Citations

Abstract Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in TP53 (87%) and KRAS (73%), amplification of MYC (47%), and homozygous deletion of CDKN2A (40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase SMYD2 and the pancreatic cancer stem cell regulator RORC in all three ASCPs, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the FGFR1-ERLIN2 fusion–positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer. Significance: These data provide a unique description of the ASCP genomic and epigenomic landscape and identify candidate therapeutic targets for this dismal cancer.

Abstract Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. It has a strong genetic basis, showing a ~ 8-fold increased risk of CLL in first-degree relatives. Genome-wide association studies (GWAS) have identified 41 risk variants across 41 loci. However, for a majority of the loci, the functional variants and the mechanisms underlying their causal roles remain undefined. Here, we examined the genetic and epigenetic features associated with 12 index variants, along with any correlated (r2 ≥ 0.5) variants, at the CLL risk loci located outside of gene promoters. Based on publicly available ChIP-seq and chromatin accessibility data as well as our own ChIP-seq data from CLL patients, we identified six candidate functional variants at six loci and at least two candidate functional variants at each of the remaining six loci. The functional variants are predominantly located within enhancers or super-enhancers, including bi-directionally transcribed enhancers, which are often restricted to immune cell types. Furthermore, we found that, at 78% of the functional variants, the alternative alleles altered the transcription factor binding motifs or histone modifications, indicating the involvement of these variants in the change of local chromatin state. Finally, the enhancers carrying functional variants physically interacted with genes enriched in the type I interferon signaling pathway, apoptosis, or TP53 network that are known to play key roles in CLL. These results support the regulatory roles for inherited noncoding variants in the pathogenesis of CLL.

Abstract In the current work we show that the profibrotic actions of TGF‐β are mediated, at least in part, through a metabolic maladaptation in glutamine metabolism and how the inhibition of glutaminase 1 (GLS1) reverses pulmonary fibrosis. GLS1 was found to be highly expressed in fibrotic vs normal lung fibroblasts and the expression of profibrotic targets, cell migration, and soft agar colony formation stimulated by TGF‐β required GLS1 activity. Moreover, knockdown of SMAD2 or SMAD3 as well as inhibition of PI3K, mTORC2, and PDGFR abrogated the induction of GLS1 by TGF‐β. We further demonstrated that the NAD‐dependent protein deacetylase, SIRT7, and the FOXO4 transcription factor acted as endogenous brakes for GLS1 expression, which are inhibited by TGF‐β. Lastly, administration of the GLS1 inhibitor CB‐839 attenuated bleomycin‐induced pulmonary fibrosis. Our study points to an exciting and unexplored connection between epigenetic and transcriptional processes that regulate glutamine metabolism and fibrotic development in a TGF‐β‐dependent manner.

ObjectiveTo compare the diagnostic performance of an artificial intelligence deep learning system with that of expert neuro‐ophthalmologists in classifying optic disc appearance.MethodsThe deep learning system was previously trained and validated on 14,341 ocular fundus photographs from 19 international centers. The performance of the system was evaluated on 800 new fundus photographs (400 normal optic discs, 201 papilledema [disc edema from elevated intracranial pressure], 199 other optic disc abnormalities) and compared with that of 2 expert neuro‐ophthalmologists who independently reviewed the same randomly presented images without clinical information. Area under the receiver operating characteristic curve, accuracy, sensitivity, and specificity were calculated.ResultsThe system correctly classified 678 of 800 (84.7%) photographs, compared with 675 of 800 (84.4%) for Expert 1 and 641 of 800 (80.1%) for Expert 2. The system yielded areas under the receiver operating characteristic curve of 0.97 (95% confidence interval [CI] = 0.96–0.98), 0.96 (95% CI = 0.94–0.97), and 0.89 (95% CI = 0.87–0.92) for the detection of normal discs, papilledema, and other disc abnormalities, respectively. The accuracy, sensitivity, and specificity of the system's classification of optic discs were similar to or better than the 2 experts. Intergrader agreement at the eye level was 0.71 (95% CI = 0.67–0.76) between Expert 1 and Expert 2, 0.72 (95% CI = 0.68–0.76) between the system and Expert 1, and 0.65 (95% CI = 0.61–0.70) between the system and Expert 2.InterpretationThe performance of this deep learning system at classifying optic disc abnormalities was at least as good as 2 expert neuro‐ophthalmologists. Future prospective studies are needed to validate this system as a diagnostic aid in relevant clinical settings. ANN NEUROL 2020;88:785–795

