Citations

Objective Antireflux surgery can be proposed in patients with GORD, especially when proton pump inhibitor (PPI) use leads to incomplete symptom improvement. However, to date, international consensus guidelines on the clinical criteria and additional technical examinations used in patient selection for antireflux surgery are lacking. We aimed at generating key recommendations in the selection of patients for antireflux surgery. Design We included 35 international experts (gastroenterologists, surgeons and physiologists) in a Delphi process and developed 37 statements that were revised by the Consensus Group, to start the Delphi process. Three voting rounds followed where each statement was presented with the evidence summary. The panel indicated the degree of agreement for the statement. When 80% of the Consensus Group agreed (A+/A) with a statement, this was defined as consensus. All votes were mutually anonymous. Results Patients with heartburn with a satisfactory response to PPIs, patients with a hiatal hernia (HH), patients with oesophagitis Los Angeles (LA) grade B or higher and patients with Barrett’s oesophagus are good candidates for antireflux surgery. An endoscopy prior to antireflux surgery is mandatory and a barium swallow should be performed in patients with suspicion of a HH or short oesophagus. Oesophageal manometry is mandatory to rule out major motility disorders. Finally, oesophageal pH (±impedance) monitoring of PPI is mandatory to select patients for antireflux surgery, if endoscopy is negative for unequivocal reflux oesophagitis. Conclusion With the ICARUS guidelines, we generated key recommendations for selection of patients for antireflux surgery.

Background:Autoimmune haemolytic anaemia (AIHA) is characterized by haemolysis mediated by autoantibodies directed against red blood cells (RBCs). Warm antibody (wAIHA; 60%>70%) and cold agglutinin disease (CAD; 20%>25%) subclasses are defined by the immunoglobulin (Ig) isotype involved and its thermal optimum for binding RBCs. wAIHA is mediated by IgG while 90% of CAD is mediated by IgM isotypes. CAD and wAIHA outcomes can be life‐threatening, but no therapies are approved. Complement C3b deposition on RBCs plays a central role in AIHA, accelerating phagocytosis in the liver and/or spleen (extravascular haemolysis) and forming membrane attack complexes (intravascular haemolysis). By blocking formation of C3b, APL‐2, a cyclic peptide, has potential as a novel therapeutic for AIHA.Aims:To assess whether inhibiting complement C3 with daily subcutaneous (SC) doses of APL‐2 (270 mg/day or 360 mg/day) prevents intra‐ and extravascular haemolysis in AIHA subjects, reducing anaemia associated signs and symptoms.Methods:Subjects with primary AIHA were eligible for this Ph 2 open‐label study to assess the safety, tolerability, efficacy, and pharmacokinetics of APL‐2. Subjects had haemoglobin (Hb) levels < 11 g/dL, signs of haemolysis, and a positive direct agglutinin test (DAT) for IgG and/or complement C3. Twenty‐four subjects (13 CAD, 11 wAIHA) were recruited and will be treated with APL‐2 for 48 weeks. Efficacy was assessed by change from baseline in Hb, transfusion requirements, absolute reticulocyte counts (ARC), lactate dehydrogenase (LDH), haptoglobin, indirect bilirubin (INDBIL), and Functional Assessment of Illness Therapy (FACIT) fatigue score. Data are reported after 16 weeks (Day 112).Results:Two of 13 CAD subjects withdrew; 7 of 11 remaining subjects reached Day 112. Mean Hb (standard error [SE]) increased from 8.9 (0.4) [n = 13] to 11.6 (0.5) [n = 7] g/dL, and mean LDH, ARC, and INDBIL returned within normal range. Mean FACIT scores (SE) increased 9.9 (3.4) points from baseline. Two subjects had pre‐study and 1 had on‐study transfusions (normalized to 112 days). All 13 CAD experienced ≥1 treatment‐emergent adverse event (TEAE), mainly Grade 1–2 and unrelated. Four subjects reported 10 unrelated serious adverse events (SAEs) (6 SAEs in 1 subject). Three subjects experienced 3 unrelated Grade 3 TEAEs (pneumonia, dyspnoea, hypertension); 1 subject reported 2 unrelated Grade 4 TEAEs (high calcium, high creatinine) and withdrew.Eight of 11 wAIHA subjects were DATmonoC3+ and 3 were DATmonoC3‐. Two of 3 DATmonoC3‐ withdrew for lack of response and efficacy data are reported for 8 DATmonoC3+ subjects. Six of these reached Day 112. Mean Hb (SE) increased from 9.2 (0.3) [n = 8] to 10.8 (0.5) [n = 6] g/dL, and mean ARC and INDBIL returned within normal. Mean FACIT scores (SE) increased 2.7 (2.8) points from baseline. One subject had pre‐study and 2 had on‐study transfusions (normalized to 112 days). Ten of 11 wAIHA (C3+ and C3‐) experienced ≥1 TEAE, mainly Grade 1–2 and unrelated. Five subjects reported 8 unrelated SAEs. Five subjects experienced 13 unrelated Grade 3 TEAEs (oral squamous cell carcinoma, haemolytic flare, purpura, acute kidney injury, dyspnoea, chest pain); 1 subject reported 1 unrelated Grade 4 TEAE (haemolytic flare) and withdrew. Six‐month data for 10 CAD and 6 wAIHA C3+ is planned for June 2019.Summary/Conclusion:APL‐2 increases Hb values in CAD and wAIHA C3+ within the first weeks of treatment with sustained benefit with longer exposure. APL‐2 reduces intra‐ and extravascular haemolysis shown by reductions in LDH, INDBIL, and ARC. APL‐2 appears to be safe and well‐tolerated.

