Comparing right- versus left-first implantation in off-pump sequential double-lung transplantation: an observational cohort study.

OBJECTIVES: Historically, the perfusion-guided sequence suggests to first transplant the side with lowest lung perfusion. This sequence is thought to limit right ventricular afterload and prevent acute heart failure after first pneumonectomy. As a paradigm shift, we adopted the right-first implantation sequence, irrespective of lung perfusion. The right donor lung generally accommodates a larger proportion of the cardiac output. We hypothesized that the right-first sequence reduces the likelihood of oedema formation in the firstly transplanted graft during second-lung implantation. Our objective was to compare the perfusion-guided and right-first sequence for intraoperative extracorporeal membrane oxygenation (ECMO) need and primary graft dysfunction (PGD). METHODS: A retrospective single-centre cohort study (2008-2021) including double-lung transplant cases (N = 696) started without ECMO was performed. Primary end-points were intraoperative ECMO cannulation and PGD grade 3 (PGD3) at 72 h. Secondary end-points were patient and chronic lung allograft dysfunction-free survival. In cases with native left lung perfusion ≤50% propensity score adjusted comparison of the perfusion-guided and right-first sequence was performed. RESULTS: When left lung perfusion was ≤50%, right-first implantation was done in 219 and left-first in 189 cases. Intraoperative escalation to ECMO support was observed in 10.96% of right-first versus 19.05% of left-first cases (odds ratio 0.448; 95% confidence interval 0.229-0.0.878; P = 0.0193). PGD3 at 72 h was observed in 8.02% of right-first versus 15.64% of left-first cases (0.566; 0.263-1.217; P = 0.1452). Right-first implantation did not affect patient or chronic lung allograft dysfunction-free survival. CONCLUSIONS: The right-first implantation sequence in off-pump double-lung transplantation reduces need for intraoperative ECMO cannulation with a trend towards less PGD grade 3.

High dose vitamin D supplementation does not improve outcome in a cutaneous melanoma population: results of a randomized double-blind, placebo-controlled study (ViDMe trial).

BACKGROUND: Observational studies in cutaneous melanoma have indicated an inverse relationship between levels of 25-hydroxy vitamin D and Breslow thickness, as well as a protective effect of high 25- hydroxy vitamin D levels on clinical outcome. OBJECTIVES: To evaluate whether high dose vitamin D supplementation in curatively resected cutaneous melanoma reduces melanoma relapse. METHODS: In a prospective, randomized, double-blind, placebo-controlled trial, 436 patients with resected cutaneous melanoma stage IA to III (8th American Joint Committee on Cancer staging) were randomized. Among them, 218 received a placebo while 218 received monthly 100,000 IU cholecalciferol for a minimum of 6 months and a maximum of 42 months (treatment arm). Following randomization, patients were followed for a median of 52 months, with a maximum follow-up of 116 months. The primary endpoint was relapse-free survival. Secondary endpoints were melanoma-related mortality, overall survival, and the evolution of 25-hydroxy vitamin D serum levels over time. RESULTS: In our population (mean age 55 years, 54% female) Vitamin D supplementation increased 25- hydroxy vitamin D serum levels after 6 months of supplementation in the treatment arm by a median 17 ng/ml (95%CI: 9; 26) compared to 0 ng/ml (95%CI: -6; 8) in the placebo arm (P < 0.001; Wilcoxon test) and remained at a steady state during the whole treatment period. The estimated event rate for relapse-free survival at 72 months after inclusion was 26.51% in the vitamin D supplemented arm (95% CI: 19.37; 35.64) versus 20.70% (95%CI: 14.26; 29.52) in the placebo arm, [hazard ratio 1.27 (95%CI 0.79; 2.03), P = 0.32]. After adjusting for confounding factors (including baseline stage, body mass index, age, gender, and baseline season), the hazard ratio was 1.20 (95% CI 0.74; 1.94, P = 0.46). Deaths from progression of cutaneous melanoma and non-melanoma related deaths were similar in both vitamin D supplemented and placebo group (n = 10 and 11 and n = 3 and 2, respectively). No major adverse events were observed during the study. CONCLUSION: In cutaneous melanoma patients, monthly high dose vitamin D supplementation was safe, resulted in a sustained increase in 25-hydroxy vitamin D levels during the treatment period, but did not improve relapse-free survival, melanoma-related death or overall survival.

Clinical and genetic determinants of vitamin D receptor expression in cutaneous melanoma patients.