514 Background: The 21- gene Breast Recurrence Score predicts benefit from adjuvant chemotherapy in estrogen receptor positive (ER+), HER-2 negative (-) breast cancer (BC). We aimed to examine whether the 21-gene assay predicts response to neoadjuvant chemotherapy (NAC). Methods: We identified patients with stage I-III ER+/HER2− BC treated with NAC from the Young Women's Breast Cancer Study, a prospective cohort of women diagnosed with BC at age ≤ 40 years. The 21-gene assay was performed on tumor specimens removed prior to NAC either as part of clinical care or retrospectively for research. Pathologic complete response (pCR) was defined as no residual invasive tumor (ypT0/is ypN0). The relationship between Recurrence Score result (RS) and pCR was evaluated using logistic regression modeling. Results: 76 women in the cohort had undergone NAC for ER+, HER2- BC and were eligible for this analysis: 5 had undergone clinical 21-gene assay testing, 71 had banked specimens retrospectively tested. Median age at diagnosis was 36.7 (24.3-40). Most tumors were of ductal histology (78%), high grade (51%), progesterone receptor (PgR) positive (86%), ≥T2 (88%), clinically node positive (74%), and anthracycline and taxane containing protocols were administered in 86% of cases. RS ranged between 5-75 with 50% > 25 and only 4 < 11. Mean RS was significantly higher among tumors achieving pCR vs. non-pCR response (51.9 vs. 26.6, pwilcoxon= 0.0005). pCR rate in patients with RS > 25 was 21% (8/38) vs. 5% in patients with RS < 25 (2/38), with both pCRs in the <25 group in patients with RS 21-25. In univariable analysis, PgR negativity (odds ratio (OR) 5.62, 95% confidence interval (CI) 1.27-24.89, p = 0.02), high grade (OR 9.03, 95%CI 1.07-76.32, p = 0.04) and higher RS as a continuous variable (OR 1.08, 95%CI 1.04-1.13, p = 0.0003) were associated with a greater likelihood of pCR. In multivariable analysis only RS remained significantly associated with pCR (OR: 1.07, 95%CI 1.01-1.12, p = 0.01): a 7% increase in the odds of pCR for every 1-point increase in RS. Conclusions: In young women with ER+, HER2- BC who received NAC, higher pretreatment RS was associated with an increased likelihood of pCR. Genomic expression profiling assays may have a role in decision-making in young women in need of neoadjuvant therapy. For women with low likelihood of benefiting from NAC, alternative approaches are clearly warranted. Given the demonstrated efficacy of neoadjuvant endocrine therapy in post-menopausal women, further evaluation in young women should be pursued.

Abstract Aims Increased medial mitral annulus early diastolic velocity (e′) plays an important role in the echocardiographic diagnosis of constrictive pericarditis (CP) and mitral e′ velocity is also a marker of underlying myocardial disease. We assessed the prognostic implication of mitral e′ for long-term mortality after pericardiectomy in patients with CP. Methods and results We studied 104 surgically confirmed CP patients who underwent echocardiography and cardiac catheterization within 7 days between 2005 and 2013. Patients were classified as primary CP (n = 45) or mixed CP (n = 59) based on the clinical history of concomitant myocardial disease. On multivariable analysis, medial e′ velocity and mean pulmonary artery pressure were independently associated with long-term mortality post-pericardiectomy. There were significant differences in survival rates among the groups divided by cut-off values of 9.0 cm/s and 29 mmHg for medial e′ and mean pulmonary artery pressure, respectively (both P &lt; 0.001). Ninety-two patients (88.5%) had elevated pulmonary artery wedge pressure (PAWP) (≥15 mmHg); there was no significant correlation between medial E/e′ and PAWP (r = 0.002, P = 0.998). However, despite the similar PAWP between primary CP and mixed CP groups (21.6 ± 5.4 vs. 21.2 ± 5.8, P = 0.774), all primary CP individuals with elevated PAWP had medial E/e′ &lt;15 as opposed to 34 patients (57.6%) in the mixed CP group (P &lt; 0.001). Conclusion Increased mitral e′ velocity is associated with better outcomes in patients with CP. A paradoxical distribution of the relationship between E/e′ and PAWP is present in these patients but there is no direct inverse correlation between them.

The World Health Organization (WHO) has declared coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a pandemic. Global health care now faces unprecedented challenges with widespread and rapid human-to-human transmission of SARS-CoV-2 and high morbidity and mortality with COVID-19 worldwide. Across the world, medical care is hampered by a critical shortage of not only hand sanitizers, personal protective equipment, ventilators, and hospital beds, but also impediments to the blood supply. Blood donation centers in many areas around the globe have mostly closed. Donors, practicing social distancing, some either with illness or undergoing self-quarantine, are quickly diminishing. Drastic public health initiatives have focused on containment and “flattening the curve” while invaluable resources are being depleted. In some countries, the point has been reached at which the demand for such resources, including donor blood, outstrips the supply. Questions as to the safety of blood persist. Although it does not appear very likely that the virus can be transmitted through allogeneic blood transfusion, this still remains to be fully determined. As options dwindle, we must enact regional and national shortage plans worldwide and more vitally disseminate the knowledge of and immediately implement patient blood management (PBM). PBM is an evidence-based bundle of care to optimize medical and surgical patient outcomes by clinically managing and preserving a patient’s own blood. This multinational and diverse group of authors issue this “Call to Action” underscoring “The Essential Role of Patient Blood Management in the Management of Pandemics” and urging all stakeholders and providers to implement the practical and commonsense principles of PBM and its multiprofessional and multimodality approaches.

