Citations

Objective To determine the prevalence and outcomes of intracranial aneurysm (IA) in patients with bicuspid aortic valve (BAV). Methods Retrospective review of patients with BAV who underwent brain MR angiography at the Mayo Clinic from 1994 to 2013. Results There were 678 patients included in this study—mean age 57±13 years, men 480 (71%), mean follow-up 10±3 years (5913 patient-years). Coarctation of aorta (COA) was present in 154 (23%) patients. There were 59 IAs identified in 52 of 678 patients (7.7%). IA was present in 20/154 patients (12.9%) with COA and 32/524 patients (5.7%) without COA (p<0.001). For the patients without COA, female gender and right–left cusp fusion were risks factors for IA in women after adjustment for all potential variables (HR 1.76, CI 1.31 to 2.68, p=0.03). There was no significant trend in the risk for IA across age tertiles: age ≤40 years versus 41–60 years (HR 1.19, p=0.34), and age 41–60 years versus 61–80 years (HR 1.06, p=0.56). Among the 52 patients with IA, enlargement occurred in three patients (6%), rupture in two patients (4%) and four patients (8%) underwent coil embolisation. For the 626 patients without IA at baseline, no patient developed IA over 7±2 years of imaging follow-up. Conclusions BAV is associated with a higher prevalence of IA compared to the general population, and this risk is higher in patients with COA, right–left cusp fusion and female gender.

Objective Limited data exist regarding the outcomes of non-cardiac procedures (NCPs) in adult patients after Fontan operations (Fontan patients). Methods To compare procedural outcomes after NCPs in Fontan patients with outcomes for two matched control groups: patients with repaired congenital heart disease and biventricular circulation (CHD-BiV) and patients with no heart disease (NHD). We defined cyanosis as oxygen saturation <90% and procedural hypoxia as saturation <80% or a decrease in saturation >10% from baseline. Results There were 538 NCPs in 154 Fontan patients (mean age, 30 years) performed in 1990–2015. Sedation and anaesthesia types were monitored anaesthesia care (256,48%), general anaesthesia (51,9%), minimal sedation (105,20%), local anaesthesia (75,14%) and regional anaesthesia (51,9%). Ninety-three complications occurred in 79 procedures (15%) and included arrhythmia requiring intervention (9), hypotension (14), bradycardia (8), hypoxia (38), heart failure requiring intravenous diuretics (2), acute kidney injury (3), bleeding requiring blood transfusion (1), unplanned procedures for dialysis catheter placement (2), readmission (2), unplanned hospitalisation for hypoxia (8) and unplanned transfer to intensive care unit (1). Baseline cyanosis was the only multivariable risk factor for complications (HR, 1.87 (95% CI 1.14 to 3.67), p=0.04). Procedural complications were more common in the Fontan group (18%) than in the CHD-BiV (5%) and NHD groups (1.4%) (p=0.001). Conclusions Complications after NCPs were more common in Fontan patients, and baseline cyanosis was a risk factor for complications. All-cause mortality was low and may be related to the multidisciplinary care approach used for Fontan patients at our centre.

LBA4 Background: Daratumumab (D), a human anti-CD38 IgGκ mAb, induces deep and durable responses with a favorable safety profile in RRMM pts. We report a pre-specified interim analysis of the first randomized controlled study of D (CASTOR; NCT02136134). Methods: Pts with ≥1 prior line of therapy were randomized (1:1) to 8 cycles (q3w) of bortezomib (V)/dexamethasone (d) (V: 1.3 mg/m2sc on Days 1, 4, 8, 11; d: 20 mg po on Days 1, 2, 4, 5, 8, 9, 11, 12) ± D (16 mg/kg iv qw in Cycles 1-3, Day 1 of Cycles 4-8, then q4w until progression). Primary endpoint was PFS. Results: 498 pts (DVd, 251; Vd, 247) were randomized. Baseline demographics and disease characteristics were well balanced. Pts received a median of 2 prior lines of therapy (range 1-10). 66% received prior V; 76% received prior IMiD; 48% received prior PI and IMiD; 33% were IMiD-refractory; 32% were refractory to last line of prior therapy. With median follow-up of 7.4 months, D significantly improved median PFS (61% reduction in risk of progression) and TTP for DVd vs Vd (Table). D significantly increased ORR (83% vs 63%, P <0.0001), and doubled rates of ≥VGPR (59% vs 29%, P <0.0001), and ≥CR (19% vs 9%, P= 0.0012) for DVd vs Vd, respectively; median duration of response was NR vs 7.9 months, respectively. Most common (>25%) AEs (DVd/Vd) were thrombocytopenia (59%/44%), peripheral sensory neuropathy (47%/ 38%), diarrhea (32%/22%) and anemia (26%/31%). Most common grade 3/4 AEs (>10%) were thrombocytopenia (45%/33%), anemia (14%/16%), neutropenia (13%/4%). 7%/9% of pts discontinued due to a TEAE. D-associated infusion-related reactions (45% of pts) mostly occurred during the first infusion; most were grade 1/2 (grade 3/4, 9%/0%). Conclusions: D significantly improved PFS, TTP, and ORR in combination with Vd vs Vd alone. DVd doubled both VGPR and sCR/CR rates vs Vd alone. Safety of DVd is consistent with the known safety profile of D and Vd. The addition of D to Vd should be considered a new standard of care for RRMM pts currently receiving Vd alone. Clinical trial information: NCT02136134. [Table: see text]