Decrease of vitamin D receptor (VDR) expression is observed in melanocytic naevi and melanoma compared to normal skin. Little is known about factors influencing VDR expression in cutaneous melanoma (CM). We investigated the correlation of VDR expression in CM with 25-hydroxy vitamin D (25OHD) levels, demographic/clinical parameters, genetic variants of VDR and pathology of the primary tumor. Demographic/clinical parameters were recorded in 407 prospectively recruited CM patients of a multi-center controlled study (ViDMe trial). We determined VDR expression both in the nucleus and in the cytoplasm by semi-quantitative assessment in CM tissue using histochemistry in 279 patients, expressed in percentages and histoscore (H-score). Genomic DNA from 332 patients was extracted to genotype thirteen VDR single nucleotide polymorphisms (SNPs) using TaqMan. VDR expression in CM tissue from 279 patients was correlated with clinical/demographic parameters and 25OHD levels (univariable and multivariable analysis), VDR SNPs (univariable analysis) and pathology parameters of primary CM tissue (univariable analysis). Cytoplasmic VDR expression was increased in patients who stated to have a high sun exposure during their life compared to patients with low sun exposure (p H-score,univariable : 0.001, p H-score,multivariable : 0.004). The A allele of the genetic VDR polymorphism Fok1 was associated with a higher expression of the VDR in the cytoplasm (p cytoplasmic, univariable : 0.001 and p H-score, univariable : 0.02). In the primary tumor, presence of mitosis (p nucleus,%, univariable : 0.002) and perineural invasion (p nucleus,%,univariable : 0.03) were significantly associated with low nuclear VDR expression. ClinicalTrials.gov Identifier: NCT01748448.

10-year follow-up results of the European Achalasia Trial: a multicentre randomised controlled trial comparing pneumatic dilation with laparoscopic Heller myotomy.

OBJECTIVE: As achalasia is a chronic disorder, long-term follow-up data comparing different treatments are essential to select optimal clinical management. Here, we report on the 10-year follow-up of the European Achalasia Trial comparing endoscopic pneumodilation (PD) with laparoscopic Heller myotomy (LHM). DESIGN: A total of 201 newly diagnosed patients with achalasia were randomised to either a series of PDs (n=96) or LHM (n=105). Patients completed symptom (Eckardt score) and quality-of-life questionnaires, underwent functional tests and upper endoscopy. Primary outcome was therapeutic success defined as Eckardt score <3 at yearly follow-up. Secondary outcomes were the need for retreatment, lower oesophageal sphincter pressure, oesophageal emptying, gastro-oesophageal reflux and the rate of complications. RESULTS: After 10 years of follow-up, LHM (n=40) and PD (n=36) were equally effective in both the full analysis set (74% vs 74%, p=0.84) and the per protocol set (74% vs 86%, respectively, p=0.07). Subgroup analysis revealed that PD was superior to LHM for type 2 achalasia (p=0.03) while there was a trend, although not significant (p=0.05), that LHM performed better for type 3 achalasia. Barium column height after 5 min at timed barium oesophagram was significantly higher for patients treated with PD compared with LHM, while other parameters, including gastro-oesophageal reflux, were not different. CONCLUSIONS: PD and LHM are equally effective even after 10 years of follow-up with limited risk to develop gastro-oesophageal reflux. Based on these data, we conclude that PD and LHM can both be proposed as initial treatment of achalasia.

Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma: Results of the phase II PRIMMO study.

A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0-31.0) in cervical cancer and 12.0% (90% CI 3.4-28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1-25.7) in cervical cancer and 3.6 weeks (95% CI 3.6-15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0-67.0) and 37.4 weeks (95% CI 19.0-50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity.Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97).

Ninety-Day Follow-up Is Inadequate for Diagnosis of Fracture-related Infections in Patients with Open Fractures.

