versus 585 min (525–637.5) p = 0.003]. After a median follow-up time of 23.7 months (10.4–71), overall survival time [22.6 (11.2–81.2) versus NA (27.3–NA) p = 0.006] and cancer-specific survival [22.6 (11.2–NA) versus NA (27.3–NA) p = 0.02] were improved in patients undergoing RATP. In carefully selected patients, robot-assisted total pancreatectomy is non-inferior to open total pancreatectomy regarding occurrence of severe post-operative complications.

Not-for-profit observational study to evaluate the quality and safety of care in outliers hospitalized with medical diseases - Study Protocol of Safety Issues and SurvIval For Medical Outliers (SISIFO study)

The progressive cutting of hospital beds in some health systems, together with the increased needs related to the aging population, has led to the phenomenon of patients hospitalized outside the appropriate ward (outliers). This is particularly relevant in the context of Internal Medicine. Despite its relevance in daily clinical practice, available evidence for the potential impact of this phenomenon is limited. The aim of this study is to evaluate the effects of this situation on patients’ outcomes and possibly identify organizational and managerial aspects related to the presence of outliers. The multicenter, observational, prospective Study Protocol of Safety Issues and SurvIval For Medical Outliers (SISIFO) was promoted by the Italian Federation of Associations of Hospital Doctors on Internal Medicine (FADOI). The primary study endpoint is the evaluation of in-hospital mortality in outliers versus controls. A sample size of 2400 patients has been estimated by assuming a mortality rate of 12% and 8% in outliers and controls, respectively. By virtue of the multicentric dimension, the expected number of patients, and the controlled design, the FADOI-SISIFO study might provide interesting and useful findings to better manage the phenomenon of outliers.

Feasibility and safety of the new coronary noncompliant balloon catheter River NC®

Aim: In this preliminary study, we aimed to confirm the clinical utility and safety of the new noncompliant balloon catheter River NC (Balton, Poland). Materials & methods: The primary study endpoint was to verify balloon diameters calculated in quantitative coronary angiography (QCA) to diameters prespecified by the manufacturer and obtained at given pressures in subjects undergoing percutaneous coronary interventions. Results: Forty-two subjects were enrolled (73.8% multivessel disease; 40.5% type B1 lesions; 100% device success). No clinically significant differences between expected balloon diameters and QCA were registered in predilatation (2.36 ± 0.11 mm vs. 2.43 ± 0.07 mm) and postdilatation (3.18 ± 0.19 mm vs. 3.21 ± 0.31 mm). Conclusions: Our study results suggest that the River NC balloon is effective and safe. In the QCA evaluation, River NC balloon obtained prespecified diameters and lengths at applied pressures. Study registration: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products (UR.D.WM.DNB.109.2019).

Predicting clinical outcome by indexed mitral valve tenting in functional mitral valve regurgitation

ObjectivesMitral valve (MV) tenting parameters are indicators of left ventricular remodelling severity and may predict outcome in functional mitral regurgitation (FMR). We hypothesised that indexing of MV tenting area to body surface area (BSA), to mitral annulus diameter or gender-adjusted analysis of tenting parameters may improve their prognostic value.MethodsWe identified retrospectively 240 patients with consecutive FMR (mean age 68±10 years; men=135) from our institutional database who underwent isolated MV annuloplasty during a period of 7 years (2010–2016). Using preoperative two-dimensional transthoracic echocardiographic images, MV tenting parameters including tenting area, tenting height and annulus diameter were systematically assessed. Follow-up protocol consisted of chart review and structured clinical questionnaire. Primary study endpoint was the composite of death and adverse cardiac events (ie, MV reoperation, cardiac resynchronisation therapy implantation, ventricular assist device implantation or heart transplantation).ResultsBSA-indexed MV tenting area was identified as independent predictor of primary study endpoint (HR 1.9; 95% CI 1.1 to 3.5; p=0.02). After cut-off point analysis, BSA-indexed MV tenting area >1.35 cm2/m2 was significantly associated with primary study outcome (HR 2.3; 95% CI 1.3 to 4.0; p=0.003). Annulus-indexed MV tenting area showed only a tendency towards primary study endpoint prediction (HR 2.8; 95% CI 0.6 to 12.6; p=0.17). Between female and male patients, BSA-indexed MV tenting area was similar (1.42±0.4 cm2/m2 vs 1.45±0.4cm2/cm2; p=0.6) and gender was not associated with primary study outcome (HR 0.8; 95% CI 0.5 to 1.4; p=0.5).ConclusionIn our FMR cohort, BSA-indexed MV tenting area showed the strongest association with negative outcomes following isolated MV annuloplasty. Patients with BSA-indexed MV tenting area >1.35cm2/m2 could potentially benefit from additional surgical maneuvers addressing left ventricular remodelling.

