Citations

AbstractThe study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.

Background: Chronic kidney disease (CKD), a growing public health issue in the elderly, is associated with increased risk of cognitive impairment. Objective: To investigate the mechanisms through which CKD impacts brain health using longitudinal imaging. Methods: We identified 97 participants (74 CKD and 23 non-CKD) from the BRINK (BRain IN Kidney Disease), a longitudinal study of CKD with two MRI scans (baseline and 3-year follow-up). We measured the associations between baseline and change in kidney disease biomarkers of estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR), considered a measure of microvascular inflammation, and imaging outcomes of cortical thickness and ventricular volume from structural MRI, white matter hyperintensities (WMH) volume from FLAIR images, and fractional anisotropy of the corpus callosum (FACC). Results: There were white matter-specific changes as observed by increased WMH volume and decreased FACC in CKD participants, as well as ventricular volume increase in both CKD and non-CKD groups reflective of aging-related changes. Decline in eGFR was associated with decrease in the FACC, suggesting that subtle early white matter changes due to kidney disease can be captured using DTI. An increase in UACR was associated with increase in ventricular volume. Conclusion: Our results support the role of eGFR as a measure of kidney microvascular disease which is associated with concurrent white matter damage in CKD. Future work is needed to investigate the possible link between endothelial microvascular inflammation (as measured by an increased UACR) and ventricular volume increase.

A novel hydroxyethylamine compound was synthesised that displayed biological potency against SARS-CoV-2.

Abstract Context Elevated concentrations of branched-chain amino acids (BCAA) are strong predictors of type 2 diabetes mellitus (T2DM). Their association with cardiovascular disease (CVD) remains uncertain, particularly in youth. Objective We investigated the role of BCAA and aromatic amino acids (AAA) in obesity, their relationships with novel biomarkers of CVD, and response to a physical activity-based lifestyle intervention (PAL-I) in a randomized controlled study in youth with normal weight (NW) and obesity (OB). Methods Age (14-18 years) and Tanner stage (≥IV) matched youth (OB, n = 15 and NW, n = 6) were studied; the 15 participants with OB underwent a 3-month randomized controlled PAL-I. Circulating amino acid profile, glucose, insulin, lipids, adiponectin, retinol binding protein-4, fibrinogen, high-sensitivity C-reactive protein, interleukin-6, and 25-hydroxy vitamin-D, along with body composition, were measured at baseline and after PAL-I. Independent t tests, analysis of covariance, and mixed-effect models were used for analysis of the data. Results Compared with NW, the concentration of various amino acids, including BCAA and AAA, were altered in OB (P < 0.05). BCAA and AAA showed baseline correlations with body composition and novel biomarkers of CVD, particularly inflammatory factors (all P < 0.05). The PAL-I produced only negligible effects (P > 0.05) on BCAA and AAA. Glutamine, glycine, and aspartic acid decreased with PAL-I (all P < 0.05). Conclusion The novel finding of the BCAA–inflammation relationship, along with strong correlations with nontraditional biomarkers of CVD, may raise the prospect of BCAA as a biomarker of CVD and evoke a potential link between obesity, T2DM, and CVD.

SummaryRuxolitinib for steroid‐refractory acute graft‐versus‐host disease (SR‐aGVHD) results in resistance or intolerance in 1/5 of patients. Outcomes of such patients are undefined. We identified these patients in a multicentre review and reported outcomes. Ruxolitinib‐resistant aGVHD was identified in 48/307 patients. Among patients receiving additional therapy, the overall response rate to next therapy was 36%. Median survival was 21 days. Ruxolitinib intolerance led to treatment discontinuation in 16/307 patients. Ten intolerant patients received additional therapy with 50% experiencing continued improvement of aGVHD. Median survival was 50 days in these patients. These data serve as a baseline for future SR‐aGVHD studies.