BACKGROUND: Fracture-related infection (FRI) is a challenging complication in musculoskeletal trauma surgery and often complicates the management of open fractures. The CDC currently advocates a surveillance period of 90 days after fracture fixation, but it is unclear what duration of follow-up constitutes adequate surveillance for FRI. Inadequate follow-up will underestimate infections and, in clinical research, will make any interventions studied appear better than they really are, thereby resulting in misleading conclusions. QUESTIONS/PURPOSES: (1) What is the timing of FRI onset in patients with open fractures? (2) What is the proportion of FRIs captured when follow-up is limited to 90 days postoperatively versus when follow-up is extended to 1 year? METHODS: This is a secondary analysis of patient data from a previous retrospective cohort study that investigated whether the duration of perioperative antibiotic prophylaxis was independently associated with FRI in patients with open fractures. Of the 530 eligible patients in the source study, 3% (14) died. Of the remaining 516 patients, 97% (502) patients with 559 long-bone open fractures had 2 years of follow-up constituted the base cohort. Forty-seven fractures in 46 patients were complicated by FRI and were the focus of this secondary analysis. Medical records were reviewed in detail specifically for the current study. Seventy-eight percent (36 of 46) of patients were male, and the mean ± SD age was 42 ± 16 years. The most common mechanism of injury was a motor vehicle accident (63% [29 of 46] of patients), and the tibia was the most involved site (53% [25 of 47] of fractures). The median (interquartile range) time to debridement was 3.0 hours (IQR 2.0 to 4.0). FRIs developed in 3% (7 of 247) of Type I open fractures, 7% (11 of 164) of Type II, 17% (18 of 107) of Type IIIA, 29% (9 of 31) of Type IIIB, and 20% (2 of 10) of Type IIIC open fractures. Each clinic visit of each patient was reviewed, and data about the time of onset of any symptoms and signs suggesting or confirming an FRI, as reported by patients and/or determined by treating surgeons, were recorded. The proportions of FRIs with onset by specific time periods were determined. A Kaplan-Meier survival analysis was performed, and the FRI event rates with 95% confidence intervals were calculated. RESULTS: The median (IQR) time to the onset of FRI was 52 days (IQR 15 to 153). Follow-up of 90 days captured only 64% (30 of 47) of FRIs, whereas follow-up of 1 year captured 89% (42 of 47) of FRIs. The proportion of FRIs with onset within 1 year increased to 95% (42 of 44) in the presence of an already healed fracture. CONCLUSION: Follow-up of 90 days after the management of an open long-bone fracture is inadequate for postoperative surveillance, especially for research purposes. Clinical research on interventions would report results appearing to be much better than they really are, potentially resulting in misleading conclusions. Follow-up of 1 year is preferable because most FRIs will develop before that time, especially when fracture union has occurred. A small percentage of patients may still develop infections beyond the first year after the management of an open fracture. The risk of missing these infections by not extending follow-up beyond 1 year must be balanced against the additional logistical burden. Future prospective multicenter studies and registries with long-term patient follow-up would help clarify this issue.Level of Evidence Level III, diagnostic study.

Impact of duration of perioperative antibiotic prophylaxis on development of fracture-related infection in open fractures.

INTRODUCTION: Infection is a common complication of open fractures potentially leading to nonunion, functional loss, and even amputation. Perioperative antibiotic prophylaxis (PAP) is standard practice for infection prevention in the management of open fractures. However, optimal duration of PAP remains controversial. The objectives were to assess whether PAP duration is independently associated with infection in open fractures and if administration of PAP beyond the commonly-recommended limit of 72 h has any effect on the infection rate. MATERIALS AND METHODS: Over a 14-year period from 2003 to 2017, 530 skeletally-mature patients with operatively-treated, non-pathologic, long-bone open fractures were treated at one institution. Twenty-eight patients were excluded because of death or loss to follow-up and the remaining 502 patients (with 559 open fractures) who completed a 24-month follow-up were included in this retrospective study. The outcome was fracture-related infection (FRI), defined by the criteria of a recent consensus definition. A logistic generalized estimating equations regression model was conducted, including PAP duration and variables selected by a least absolute shrinkage and selection operator (LASSO) method, to assess the association between PAP duration and FRI. Propensity score analysis using a 72-h cut-off was performed to further cope with confounding. RESULTS: PAP duration, adjusted for the LASSO selected predictors, was independently associated with FRI (OR: 1.11 [95%CI, 1.04-1.19] for every one-day increase in PAP duration, p = 0.003). PAP duration longer than 72 h did not significantly increase the odds for FRI compared to shorter durations (p = 0.06, analysis adjusted for propensity score). CONCLUSIONS: This study found no evidence that administration of prophylactic antibiotics beyond 72 h in patients with long-bone open fractures is warranted. Analyses adjusted for known confounders even revealed a higher risk for FRI for longer PAP. However, this effect cannot necessarily be considered as causal and further research is needed.

Patient satisfaction with intravenous regional anaesthesia or an axillary block for minor ambulatory hand surgery: A randomised controlled study.