Adaptive development of concomitant secondary mitral and tricuspid regurgitation after TAVR

Background Concomitant secondary atrioventricular regurgitation is frequent in patients with severe aortic stenosis scheduled fortranscatheter aortic valve replacement (TAVR). The future implications of leaving associated valve lesions untreated after TAVR remain unknown. Aim of the present study wasto characterize the evolution of concomitant secondary atrioventricular regurgitations and to evaluate their impact on long-term prognosis. Methods We prospectively enrolled 429 consecutive TAVR patients. All patients underwent comprehensive clinical, laboratory, and echocardiographic assessments prior to TAVR, at discharge, and yearly thereafter. All-cause mortality was chosen as primary study endpoint. Results At baseline, severe concomitant secondary mitral regurgitation (sMR) was present in 54 (13%) and severe concomitant secondary tricuspid regurgitation (sTR) in 75 patients (17%). After TAVR 59% of patients with severe sMR at baseline experienced sMR regression, whereas analogously sTR regressed in 43% of patients with severe sTR at baseline. Persistence of sTR and sMR were associated with excess mortality after adjustment for our bootstrap-selected confounder model with an adjusted HR of 2.44 (95% CI 1.15–5.20, P=0.021) for sMR and of 2.09 (95% CI 1.20–3.66, P=0.01) for sTR (Figure 1). Furthermore patients showing regression of atrioventricular regurgitation exhibited survival rates indistinguishable to those seen in patients without concomitant atrioventricular regurgitation (sMR: P=0.83; sTR: P=0.74) Conclusion Concomitant secondary atrioventricular regurgitation in patients with severe AS is a highly dynamic process with up to half of all patients showing regression of associated valvular regurgitation after TAVR and subsequent favorable post-interventional outcome. Persistent atrioventricular regurgitation is a major determinant of TAVR futility and proposes a window of early sequel intervention. Funding Acknowledgement Type of funding source: None

Thromboprophylaxis in congenital nephrotic syndrome: 15-year experience from a national cohort

Introduction Congenital nephrotic syndrome (CNS) is an ultra-rare disease associated with a pro-thrombotic state and venous thromboembolisms (VTE). There is very limited evidence evaluating thromboprophylaxis in patients with CNS. This study aimed to determine the doses and duration of treatment required to achieve adequate thromboprophylaxis in patients with CNS. Methods From 2005 to 2018 children in Scotland with a confirmed genetic or histological diagnosis of CNS were included if commenced on thromboprophylaxis. The primary study endpoint was stable drug monitoring. Secondary outcomes included VTE or significant haemorrhage. Results Eight patients were included; all initially were commenced on low-molecular weight heparin (enoxaparin). Four patients maintained therapeutic anti-Factor Xa levels (time 3–26 weeks, dose 3.2–5.07 mg/kg/day), and one patient developed a thrombosis (Anti-Factor Xa: 0.27 IU/ml). Four patients were subsequently treated with warfarin. Two patients maintained therapeutic INRs (time 6–11 weeks, dose 0.22–0.25 mg/kg/day), and one patient had two bleeding events (Bleed 1: INR 6, Bleed 2: INR 5.5). Conclusions Achieving thromboprophylaxis in CNS is challenging. Similar numbers of patients achieved stable anticoagulation on warfarin and enoxaparin. Enoxaparin dosing was nearly double the recommended starting doses for secondary thromboprophylaxis. Bleeding events were all associated with supra-therapeutic anticoagulation.

Randomized phase II study of adjuvant afatinib for three months versus two years in patients with resected stage I-III EGFR mutant NSCLC.