ObjectiveDegeneration of oligodendroglial distal processes has been identified as an early event in multiple sclerosis (MS) lesion development. Our objective was to further define the development of the “dying‐back” oligodendrocyte lesion in situ and to model the development and potential reversibility of such responses using dissociated cultures of adult human brain‐derived oligodendrocytes.MethodsIn situ analyses were performed on glutaraldehyde‐fixed thin sections of clinically acute and pathologically active cases of MS. In vitro studies were conducted using adult human brain‐derived oligodendrocytes challenged by metabolic stress conditions (low nutrient/glucose).ResultsIn situ analyses indicated a spectrum of myelin changes in the presence of morphologically intact oligodendrocytes; these included degeneration of the inner cytoplasmic tongue with increasing sizes of intramyelinic bleb formation that could result in radial fractures of the myelin sheath. Macrophages with ingested myelin fragments were identified only once the fragmentation was established. In vitro studies indicated that oligodendrocyte process retraction, which was linked to reduced glycolytic respiratory activity, is reversible until a critical time point. Subsequent cell death was not linked to caspase‐3–dependent programs. Gene expression studies conducted at the latest reversible time point revealed reduced expression of pathways associated with cell process outgrowth and myelination, as well as with metabolic activity.InterpretationOur findings reveal the potential to protect and possibly restore myelin elaborated by existent oligodendrocytes in early and evolving MS lesions, and suggest the necessity of ongoing studies of the mechanisms underlying subsequent adult human oligodendrocyte cell death. Ann Neurol 2017;81:811–824

ABSTRACT Objectives: The aim of the study was to describe changes in intestinal permeability in early childhood in diverse epidemiologic settings. Methods: In a birth cohort study, the lactulose:mannitol (L:M) test was administered to 1980 children at 4 time points in the first 24 months of life in 8 countries. Data from the Brazil site with an incidence of diarrhea similar to that seen in the United States and no growth faltering was used as an internal study reference to derive age‐ and sex‐specific z scores for mannitol and lactulose recoveries and the L:M ratio. Results: A total of 6602 tests demonstrated mannitol recovery, lactulose recovery, and the L:M ratio were associated with country, sex, and age. There was heterogeneity in the recovery of both probes between sites with mean mannitol recovery ranging for 1.34% to 5.88%, lactulose recovery of 0.19% to 0.58%, and L:M ratios 0.10 to 0.17 in boys of 3 months of age across different sites. We observed strong sex‐specific differences in both mannitol and lactulose recovery, with boys having higher recovery of both probes. Alterations in intestinal barrier function increased in most sites from 3 to 9 months of age and plateaued or diminished from 9 to 15 months of age. Conclusions: Alterations in recovery of the probes differ markedly in different epidemiologic contexts in children living in the developing world. The rate of change in the L:M‐ z ratio was most rapid and consistently disparate from the reference standard in the period between 6 and 9 months of age, suggesting that this is a critical period of physiologic impact of enteropathy in these populations.

Key Points Pembrolizumab was first shown to be clinically active in CLL patients with RT. PD-1 and PD-L1 expression in tumor microenvironment are promising biomarkers to select RT patients for PD-1 blockade.

677 Background: Napabucasin a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting Stat3-driven gene transcription. Preclinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with other agents. In a phase 1 study, napabucasin monotherapy was well tolerated with encouraging signs of anti-tumor activity at the RP2D of 500 mg BID. Methods: The current open-label, multi-center study includes phase II expansion in pts with refractory, K- Raswt mCRC to confirm safety and anti-tumor activity of napabucasin administered orally at 480mg BID in combination with panitumumab (6mg/kg bi-weekly). Results: 72 pts were enrolled, 48 pts were evaluable by RECIST of which 7 (15%) and 41 (85%) had 2 or >3 prior treatment lines, respectively. Of the 48 evaluable pts, 64.6% (31/48) were previously treated with an anti-EGFR agent. No new adverse events (AEs) were observed and most common AEs included grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. Among 48 pts enrolled who received RECIST evaluation, Disease Control Rate (DCR) was observed in 25 pts (52.1%) of which 3 pts achieved PR (6%) and 22 pts achieved SD (45%). Among 31 pts previously treated with anti-EGFR therapy, DCR was observed in 15 pts (48%) compared with DCR of 59% observed in 10 out of 17 anti-EGFR naïve pts receiving a scan. Conclusions: This phase II study confirmed that napabucasin can be safely combined with panitumumab at full dose and shows encouraging anti-tumor activity in pts with K- Ras wt mCRC, regardless of prior anti-EGFR exposure, suggesting that napabucasin may sensitize pts to repeat anti-EGFR therapy. Clinical trial information: NCT01776307. [Table: see text]