BACKGROUND: Intravenous regional anesthesia (IVRA) and the axillary brachial plexus block are popular alternatives to general anaesthesia in ambulatory hand surgery. Although both have proven their effectiveness, patients' preferences have never been evaluated. OBJECTIVES: We investigated patient satisfaction with both techniques and hypothesised that satisfaction after IVRA is noninferior compared with axillary brachial plexus block. DESIGN: A prospective, randomised controlled trial. SETTING: Ambulatory surgical day care centre, University Hospitals of Leuven, Belgium, from September 2016 to November 2017. PATIENTS: One hundred and twenty adults undergoing minor ambulatory hand surgery were included in this study. INTERVENTION: Patients received either IVRA with 300 mg lidocaine or an axillary block with 280 mg mepivacaine. MAIN OUTCOME MEASURES: The primary endpoint was the evaluation of patient satisfaction using the 'Evaluation du Vécu de l'Anésthesie Locoregional' (EVAN-LR) questionnaire. Secondary outcomes included different procedural times, block quality, tourniquet discomfort, the incidence of block failure and postoperative nausea and vomiting (PONV), the severity of postoperative pain and the need for postoperative analgesics during the first 24 h. RESULTS: Noninferiority of IVRA was shown for the median [IQR] total score on the EVAN-LR questionnaire, IVRA-group: 92 [87 to 96] vs. axillary brachial plexus block-group: 91[87 to 97]; Hodges--Lehmann estimator (95% confidence interval (CI)] for the shift: -0.25 (-2.60 to 2.20). Induction of anaesthesia and time to discharge, requiring partial recovery of the motor block, were significantly longer in the axillary brachial plexus block group. The IVRA-group had a lower block quality, a higher incidence of tourniquet-discomfort and higher median intra-operative and postoperative pain scores on day 0; 0 [0 to 2] vs. 0 [0 to 0] and 0.8 [0 to 1.8] vs. 0 [0 to 0.25], respectively, but no increase in the need for supplementary analgesics or conversion rate to general anaesthesia. CONCLUSION: IVRA and axillary brachial plexus block result in comparably high patient satisfaction in ambulatory hand surgery. CLINICAL TRIAL REGISTRATION: EudraCT 2016-002325-11.

The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: the BAMI trial.

AIMS: Bone marrow-derived mononuclear cell (BM-MNC) therapy may improve myocardial recovery in patients following acute myocardial infarction (AMI), though existing trial results are inconsistent. METHODS AND RESULTS: Originally an open-label, multicentre Phase III trial, BAMI was designed to demonstrate the safety and efficacy of intracoronary infusion of BM-MNCs in reducing the time to all-cause mortality in patients with reduced left ventricular ejection fraction (LVEF, ≤45%) after primary angioplasty (PPCI) for ST-elevation AMI. Unexpectedly low recruitment means the trial no longer qualifies as a hypothesis-testing trial, but is instead an observational study with no definitive conclusions possible from statistical analysis. In total, 375 patients were recruited: 185 patients were randomized to the treatment arm (intracoronary infusion of BM-MNCs 2-8 days after PPCI) and 190 patients to the control arm (optimal medical therapy). All-cause mortality at 2 years was 3.26% [6 deaths; 95% confidence interval (CI): 1.48-7.12%] in the BM-MNC group and 3.82% (7 deaths; 95% CI: 1.84-7.84%) in the control group. Five patients (2.7%, 95% CI: 1.0-5.9%) in the BM-MNC group and 15 patients (8.1%, CI : 4.7-12.5%) in the control group were hospitalized for heart failure during 2 years of follow-up. Neither adverse events nor serious adverse events differed between the two groups. There were no patients hospitalized for stroke in the control group and 4 (2.2%) patients hospitalized for stroke in the BM-MNC group. CONCLUSIONS: Although BAMI is the largest trial of autologous cell-based therapy in the treatment of AMI, unexpectedly low recruitment and event rates preclude any meaningful group comparisons and interpretation of the observed results.

Treatment failure and hospital readmissions in severe COPD exacerbations treated with azithromycin versus placebo - a post-hoc analysis of the BACE randomized controlled trial.