Background:Patients (pts) with multiple myeloma associated with high cytogenetic risk abnormalities have poor outcomes. In CASTOR, D‐Vd prolonged progression‐free survival (PFS) vs bortezomib and dexamethasone (Vd) alone, and exhibited a manageable safety profile in pts with RRMM. We conducted a subgroup analysis of D‐Vd vs Vd in CASTOR, based on cytogenetic risk.Aims:The purpose of this analysis was to determine the efficacy and safety of D‐Vd in CASTOR based on cytogenetic risk status.Methods:Eligible pts received ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of next‐generation sequencing (NGS) and fluorescence in situ hybridization (FISH)/karyotype testing. High‐risk pts had t(4;14), t(14;16), or del17p abnormalities. Standard (std)‐risk pts were confirmed negative for all 3 abnormalities. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ® assay V2.0.Results:In CASTOR (D‐Vd, n = 251; Vd, n = 247), high‐risk was confirmed in 26.7% and 25.9% of pts in the D‐Vd and Vd groups, respectively. At a median follow up of 40.0 months (mo), D‐Vd prolonged PFS vs Vd in pts with high‐ (median 13.4 vs 7.2 mo; HR, 0.40 [95% CI, 0.24–0.65]; P = 0.0002) or std‐risk (median 18.4 vs 6.8 mo; HR, 0.28 [95% CI, 0.20–0.37]; P <0.0001). Higher ORR was seen with D‐Vd vs Vd (high risk: 84.8% vs 60.0%; P = 0.0226; std risk: 85.4% vs 65.0%; P <0.0001), including deep responses of ≥CR (high risk: 33.3% vs 8.3%; std risk: 29.9% vs 10.2%) and ≥VGPR (high risk: 65.2% vs 35.0%; P = 0.0049; std risk: 64.3% vs 28.0%; P <0.0001). Higher rates of MRD negativity (high risk: 17.9% vs 0%; P = 0.0003; std risk: 13.3% vs 2.4%; P = 0.0003), and sustained MRD negativity for ≥6 mo (high risk: 16.4% vs 0%; P = 0.0006; std risk: 6.1% vs 1.8%; P = 0.0859) and ≥12 mo (high risk: 7.5% vs 0%; P = 0.0581; std risk: 1.8% vs 0%; P = 0.2477) were seen with D‐Vd vs Vd. D‐Vd significantly prolonged PFS vs Vd in pts with one prior line of therapy only (high risk: median 20.1 vs 8.4 mo; HR, 0.30 [95% CI, 0.14–0.64]; P = 0.0012; std risk: median 32.6 vs 7.9 mo; HR, 0.18 [95% CI, 0.11–0.29]; P <0.0001; Figure). Additionally, D‐Vd significantly prolonged PFS2 (high risk: median 27.9 vs 18.6 mo; HR, 0.59 [95% CI, 0.37–0.94]; P = 0.0258; std risk: median 40.1 vs 21.6 mo; HR, 0.43 [95% CI, 0.32–0.59]; P <0.0001) regardless of cytogenetic risk status.Additional data including safety analyses will be presented.Summary/Conclusion:Adding daratumumab to Vd demonstrates significant efficacy in pts with high‐risk RRMM including PFS2. Among high‐risk RRMM pts, MRD negativity was only achieved with D‐Vd. These findings support use of D‐Vd for high‐risk RRMM. NCT02136134image

