Citations

Abstract This International evidence-based nomenclature and classification consensus on the congenital bicuspid aortic valve and its aortopathy recognizes 3 types of bicuspid aortic valve: 1. Fused type, with 3 phenotypes: right-left cusp fusion, right-non cusp fusion and left-non cusp fusion; 2. 2-sinus type with 2 phenotypes: Latero-lateral and antero-posterior; and 3. Partial-fusion or forme fruste. This consensus recognizes 3 bicuspid-aortopathy types: 1. Ascending phenotype; root phenotype; and 3. extended phenotypes.

AbstractBackgroundCSF neurofilament light protein (NfL) is an important biomarker in several neurologic diseases. CSF NfL concentrations are known to increase with age, but sex differences have been less examined. The CSF/serum albumin ratio (QAlb) is a biomarker for blood‐brain barrier integrity, which has previously been found to be higher in men. As NfL and QAlb are used in clinical routine, the impact of demographic factors on these biomarkers is important to understand.MethodParticipants were derived from two samples. The first was a population‐based cohort of 308 70‐year olds from the Gothenburg H70 Birth Cohort Study, Sweden. The second data set comprised CSF NfL and QAlb results from 8995 and 39252 subjects respectively, generated in clinical practice between 2005‐2012 in Gothenburg, Sweden. In the population‐based study, QAlb and NfL concentrations were examined in relation to sex, cardiovascular risk factors, and MRI signs of cerebral white matter lesions. In the clinical routine cohort, sex differences in QAlb and NfL were tested in relation to age.ResultIn the population‐based sample, men had higher QAlb and NfL concentrations than women. NfL was not related to cerebral vascular pathology, but QAlb correlated positively with several measures of white matter lesions. In the clinical routine cohort, men also had higher QAlb and NfL concentrations from adolescence and throughout life.ConclusionQAlb ratios and CSF NfL levels are higher in men throughout life. The CSF NfL sex difference could not be explained by vascular pathology. Future studies should consider using different reference limits for men and women.

Recent successes and FDA approvals of CD19 redirected chimeric antigen receptor T cell (CART19) therapy have been achieved in pivotal clinical trials in patients with B cell malignancies. However, durable response rates in non-Hodgkin B cell lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL) are low. Tumor-associated macrophages have emerged as key mediators of tumor-induced CART cell immunosuppression. Axl receptor tyrosine kinase (Axl-RTK) is overexpressed in various human cancers including B-NHL or CLL and correlates with poor overall survival. Thus, several Axl-RTK inhibitors are currently being investigated in clinical trials. We have previously reported that the Axl-RTK inhibitor TP-0903 modulates CART19 function by Th1 polarization. Moreover, we observed a significant reduction in myeloid-derived cytokines in preclinical models. This led us to hypothesize that Axl-RTK inhibition also modulates monocytes which in turn affects CART function. To test our hypothesis, we interrogated the interactions between Axl-RTK inhibition, monocytes, and CART. First, we isolated CD14+ monocytes from peripheral mononuclear cells (PBMCs) from healthy donors by magnetic negative selection. Flow cytometric analysis revealed a robust Axl expression on monocytes (Fig.1A). Monocytes were maintained in ImmunoCult Macrophage Medium (STEMCELL Technologies) and differentiated with lipopolysaccharide and interferon-γ for M1-type and interleukin (IL)-4 for M2-type macrophages. After confirming the macrophage phenotypes, cells were assessed for Axl expression. Flow cytometric analysis demonstrated that M2-type macrophages expressed higher Axl compared to M1 macrophages (Fig.1B). Then, we treated PBMCs from healthy donors with TP-0903 for 24 hours to determine the specific cell types affected by Axl-RTK inhibition. Flow cytometric analysis revealed that monocytes were significantly inhibited by TP-0903 compared to B cells or T cells (Fig.1C). Having demonstrated that TP-0903 strongly suppresses monocytes and that M2-type macrophages express Axl on their surface, we then performed a cytotoxicity assay against CD19+ mantle cell lymphoma cell line, JeKo-1, to study the impact of Axl-RTK inhibition on monocyte-induced CART suppression. We used CART19 generated in our laboratory (FMC63-41BBζ). CART19, JeKo-1, and M2-type macrophages were co-cultured at 1:2:1 ratio and incubated for 3 days. The data revealed that M2-type macrophages strongly suppress CART19 killing (Fig.1D) which could be overcome with TP-0903 (Fig.1E). Next we studied monocyte-induced CART19 suppression with antigen-specific proliferation. CART19, JeKo-1, and monocytes were co-cultured at 1:5:1 ratio and incubated for 5 days. Flow cytometric analysis revealed that in the presence of monocytes, antigen-specific proliferation of CART19 was significantly suppressed, which was reversed in the presence of TP-0903 (Fig.1F). To assess how Axl inhibition modulates myeloid cell-derived cytokines/chemokines, we performed Multiplex (Millipore-Sigma) with the supernatants obtained from these co-culture assays. The presence of monocytes resulted in a significant increase in IL-17a, IL-6, IL-1 receptor agonist, IL-1β, and soluble CD40 ligand. However, Axl-RTK inhibition resulted in selective reduction of those cytokines/chemokines (Fig.1G) while preserving other effector cytokines. Finally, we tested whether Axl-RTK inhibition with TP-0903 could overcome the negative effects of monocytes in vivo. Here, immunocompromised NSG mice were injected with 1x106 luciferase+ JeKo-1 cells intravenously. Ten days later, mice were injected with freshly isolated monocytes derived from a healthy donor. Two weeks after JeKo-1 inoculation, tumor burden was assessed with bioluminescence imaging. Mice were then randomized according to the tumor burden to receive 0.5x106 CART19 as a monotherapy or in combination with 20 mg/kg/day of oral TP-0903. The combination therapy resulted in superior anti-tumor effects and overall survival compared to CART19 monotherapy (Fig.1H-I). In summary, Axl-RTK inhibition with TP-0903 demonstrates a direct suppression of inhibitory monocytes, which in turn enhances CART cell function. Our findings support the strategy of further refining and testing the novel and potent combination of Axl-RTK inhibition and CART cell therapy for the treatment of B cell malignancies. Figure 1 Disclosures Sakemura: Humanigen: Patents & Royalties. Cox:Humanigen: Patents & Royalties. Mouritsen:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment. Foulks:Tolero Pharmaceuticals, Inc.: Current Employment. Warner:Tolero Pharmaceuticals, Inc.: Current Employment. Ding:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees. Parikh:GlaxoSmithKline: Honoraria; Verastem Oncology: Honoraria; Genentech: Honoraria; Ascentage Pharma: Research Funding; AbbVie: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; MorphoSys: Research Funding; Pharmacyclics: Honoraria, Research Funding. Kay:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Research Funding; Abbvie: Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Sunesis: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees. Kenderian:Mettaforge: Patents & Royalties; Lentigen: Research Funding; MorphoSys: Research Funding; Sunesis: Research Funding; Tolero: Research Funding; BMS: Research Funding; Juno: Research Funding; Gilead: Research Funding; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy; Humanigen: Consultancy, Patents & Royalties, Research Funding.