BACKGROUND: In the BACE trial, a 3-month (3 m) intervention with azithromycin, initiated at the onset of an infectious COPD exacerbation requiring hospitalization, decreased the rate of a first treatment failure (TF); the composite of treatment intensification (TI), step-up in hospital care (SH) and mortality. OBJECTIVES: (1) To investigate the intervention's effect on recurrent events, and (2) to identify clinical subgroups most likely to benefit, determined from the incidence rate of TF and hospital readmissions. METHODS: Enrolment criteria included the diagnosis of COPD, a smoking history of ≥10 pack-years and ≥ 1 exacerbation in the previous year. Rate ratio (RR) calculations, subgroup analyses and modelling of continuous variables using splines were based on a Poisson regression model, adjusted for exposure time. RESULTS: Azithromycin significantly reduced TF by 24% within 3 m (RR = 0.76, 95%CI:0.59;0.97, p = 0.031) through a 50% reduction in SH (RR = 0.50, 95%CI:0.30;0.81, p = 0.006), which comprised of a 53% reduction in hospital readmissions (RR = 0.47, 95%CI:0.27;0.80; p = 0.007). A significant interaction between the intervention, CRP and blood eosinophil count at hospital admission was found, with azithromycin significantly reducing hospital readmissions in patients with high CRP (> 50 mg/L, RR = 0.18, 95%CI:0.05;0.60, p = 0.005), or low blood eosinophil count (<300cells/µL, RR = 0.33, 95%CI:0.17;0.64, p = 0.001). No differences were observed in treatment response by age, FEV1, CRP or blood eosinophil count in continuous analyses. CONCLUSIONS: This post-hoc analysis of the BACE trial shows that azithromycin initiated at the onset of an infectious COPD exacerbation requiring hospitalization reduces the incidence rate of TF within 3 m by preventing hospital readmissions. In patients with high CRP or low blood eosinophil count at admission this treatment effect was more pronounced, suggesting a potential role for these biomarkers in guiding azithromycin therapy. TRIAL REGISTRATION: ClinicalTrials.gov number. NCT02135354 .

Azithromycin during Acute Chronic Obstructive Pulmonary Disease Exacerbations Requiring Hospitalization (BACE). A Multicenter, Randomized, Double-Blind, Placebo-controlled Trial.

Rationale: Azithromycin prevents acute exacerbations of chronic obstructive pulmonary disease (AECOPDs); however, its value in the treatment of an AECOPD requiring hospitalization remains to be defined.Objectives: We investigated whether a 3-month intervention with low-dose azithromycin could decrease treatment failure (TF) when initiated at hospital admission and added to standard care.Methods: In an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial, patients who had been hospitalized for an AECOPD and had a smoking history of ≥10 pack-years and one or more exacerbations in the previous year were randomized (1:1) within 48 hours of hospital admission to azithromycin or placebo. The study drug (500 mg/d for 3 d) was administered on top of a standardized acute treatment of systemic corticosteroids and antibiotics, and subsequently continued for 3 months (250 mg/2 d). The patients were followed for 6 months thereafter. Time-to-first-event analyses evaluated the TF rate within 3 months as a novel primary endpoint in the intention-to-treat population, with TF defined as the composite of treatment intensification with systemic corticosteroids and/or antibiotics, a step-up in hospital care or readmission for respiratory reasons, or all-cause mortality.Measurements and Main Results: A total of 301 patients were randomized to azithromycin (n = 147) or placebo (n = 154). The TF rate within 3 months was 49% in the azithromycin group and 60% in the placebo group (hazard ratio, 0.73; 95% confidence interval, 0.53-1.01; P = 0.0526). Treatment intensification, step-up in hospital care, and mortality rates within 3 months were 47% versus 60% (P = 0.0272), 13% versus 28% (P = 0.0024), and 2% versus 4% (P = 0.5075) in the azithromycin and placebo groups, respectively. Clinical benefits were lost 6 months after withdrawal.Conclusions: Three months of azithromycin for an infectious AECOPD requiring hospitalization may significantly reduce TF during the highest-risk period. Prolonged treatment seems to be necessary to maintain clinical benefits.

Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With ST-Segment Elevation Myocardial Infarction and Left Ventricular Dysfunction.