Diabetes is a metabolic disease which affects not only glucose metabolism but also lipid and protein metabolism. It encompasses two major types: type 1 and 2 diabetes. Despite the different etiologies of type 1 and 2 diabetes mellitus (T1DM and T2DM, respectively), the defining features of the two forms are insulin deficiency and resistance, respectively. Stem cell therapy is an efficient method for the treatment of diabetes, which can be achieved by differentiating pancreatic β-like cells. The consistent generation of glucose-responsive insulin releasing cells remains challenging. In this review article, we present basic concepts of pancreatic organogenesis, which intermittently provides a basis for engineering differentiation procedures, mainly based on the use of small molecules. Small molecules are more auspicious than any other growth factors, as they have unique, valuable properties like cell-permeability, as well as a nonimmunogenic nature; furthermore, they offer immense benefits in terms of generating efficient functional beta-like cells. We also summarize advances in the generation of stem cell-derived pancreatic cell lineages, especially endocrine β-like cells or islet organoids. The successful induction of stem cells depends on the quantity and quality of available stem cells and the efficient use of small molecules.

Abstract Background: Young women with breast cancer (BC) often receive aggressive local therapy and are more likely to undergo (bilateral) mastectomy and receive postmastectomy radiation (RT) than older women. Our previous work suggested better quality of life (QOL) outcomes among women undergoing breast conserving therapy (BCT) vs. mastectomy, even with reconstruction (recon), although limited data was available regarding recon. In the current analysis, we sought to understand the impact of recon, accounting for RT, on long-term satisfaction and QOL. Methods: Between 10/2016-11/2017, we administered the BREAST-Q, a validated patient-reported outcomes measure designed to evaluate satisfaction and QOL after breast cancer surgery and recon, to 743 women in the Young Women’s Breast Cancer Study, a multi-site prospective cohort that enrolled women diagnosed (dx’d) at age &lt; 40 from 2006-2016. Demographic and treatment information was obtained by surveys and chart review. Recon was defined as autologous, implant or complex (combination of autologous and implant). Mean BREAST-Q scores for each domain (breast satisfaction, physical, psychosocial, and sexual) were compared by recon types and stratified by receipt of RT; higher BREAST-Q scores (range: 0-100) indicate better QOL. Linear regression was used to identify predictors of BREAST-Q scores. Results: 584 women with Stage 0-3 BC completed the Breast-Q at a median of 5.7 [range 2-10] years from dx), 357 (61%) had mastectomy and recon and were included in the analytic sample. Median age at dx was 36 years; 85% had stage 0, 1 or 2 disease; 41% received RT and 76% underwent bilateral mastectomy. 90.5% underwent immediate recon; of which 65.5% were tissue expander placement. Definitive recon included autologous tissue in 16%; implants in 81% and complex recon in 3%. Mean BREAST-Q breast satisfaction, psychosocial, and physical well-being scores differed based on recon type accounting for RT (Table 1). Significantly lower scores for breast satisfaction were seen in women having implant +RT. Scores were not impacted by bilateral procedure, timing of recon, use of tissue expander, extent of axillary surgery, cancer stage or other treatment factors. In multivariate analyses, receipt of RT, lymphedema and implant-based recon were associated with lower breast satisfaction scores. Physical well-being scores were lower for those with complex recon, for non-White women, for women who reported being financially uncomfortable, for those with lymphedema, and for those &lt;5 years from surgery. Psychosocial well-being scores were lower for women who received RT, had BMI &gt;25, and for those who reported being financially uncomfortable. Sexual well-being scores were lower for women with a BMI &gt;25 and for those who reported being financially uncomfortable. Conclusion Type of recon and receipt of radiation among young survivors who undergo mastectomy and recon for early breast cancer appears to have a differential impact on satisfaction and QOL. Our finding of lower breast satisfaction among young women who received RT, particularly after implant recon, underscores the importance of counseling regarding surgical options, especially for women who may receive RT after mastectomy and who are candidates for BCT. Table 1. Unadjusted BREAST-Q scores stratified by RTBREAST-Q DomainAutologous -RT N=29Autologous +RT N=27Implant -RT N=174Implant +RT N=113Complex N=13Global p-valueSatisfaction with Breasts, mean (sd)67 (19)63 (18)64 (18)53 (18)58 (22)&lt;0.01Physical well-being, mean (sd)81 (13)80 (14)80 (15)77 (14)67 (18)0.01Psychosocial well-being, mean (sd)71 (18)64 (18)72 (20)66 (23)62 (20)0.03Sexual well-being, mean (sd)54 (21)50 (24)52 (20)47 (22)48 (27)0.26RT= radiation Citation Format: Laura Dominici, Jiani Hu, Hee Jeong Kim, Tari King, Kathryn Ruddy, Rulla Tamimi, Jeffrey Peppercorn, Lidia Schapira, Virginia Borges, Stephen Come, Ellen Warner, Julia Wong, Ann Partridge, Shoshana Rosenberg. BREAST-Q satisfaction and quality of life outcomes in young women undergoing mastectomy and reconstruction for breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD6-1.