8507 Background: EGFR tyrosine kinase inhibitors are superior to chemotherapy in patients with advanced EGFR+ lung cancers. In the adjuvant setting, erlotinib for two years improves recurrence free survival (RFS) compared to historical controls. The optimal duration of adjuvant TKI is unknown. Methods: Patients with completely resected Stage I-III NSCLC with a sensitizing EGFR mutation were enrolled after standard adjuvant therapy. Pts were randomly assigned to 3 months (3m) or 2 years (2y) of adjuvant afatinib. Afatinib was started at 30 mg by mouth daily. Patients without toxicity after 28 days were allowed to escalate to 40 mg daily. Patients were imaged with CT every 6 months for 3 years and then annually or as clinically indicated. RFS was measured from the date of randomization. The primary study endpoint was recurrence rate at 2 years. 60 randomized patients would provide 82.5% power to detect a 26% difference in 2y-recurrence rate. Results: Patient characteristics are in the Table. The study was terminated for slow accrual after 46 of the planned 60 patients. Planned treatment was completed by 92% (22/24) pts in the 3m arm and 41% (9/22) of pt in the 2y arm. 22 patients required ≥1 dose modification due to toxicity including expected GI, mucosal, and skin AEs. With a median follow-up of ≥38 months there were 10 recurrences and 3 deaths in the 3m arm and there were 5 recurrences (2 on treatment) and 2 deaths in the 2y arm. Median RFS has not been reached in either arm, but recurrence was more common in the 3m arm at every landmark. 2y-recurrence rates were 29% for 3m and 15% for 2y. Conclusions: Recurrences at 2 years were 14% less common with 2y versus 3m of adjuvant afatinib. This difference did not meet the primary study endpoint. The RFS curves show a durable and clinically meaningful separation with substantial follow-up. Failure to meet significance was likely influenced by under-accrual and early drug discontinuation on the 2y arm. In the era of TKIs with improved tolerance, duration of adjuvant therapy remains an important question. Clinical trial information: NCT01746251. [Table: see text]

Efficacy of gemcitabine with erlotinib in rash-positive patients selected according to eligibility for FOLFIRINOX.

4108 Background: The efficacy and safety of gemcitabine + erlotinib has not yet been defined prospectively in patients (pts) with metastatic pancreatic cancer (mPC) selected according to the inclusion criteria defined by Conroy et al. for FOLFIRINOX (e. g. ECOG 0-1, age < 75, bilirubin < 1.5xULN). Methods: In this German phase II trial, 150 pts with histologically confirmed mPC were recruited between July 2012 and July 2015 in 20 centers. If pts showed skin rash of any grade within 4 weeks after start of treatment with gemcitabine (1000 mg/m2 weekly) and erlotinib (100 mg daily), this regimen was continued; rash-negative pts were switched to FOLFIRINOX. The primary study endpoint was the 1-year survival rate in rash-positive pts (hypothesis: ≥40%). Results: Ninety pts who were under treatment with gemcitabine + erlotinib for 4 weeks developed skin rash of any grade: the 1-year survival rate in those pts positive for skin rash was 40.0% (95%CI 29.8-50.9); median overall survival (OS) counted from day of first treatment was 10.1 months (mo) (95%CI 9.0-12.5), progression-free survival (PFS) 3.9 mo (95%CI 3.5-4.9), objective response rate (ORR) and disease control rate (DCR) were 21% and 64%, respectively. Median treatment duration with gemcitabine+erlotinib was 3.7 mo (Range 0.7-17.5). In rash-negative pts who were switched to FOLFIRINOX after 4 weeks of gemcitabine + erlotinib (n = 28) the 1-year survival rate was 46.4% (95%CI 27.5-66.1), median OS 10.6 mo (95%CI 6.6-13.6), median PFS 5.2 mo (95%CI 2.3-7.9) and the corresponding ORR and DCR rates were 29 and 54%, respectively. The rate of salvage therapy was 53% after gemcitabine+erlotinib, mostly consisting of 5-FU-based schemas (42 % 5-FU/folinic acid + irinotecan or oxaliplatin, 38% FOLFIRINOX) and 43% after FOLFIRINOX (all pts received gemcitabine, 67% in combination with nab-paclitaxel). In the Intention To Treat (ITT) population (n = 145) OS was 9.7 mon (95%CI 7.8-10.9). Conclusions: In rash-positive pts deemed fit for FOLFIRINOX first-line treatment with gemcitabine + erlotinib appears effective achieving a one-year-survival rate of 40%. Early switch to FOLFIRINOX was an effective strategy in rash-negative patients. Clinical trial information: NCT01729481.