Abstract Microbiota-accessible carbohydrates (MACs) are powerful modulators of microbiota composition and function. These substrates are often derived from diet, such as complex polysaccharides from plants or human milk oligosaccharides (HMOs) during breastfeeding. Host-derived mucus glycans on gut-secreted mucin proteins serve as a continuous endogenous source of MACs for resident microbes; here we investigate the potential role of purified, orally administered mucus glycans in maintaining a healthy microbial community. In this study, we liberated and purified O-linked glycans from porcine gastric mucin and assessed their efficacy in shaping the recovery of a perturbed microbiota in a mouse model. We found that porcine mucin glycans (PMGs) and HMOs enrich for taxonomically similar resident microbes. We demonstrate that PMGs aid recovery of the microbiota after antibiotic treatment, suppress Clostridium difficile abundance, delay the onset of diet-induced obesity, and increase the relative abundance of resident Akkermansia muciniphila. In silico analysis revealed that genes associated with mucus utilization are abundant and diverse in prevalent gut commensals and rare in enteric pathogens, consistent with these glycan-degrading capabilities being selected for during host development and throughout the evolution of the host–microbe relationship. Importantly, we identify mucus glycans as a novel class of prebiotic compounds that can be used to mitigate perturbations to the microbiota and provide benefits to host physiology.

Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24–1.66]; P =1.6×10 −6 ), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97–1.15]; P =0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratio PRS , 1.26 [95% CI, 1.18–1.36]; P PRS =2.7×10 −11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratio PRS+family history+smoking , 1.24 [95% CI, 1.14–1.35]; P PRS =1.27×10 −6 ). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