Background: Collateral blood flow, modulated by inflammation and arteriogenesis, alters ischemic injury in intracranial atherosclerosis. We investigated the potential link between several inflammatory and arteriogenic biomarkers with angiographic findings at enrollment in BIOSIS/SAMMPRIS. Methods: Baseline angiography and blood biomarkers of BIOSIS/SAMMPRIS, which included subjects with stroke or TIA due to 70-99% intracranial stenosis were analyzed. Collateral blood flow status at angiography was categorized by the combination of antegrade flow (TICI) and corresponding extent of collaterals (ASITN/SIR). Collateral status was analyzed with respect to blood progenitor cell markers (CD34) at baseline and inflammatory biomarkers (Plasminogen Activator Inhibitor-1 (PAI-1), E-selectin, high sensitivity C-reactive protein (hsCRP) and Lipoprotein-associated phospholipase A2 (Lp-PLA 2 ) activity and concentrations) at baseline, 30 days and 4 months. Results: 376 subjects (mean age 60.44 years SD 11; 149/376 (39.6%) women) enrolled in BIOSIS/SAMMPRIS had angiography of collaterals and biomarker data. Collateral perfusion was impaired in 71 (19%) and intermediate in 188 (50%), with robust collaterals in 117 (30%) subjects. Better collateral status was associated with younger age (p=0.001), male sex (p=0.029) and greater baseline physical activity (p=0.007). Baseline blood progenitor cell (CD34+) counts were unrelated to angiographic features at enrollment, whereas inflammatory Lp-PLA 2 activity was linked (p=0.059) with blood flow categories, and lower hsCRP (p=0.025) with better collaterals. Lp-PLA 2 activity was lowest in those with robust collaterals at 30 days (p=0.070) and 4 months (p=0.120). Those with robust collaterals had the greatest decrease in Lp-PLA 2 activity (p=0.021) and concentration (p=0.027) by 30 days, with a continued decline of Lp-PLA 2 activity (p=0.037) to 4 months. Disparate trends in inflammatory markers were seen in the medical and stenting arms. Conclusions: Inflammatory biomarkers are linked with collateral blood flow status in intracranial atherosclerosis. The impact of physical activity, medications and other therapeutic investigations may disclose important mechanisms to avert ischemia.

Abstract Background: Prostate cancer is the most common cancer among men. Monitoring of patient-reported outcomes (PROs) can enhance provider-patient communication, promote better decision-making, and improve survival. Geospatial factors, namely rurality and neighborhood socioeconomic deprivation, could influence the experience across cancer treatment, thus impacting PROs and survival. This study examined associations of rurality, neighborhood socioeconomic deprivation (Area Deprivation Index [ADI]) with cancer treatment-related PROs and survival in men with prostate cancer. Methods: Data from men with prostate cancer in the trial NRG Oncology/RTOG 0415 were analyzed. In this trial, 1092 men were randomized to receive conventional radiotherapy (RT) or hypofractionated RT. Patients had Gleason scores of 2-6 and prostate-specific antigen of <10 ng/mL. Rurality was categorized as urban vs rural using Rural-Urban Continuum Codes via patient zip codes. Neighborhood socioeconomic deprivation was assessed by the ADI calculated via the American Community Survey by patient zip codes. The Expanded Prostate Cancer Index Composite (EPIC) measures cancer-specific quality of life (QOL); Hopkins Symptom Checklist measures anxiety and depression; EuroQoL-5 Dimension (EQ-5D) VAS and Index scores assess general health. All PROs were measured at baseline before and 6, 12, 24 and 60 months after RT. Overall survival (OS) and disease-free survival (DFS) were assessed using Cox proportional hazards models. Mixed effects models and generalized estimating equations were used to analyze PROs. Results: We analyzed 751 patients with complete data. Patients from the ADI 25% most deprived neighborhoods (vs. the other 75% of neighborhoods) were more likely to be non-white, unmarried and from rural areas. At baseline, patients from the most deprived areas had worse EPIC bowel score (P=0.011), worse sexual score (P=0.042) and worse hormonal score (P=0.015); patients from the most deprived areas had worse self-care (P=0.04) and more pain (P=0.047). Patients from rural areas had worse EPIC urinary score (P=0.03) and sexual score (P=0.003). Longitudinal analyses showed that ADI 25% most deprived areas (β=4.05, P=0.001) and rural areas (β=-5.70, P=0.003) were associated with worse EQ-5D VAS score. Compared to the 75% less deprived neighborhoods and urban, the ADI 25% most deprived neighborhoods and rural areas respectively had 47% (HR=1.466, P=0.033) and 93% (HR=1.925, P=0.026) relative increase in risk of recurrence or death (DFS). No differences were seen in OS. Conclusions: Patients with prostate cancer from the most deprived neighborhoods and rural areas had low QOL at baseline, poor general health and DFS. Interventions should target populations from socioeconomic deprived neighborhoods and rural areas to improve patient access to supportive care services and DFS. Citation Format: Jinbing Bai, Stephanie L. Pugh, Ronald Eldridge, Katherine Yeager, Qi Zhang, W Robert Lee, Amit B. Shah, Ian S. Dayes, David P. D'Souza, Jeff M. Michalski, Jason A. Efstathiou, John M. Longo, Thomas M. Pisansky, Jordan M. Maier, Sergio L. Faria, Anand B. Desai, Samantha A. Seaward, Howard M. Sandler, Mary E. Cooley, Deborah W. Bruner. Rurality and neighborhood socioeconomic deprivation associated with patient-reported outcomes andsurvivalin men with prostate cancer in NRG RTOG 0415 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2528.