Objectives: To evaluate the ability of 18F-labeled fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to predict survivorship of patients with bladder cancer (BC) and/or upper urinary tract carcinoma (UUTC). Materials: Data from patients who underwent FDG PET/CT for suspicion of recurrent urothelial carcinoma (UC) between 2007 and 2015 were retrospectively collected in a multicenter study. Disease management after the introduction of FDG PET/CT in the diagnostic algorithm was assessed in all patients. Kaplan-Meier and log-rank analysis were computed for survival assessment. A Cox regression analysis was used to identify predictors of recurrence and death, for BC, UUTC, and concomitant BC and UUTC. Results: Data from 286 patients were collected. Of these, 212 had a history of BC, 38 of UUTC and 36 of concomitant BC and UUTC. Patient management was changed in 114/286 (40%) UC patients with the inclusion of FDG PET/CT, particularly in those with BC, reaching 74% (n = 90/122). After a mean follow-up period of 21 months (Interquartile range: 4–28 mo.), 136 patients (47.4%) had recurrence/progression of disease. Moreover, 131 subjects (45.6%) died. At Kaplan-Meier analyses, patients with BC and positive PET/CT had a worse overall survival than those with a negative scan (log-rank < 0.001). Furthermore, a negative PET/CT scan was associated with a lower recurrence rate than a positive examination, independently from the primary tumor site. At multivariate analysis, in patients with BC and UUTC, a positive FDG PET/CT resulted an independent predictor of disease-free and overall survival (p < 0,01). Conclusions: FDG PET/CT has the potential to change patient management, particularly for patients with BC. Furthermore, it can be considered a valid survival prediction tool after primary treatment in patients with recurrent UC. However, a firm recommendation cannot be made yet. Further prospective studies are necessary to confirm our findings.

Background: The management of complex perianal fistulas in Crohn’s disease (CD) represents a challenge for patients, gastroenterologists and colorectal surgeons. There are clear limitations with current medical and surgical options, and healing rates remain far from what is expected. A multidisciplinary approach with optimized medical therapy, usually anti-TNF agents, associated with setons and additional surgical techniques is currently the best strategy to aim fistula healing. Methods: A comprehensive review of the literature was conducted on the use of mesenchymal stem cells (MSCs). Results: The use of mesenchymal stem cells (MSCs) has recently emerged as a promising new therapeutic strategy for complex fistulas in CD patients. This review summarizes the evidence of the use of MSCs in complex CD fistulas, by exploring in detail the types of cells that can be used and their modes of delivery. Additionally, the results of the most recent phase III randomized trial with local MSCs injection are described, and future challenges of this therapeutic option are discussed. Conclusion: The use of MSCs represents hope for better outcomes in patients with CD-related perianal fistulas. More research in the field will help to position this specific therapy in treatment algorithms.

Abstract MRI has improved the diagnostic work-up of multiple sclerosis, but inappropriate image interpretation and application of MRI diagnostic criteria contribute to misdiagnosis. Some diseases, now recognized as conditions distinct from multiple sclerosis, may satisfy the MRI criteria for multiple sclerosis (e.g. neuromyelitis optica spectrum disorders, Susac syndrome), thus making the diagnosis of multiple sclerosis more challenging, especially if biomarker testing (such as serum anti-AQP4 antibodies) is not informative. Improvements in MRI technology contribute and promise to better define the typical features of multiple sclerosis lesions (e.g. juxtacortical and periventricular location, cortical involvement). Greater understanding of some key aspects of multiple sclerosis pathobiology has allowed the identification of characteristics more specific to multiple sclerosis (e.g. central vein sign, subpial demyelination and lesional rims), which are not included in the current multiple sclerosis diagnostic criteria. In this review, we provide the clinicians and researchers with a practical guide to enhance the proper recognition of multiple sclerosis lesions, including a thorough definition and illustration of typical MRI features, as well as a discussion of red flags suggestive of alternative diagnoses. We also discuss the possible place of emerging qualitative features of lesions which may become important in the near future.

Abstract Aims Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.