Background: Mitral valve-in-valve (ViV) and valve-in-ring (ViR) are alternatives to surgical reoperation in patients with recurrent mitral valve failure after previous surgical valve repair or replacement. Our aim was to perform a large-scale analysis examining midterm outcomes after mitral ViV and ViR. Methods: Patients undergoing mitral ViV and ViR were enrolled in the Valve-in-Valve International Data Registry. Cases were performed between March 2006 and March 2020. Clinical endpoints are reported according to the Mitral Valve Academic Research Consortium (MVARC) definitions. Significant residual mitral stenosis (MS) was defined as mean gradient ≥10 mm Hg and significant residual mitral regurgitation (MR) as ≥ moderate. Results: A total of 1079 patients (857 ViV, 222 ViR; mean age 73.5±12.5 years; 40.8% male) from 90 centers were included. Median STS-PROM score 8.6%; median clinical follow-up 492 days (interquartile range, 76–996); median echocardiographic follow-up for patients that survived 1 year was 772.5 days (interquartile range, 510–1211.75). Four-year Kaplan-Meier survival rate was 62.5% in ViV versus 49.5% for ViR ( P <0.001). Mean gradient across the mitral valve postprocedure was 5.7±2.8 mm Hg (≥5 mm Hg; 61.4% of patients). Significant residual MS occurred in 8.2% of the ViV and 12.0% of the ViR patients ( P =0.09). Significant residual MR was more common in ViR patients (16.6% versus 3.1%; P <0.001) and was associated with lower survival at 4 years (35.1% versus 61.6%; P =0.02). The rates of Mitral Valve Academic Research Consortium–defined device success were low for both procedures (39.4% total; 32.0% ViR versus 41.3% ViV; P =0.01), mostly related to having postprocedural mean gradient ≥5 mm Hg. Correlates for residual MS were smaller true internal diameter, younger age, and larger body mass index. The only correlate for residual MR was ViR. Significant residual MS (subhazard ratio, 4.67; 95% CI, 1.74–12.56; P =0.002) and significant residual MR (subhazard ratio, 7.88; 95% CI, 2.88–21.53; P <0.001) were both independently associated with repeat mitral valve replacement. Conclusions: Significant residual MS and/or MR were not infrequent after mitral ViV and ViR procedures and were both associated with a need for repeat valve replacement. Strategies to improve postprocedural hemodynamics in mitral ViV and ViR should be further explored.

10017 Background: In preclinical models, temozolomide (TMZ) and vincristine (VCR) are synergistic with irinotecan (IRN). We sought to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of orally administered IRN given on two different schedules together with TMZ and VCR in children with refractory solid tumors, using cefixime to reduce IRN-associated diarrhea. Methods: Schedule A: Oral IRN daily for 5 days for 2 weeks (dx5x2), with VCR 1.5 mg/m2 on days 1 and 8 and TMZ 100 mg/m2 on days 1 - 5. Schedule B: Oral IRN daily for 5 days for 1 week (dx5x1) with VCR 1.5 mg/m2 on day 1 and TMZ 100 - 150 mg/m2 on days 1 - 5. Courses were repeated every 3 weeks. A standard cohorts of 3 + 3 design was used. Results: On Schedule A, 18 evaluable patients (median age 15 yrs, range 3 - 21) received 55 courses. At IRN 50 mg/m2/day, 4/12 pts had DLT (hepatotoxicity, abdominal pain, anorexia, hypokalemia, and thrombocytopenia). The oral IRN MTD on this dx5x2 schedule was 35 mg/m2/d (1/6 pts with DLT of hypoalbuminemia). On Schedule B, 18 evaluable patients (median age 9 yrs, range 3–21) received 71 courses of oral IRN 70 - 90 mg/m2/d x 5 with TMZ 100 - 150 mg/m2/d x 5. At oral IRN 90 mg/m2/d with TMZ 150 mg/m2/d, 0/6 pts had DLT, and no Grade 4 toxicities were seen. No further doses were explored. First-course and cumulative toxicity appeared worse with Schedule A, including 3 patients with responding or stable tumors who withdrew due to fatigue, nausea, and weight loss. UGT1A1*28genotype did not correlate with DLT. At the oral IRN MTD of 90 mg/m2/d, the median SN-38 AUCinf was 72 ng/ml*h. One patient with osteosarcoma had a confirmed partial response. Unconfirmed complete and partial responses were seen in 2 Ewing sarcoma patients. Eight additional patients received > 6 courses, including 2 each with neuroblastoma and medulloblastoma. Conclusions: The dx5x1 schedule of VOIT was well tolerated, with SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in sarcoma patients. No significant financial relationships to disclose.

AbstractIntroductionMicroscopic colitis is a chronic inflammatory bowel disease characterised by normal or almost normal endoscopic appearance of the colon, chronic watery, nonbloody diarrhoea and distinct histological abnormalities, which identify three histological subtypes, the collagenous colitis, the lymphocytic colitis and the incomplete microscopic colitis. With ongoing uncertainties and new developments in the clinical management of microscopic colitis, there is a need for evidence‐based guidelines to improve the medical care of patients suffering from this disorder.MethodsGuidelines were developed by members from the European Microscopic Colitis Group and United European Gastroenterology in accordance with the Appraisal of Guidelines for Research and Evaluation II instrument. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists, pathologists and basic scientists, and voted upon using the Delphi method.ResultsThese guidelines provide information on epidemiology and risk factors of microscopic colitis, as well as evidence‐based statements and recommendations on diagnostic criteria and treatment options, including oral budesonide, bile acid binders, immunomodulators and biologics. Recommendations on the clinical management of microscopic colitis are provided based on evidence, expert opinion and best clinical practice.ConclusionThese guidelines may support clinicians worldwide to improve the clinical management of patients with microscopic colitis.