Abstract Benign breast disease (BBD) is an established risk factor for development of breast cancer (BC). However, little is known about the prevalence of somatic genetic alterations at the time of BBD diagnosis and relationship to subsequent BC. To characterize DNA variants in BBD and investigate association with BC risk, we isolated DNA from formalin-fixed paraffin-embedded (FFPE) BBD biopsies and assessed mutations using a panel of 93 breast cancer predisposition genes (Qiagen GeneRead). The study set consisted of 120 BBD patients from three age-matched groups defined based on 16 years of BC follow-up: BBD-controls (cancer-free after 16 years), BBD-ER+, or BBD-ER- breast cancer (within 16 years). Bioinformatics quality checks included comparisons of paired fresh-frozen and FFPE replicates to reduce false variant calls induced by FFPE artifacts. Gene-level variant burden differences among study groups were assessed using 12 statistical approaches, adjusted for patient age, year of biopsy, and histology. To investigate possible immune implications of increased variant burden, extent of leukocytes in the BBD biopsies was assessed using CD45 immunohistochemistry. To assess variant profile changes during the progression from BBD to BC, we also performed targeted sequencing of 12 BBD-matched subsequent tumor samples (six ER+ and six ER-) developed within 5 years of BBD diagnosis. Gene-level association results showed consistently skewed distributions suggesting a higher variant burden in BBD controls: among the top 10 genes associated with case-status (p<0.05), all had BC-risk odds ratio estimates less than 1.0. Immune infiltrates, assessed by CD45 H-scores, were positively associated with overall variant burden (r=0.42, p=0.0031), and noticeably higher in cancer-free controls (r=0.50, p=0.005). Comparison of mutation variants in 12 BBD cases that developed cancer within 5 years of diagnosis and their subsequent tumors revealed that more than half of the non-SNP variants were shared between the BBD and the subsequent tumor (54.6%), whereas less than one quarter were unique to the tumor (20.6%) or unique to the BBD (24.9%). Through BBD-BC paired variant analysis, three subjects were found with newly emergent clones uniquely appearing in the tumors and four subjects had loss of clones in the tumor that were present in the BBD. These results show that somatic variant burden is lower in patients with BBD that progress to BC, mutation profiles of BC progression are heterogeneous, and BBD tissues with reduced variant burden also show reduced immune infiltrate. This implicates a potential protective role for immune activation in BBD. Future directions will define the characteristics of the potentially protective immune response and its role in variant heterogeneity in a larger sample set, integrated with paired RNA sequencing to better understand the pathways involved and the relationship to immune infiltration. Citation Format: Stacey J. Winham, Julie M. Cunningham, Yuanhang Liu, Aditya V. Bhagwate, Ethan P. Heinzen, Samantha J. McDonough, Melody L. Stallings-Mann, Robert A. Vierkant, Jodi M. Carter, Mark E. Sherman, Derek C. Radisky, Amy C. Degnim, Chen Wang. Somatic variant burdenin benign breast disease and association with risk of subsequent breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2274.

Multiple myeloma, a malignant neoplasm of plasma cells that accumulate in bone marrow, accounts for approximately 18% of hematologic malignancies in the United States. Patients are often treated with triplet therapy and may undergo stem cell transplantation. Despite effective therapies, multiple myeloma remains incurable. Patients often require maintenance therapy, and many will progress or relapsed following upfront treatment. Selection of treatment in the relapse/refractory setting is complex due numerous active therapeutic agents and combinations. Treatment is often tailored to prior exposure and duration. In 2020, three novel pharmacological agents were approved in the relapsed setting. We highlight the clinical safety and efficacy of selinexor, isatuximab-irfc, and belantamab mafodotin for patients with multiple myeloma.

Abstract Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10–8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15–1.34; P = 1.47 × 10–8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options. See related commentary by Peres and Monteiro, p. 1604