RATIONALE: Allogeneic cardiac stem cells (AlloCSC-01) have shown protective, immunoregulatory, and regenerative properties with a robust safety profile in large animal models of heart disease. OBJECTIVE: To investigate the safety and feasibility of early administration of AlloCSC-01 in patients with ST-segment-elevation myocardial infarction. METHODS AND RESULTS: CAREMI (Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With STEMI and Left Ventricular Dysfunction) was a phase I/II multicenter, randomized, double-blind, placebo-controlled trial in patients with ST-segment-elevation myocardial infarction, left ventricular ejection fraction ≤45%, and infarct size ≥25% of left ventricular mass by cardiac magnetic resonance, who were randomized (2:1) to receive AlloCSC-01 or placebo through the intracoronary route at days 5 to 7. The primary end point was safety and included all-cause death and major adverse cardiac events at 30 days (all-cause death, reinfarction, hospitalization because of heart failure, sustained ventricular tachycardia, ventricular fibrillation, and stroke). Secondary safety end points included major adverse cardiac events at 6 and 12 months, adverse events, and immunologic surveillance. Secondary exploratory efficacy end points were changes in infarct size (percentage of left ventricular mass) and indices of ventricular remodeling by magnetic resonance at 12 months. Forty-nine patients were included (92% male, 55±11 years), 33 randomized to AlloCSC-01 and 16 to placebo. No deaths or major adverse cardiac events were reported at 12 months. One severe adverse events in each group was considered possibly related to study treatment (allergic dermatitis and rash). AlloCSC-01 elicited low levels of donor-specific antibodies in 2 patients. No immune-related adverse events were found, and no differences between groups were observed in magnetic resonance-based efficacy parameters at 12 months. The estimated treatment effect of AlloCSC-01 on the absolute change from baseline in infarct size was -2.3% (95% confidence interval, -6.5% to 1.9%). CONCLUSIONS: AlloCSC-01 can be safely administered in ST-segment-elevation myocardial infarction patients with left ventricular dysfunction early after revascularization. Low immunogenicity and absence of immune-mediated events will facilitate adequately powered studies to demonstrate their clinical efficacy in this setting. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02439398.

Reversibility of severe mitral valve regurgitation after left ventricular assist device implantation: single-centre observations from a real-life population of patients.

OBJECTIVES: This study evaluates the impact of untreated preoperative severe mitral valve regurgitation (MR) on outcomes after left ventricular assist device (LVAD) implantation. METHODS: Of the 234 patients who received LVAD therapy in our centre during a 6-year period, we selected those who had echocardiographic images of good quality and excluded those who underwent mitral valve replacement prior to or mitral valve repair during LVAD placement. The 128 patients selected were divided into 2 groups: Group A with severe MR (n = 65) and Group B with none to moderate MR (n = 63, 28 with moderate MR). We evaluated transthoracic echocardiography preoperatively [15 (7-28) days before LVAD implantation; median (interquartile range)] and postoperatively up to the last available follow-up [501 (283-848) days after LVAD]. We collected mortality, complications and clinical status indicators of the patient cohort. RESULTS: We observed a significant decrease in the severity of MR after LVAD implantation (severe MR 51% pre- vs 6% post-LVAD implantation, P < 0.001). There was no difference between groups in terms of right heart failure, rate of urgent heart transplantation, pump thrombosis or ventricular arrhythmias. There was no difference in 1-year survival and 3-year survival (87.7% vs 88.4% and 71.8% vs 66.6% for Groups A and B, respectively, P = 0.97). CONCLUSIONS: Preoperative severe MR resolves in the majority of patients early on after LVAD implantation and is not associated with worse clinical outcomes or intermediate-term survival.

The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: rationale and design of the BAMI trial.

Over the past 13 years bone marrow-derived mononuclear cells (BM-MNCs) have been widely investigated for clinical efficacy in patients following acute myocardial infarction (AMI). These early phase II trials have used various surrogate markers to judge efficacy and, although promising, the results have been inconsistent. The phase III BAMI trial has therefore been designed to demonstrate that intracoronary infusion of BM-MNCs is safe and will significantly reduce the time to first occurrence of all-cause death in patients with reduced left ventricular ejection fraction after successful reperfusion for ST-elevation AMI (powered with the aim of detecting a 25% reduction in all-cause mortality). This is a multinational, multicentre, randomized, open-label, controlled, parallel-group phase III study aiming to enrol approximately 3000 patients in 11 European countries with at least 17 sites. Eligible patients who have impaired left ventricular ejection (≤45%) following successful reperfusion for AMI will be randomized to treatment or control group in a 1:1 ratio. The treatment group will receive intracoronary infusion of BM-MNCs 2-8 days after successful reperfusion for AMI added on top of optimal standard of care. The control group will receive optimal standard of care. The primary endpoint is time from randomization to all-cause death. The BAMI trial is pivotal and the largest trial to date of BM-MNCs in patients with impaired left ventricular function following AMI. The aim of the trial is to provide a definitive answer as to whether BM-MNCs reduce all-cause mortality in this group of patients.

Reduction of the dose of radiotherapy to the elective neck in head and neck squamous cell carcinoma; a randomized clinical trial. Effect on late toxicity and tumor control.

BACKGROUND AND PURPOSE: A multi-center prospective randomized clinical trial has been performed investigating whether a reduction of the dose to the elective nodal sites in head and neck cancer delivered by intensity modulated radiotherapy (IMRT) would result in a reduction of late side effects without compromising tumor control. MATERIALS AND METHODS: Two hundred patients were included. The prescription dose to the elective nodal volumes was a normalized iso-effective dose in 2Gy fractions (NID2Gy) of 50Gy in the standard arm and of 40Gy in the experimental arm. Late toxicity was scored at 6, 12, 18 and 24months using the RTOG scoring system. RESULTS: We observed a trend toward less dysphagia at 6months in the experimental arm, however this was not confirmed after longitudinal analysis. Regarding moderate salivary gland toxicity we observed lower incidence of salivary gland toxicity ⩾grade 1, at 6 (p=0.01) and 18months (p=0.03). After two years of follow up, we did not observe significant differences in estimated local failure rate (14.1% in the 40Gy arm vs 14.4% in the 50Gy arm), estimated regional failure rate (13.0% vs 5.5% in the 40 and the 50Gy arm respectively), estimated metastatic recurrence (13.4% vs 18.5% in the 40 and the 50Gy arm respectively), estimated disease-free survival (57.9% vs 65.3% in the 40 and the 50Gy arm respectively) nor estimated overall survival (72.0% vs 73.2% in the 40 and the 50Gy arm respectively). CONCLUSIONS: In our study population there was no statistically significant difference regarding survival and estimated recurrence rates between both arms of this study. We found a trend toward less dysphagia at 6months (however not significant after longitudinal analysis) and found a significant reduction of any salivary gland toxicity at 6 and 18months in the 40Gy arm.

Histamine Receptor H1-Mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Histamine sensitizes the nociceptor transient reporter potential channel V1 (TRPV1) and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo-controlled trial. METHODS: By using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsy specimens collected from 9 patients with IBS (ROME 3 criteria) and 15 healthy subjects. The sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsy specimens was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 y; range, 18-65 y; 34 female). After a 2-week run-in period, subjects were assigned randomly to groups given either the HRH1 antagonist ebastine (20 mg/day; n = 28) or placebo (n = 27) for 12 weeks. Rectal biopsy specimens were collected, barostat studies were performed, and symptoms were assessed (using the validated gastrointestinal symptom rating scale) before and after the 12-week period. Patients were followed up for an additional 2 weeks. Abdominal pain, symptom relief, and health-related quality of life were assessed on a weekly basis. The primary end point of the study was the effect of ebastine on the symptom score evoked by rectal distension. RESULTS: TRPV1 responses of submucosal neurons from patients with IBS were potentiated compared with those of healthy volunteers. Moreover, TRPV1 responses of submucosal neurons from healthy volunteers could be potentiated by their pre-incubation with histamine; this effect was blocked by the HRH1 antagonist pyrilamine. Supernatants from rectal biopsy specimens from patients with IBS, but not from the healthy volunteers, sensitized TRPV1 in mouse nociceptive dorsal root ganglion neurons via HRH1; this effect could be reproduced by histamine and imidazole acetaldehyde. Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief (ebastine 46% vs placebo 13%; P = .024), and reduced abdominal pain scores (ebastine 39 ± 23 vs placebo 62 ± 22; P = .0004). CONCLUSIONS: In studies of rectal biopsy specimens from patients, we found that HRH1-mediated sensitization of TRPV1 is involved in IBS. Ebastine, an antagonist of HRH1, reduced visceral hypersensitivity, symptoms, and abdominal pain in patients with IBS. Inhibitors of this pathway might be developed as a new treatment approach for IBS. ClinicalTrials.gov no: NCT01144832.

Long-term results of the European achalasia trial: a multicentre randomised controlled trial comparing pneumatic dilation versus laparoscopic Heller myotomy.

OBJECTIVE: Achalasia is a chronic motility disorder of the oesophagus for which laparoscopic Heller myotomy (LHM) and endoscopic pneumodilation (PD) are the most commonly used treatments. However, prospective data comparing their long-term efficacy is lacking. DESIGN: 201 newly diagnosed patients with achalasia were randomly assigned to PD (n=96) or LHM (n=105). Before randomisation, symptoms were assessed using the Eckardt score, functional test were performed and quality of life was assessed. The primary outcome was therapeutic success (presence of Eckardt score ≤3) at the yearly follow-up assessment. The secondary outcomes included the need for re-treatment, lower oesophageal sphincter pressure, oesophageal emptying and the rate of complications. RESULTS: In the full analysis set, there was no significant difference in success rate between the two treatments with 84% and 82% success after 5 years for LHM and PD, respectively (p=0.92, log-rank test). Similar results were obtained in the per-protocol analysis (5-year success rates: 82% for LHM vs. 91% for PD, p=0.08, log-rank test). After 5 years, no differences in secondary outcome parameter were observed. Redilation was performed in 24 (25%) of PD patients. Five oesophageal perforations occurred during PD (5%) while 12 mucosal tears (11%) occurred during LHM. CONCLUSIONS: After at least 5 years of follow-up, PD and LHM have a comparable success rate with no differences in oesophageal function and emptying. However, 25% of PD patients require redilation during follow-up. Based on these data, we conclude that either treatment can be proposed as initial treatment for achalasia. TRIAL REGISTRATION NUMBERS: Netherlands trial register (NTR37) and Current Controlled Trials registry (ISRCTN56304564).

Impact of tumor chronology and tumor biology on lymph node metastasis in breast cancer.

SYNOPSIS: The significance of nodal metastasis in breast cancer is under discussion. We investigated the impact of variables of tumor chronology and tumor biology on the presence of lymph node metastases. PURPOSE: Lymph node involvement is the main prognostic factor in breast cancer. However, it is under discussion whether nodal metastasis in breast cancer only reflects the chronological age of the tumor or whether it is also a marker of tumor biology. The goal of our study was to investigate the impact of variables of tumor chronology and biology on the presence of lymph node metastases. METHODS: We performed a retrospective analysis of data from 3002 patients with an early invasive breast carcinoma. All patients underwent primary surgery at the University Hospitals Leuven between 2001 and 2009. First, the impact of tumor size on the presence of lymph node metastasis was evaluated as the chronological age of a tumor is supposed to be reflected in its size. Next, the impact of tumor grade, lymphovascular invasion and the hormone receptor status, which are all variables of tumor biology, was studied. Logistic regression analyses were performed and the area under the ROC curve (AUC) was calculated as a measure of discrimination between logistic regression models. RESULTS: Using pathological tumor size the AUC of prediction was 0.67. Based on variables of tumor biology, axillary lymph node positivity could be predicted with an AUC of 0.68. Combining variables of tumor chronology and biology an AUC of 0.74 for the prediction of axillary lymph node (ALN) positivity was calculated. CONCLUSIONS: According to our data variables of tumor chronology and tumor biology have a similar impact on the presence of lymph node metastasis.

Prospective evaluation of clinical outcomes in all-comer high-risk patients with aortic valve stenosis undergoing medical treatment, transcatheter or surgical aortic valve implantation following heart team assessment.

OBJECTIVES: Transcatheter aortic valve implantation (TAVI) has been proposed as a treatment alternative for patients with aortic valve stenosis (AS) at high or prohibitive risk for surgical aortic valve replacement (AVR). We aimed to assess real-world outcomes after treatment according to the decisions of the multidisciplinary heart team. METHODS: At a tertiary centre, all high-risk patients referred between 1 March 2008 and 31 October 2011 for symptomatic AS were screened and planned to undergo AVR, TAVI or medical treatment. We report clinical outcomes as defined by the Valve Academic Research Consortium. RESULTS: Of 163 high-risk patients, those selected for AVR had lower logistic EuroSCORE and STS scores when compared with TAVI or medical treatment (median [interquartile range] 18 [12-26]; 26 [17-36]; 21 [14-32]% (P = 0.015) and 6.5 [5.1-10.7]; 7.6 [5.8-10.5]; 7.6 [6.1-15.7]% (P = 0.056)). All-cause mortalities at 1 year in 35, 73 and 55 patients effectively undergoing AVR, TAVI and medical treatment were 20, 21 and 38%, respectively (P = 0.051). Cardiovascular death and major stroke occurred in 9, 8 and 33% (P < 0.001) and 6, 4 and 2% (P = 0.62), respectively. For patients undergoing valve implantation, device success was 91 and 92% for AVR and TAVI, respectively. The combined safety endpoint at 30 days was in favour of TAVI (29%) vs AVR (63%) (P = 0.001). In contrast, the combined efficacy endpoint at 1 year tended to be more favourable for AVR (10 vs 24% for TAVI, P = 0.12). CONCLUSIONS: Patients who are less suitable for AVR can be treated safely and effectively with TAVI with similar outcomes when compared with patients with a lower-risk profile undergoing AVR. Patients with TAVI or AVR have better survival than those undergoing medical treatment only.