Citations

Extremes of sleep duration and obstructive sleep apnea (OSA) are both associated with hypertension. We aimed to explore whether sleep duration modifies the relationship between OSA and prevalent hypertension, using both objective and subjective measures of total sleep duration. A total of 7107 OSA patients and 1118 primary snorers were included in the study. Hypertension was defined based either on direct blood pressure measures or on diagnosis by a physician. Objective sleep duration was derived by polysomnography and subjective sleep duration was self-reported. Logistic regression models were used to estimate the associations between objective/subjective sleep duration and hypertension prevalence in OSA and primary snorers. Compared with primary snorers, OSA combined with objective sleep duration of 5 to 6 hours increased the odds of hypertension by 45% (odds ratio, 1.45; 95% confidence interval, 1.14–1.84), whereas OSA combined with objective sleep duration <5 hours further increased the odds of hypertension by 80% (odds ratio, 1.80; 95% confidence interval, 1.33–2.42). These results were independent of major confounding factors frequently associated with OSA or hypertension. In stratified analysis by sleep duration, risk of hypertension in those with extremely short sleep (<5 hours) was not significantly different between OSA and primary snorers, whereas odds were significant for OSA in the other 4 sleep duration strata (5–6, 6–7, 7–8, and >8 hours). No significance was evident using subjective sleep duration. We conclude that objective short sleep duration is associated with hypertension in OSA patients. Extremely short sleep duration in itself may actually be even more detrimental than OSA in terms of hypertension risk.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a low-grade B-cell neoplasm and ∼2% to 9% patients develop an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (Richter transformation, DLBCL-RT). Programmed death-1 (PD-1) pathway plays a crucial role in tumor host immunity evasion and its blockade has emerged as an effective anti-cancer immunotherapy. PD-L1 and PD-1 expression has shown predictive value in anti-PD cancer immunotherapy; however, it has not been well documented in CLL/SLL and DLBCL-RT. We evaluated PD-1 and PD-L1 expression by immunohistochemistry in 39 CLL/SLL, 15 DLBCL-RT, and 26 other DLBCL. In CLL/SLL, neoplastic B-cell PD-1 expression was weak and restricted to prolymphocytes/paraimmunoblasts within proliferation centers (PCs) and accentuated PCs of all sizes. Neoplastic B-cell PD-1 expression was highly prevalent and demonstrated increased intensity in DLBCL-RT, but in contrast was only rarely seen in other DLBCL (12/15 vs. 1/26; P<0.0001). An excellent correlation (90% concordance) was observed between neoplastic B-cell PD-1 immunohistochemistry positivity and molecularly defined CLL/SLL clonal relatedness in DLBCL-RT. PD-L1 expression was observed on the neoplastic B cells in rare DLBCL-RT and other DLBCL cases (1/15 vs. 1/26; P>0.05) as well as background histiocytes and dendritic cells. Overall survival of DLBCL-RT was significantly inferior to that of the other DLBCL (median, 16.9 vs. 106.1 mo; P=0.002). Our findings suggest a biological continuum from prolymphocytes/paraimmunoblasts in CLL/SLL PCs to the neoplastic B-cells in DLBCL-RT. The characteristic PD-1 expression in DLBCL-RT makes it a potential surrogate marker for determining clonal relatedness to CLL/SLL, which may have important prognostic and therapeutic implications.

Abstract Background:Late recurrence (emergence from dormancy) is characteristic of ER+ breast cancers. Despite adjuvant endocrine therapy, many breast cancers recur decades after their initial diagnosis and treatment. Why this occurs is poorly understood. Methods: We studied 2 independent datasets of endocrine treated, ER+ breast cancers with up to 20 years follow-up. The 1st comprised matched samples from the primary tumor pretreatment at diagnosis and the first recurrence after or during adjuvant endocrine therapy (all FFPE). The 2nd dataset comprised pretreatment biopsies only (all snap frozen). For both datasets, high quality RNA was amplified, labelled, and subjected to transcriptome analysis using the Affymetrix technology (U133 Plus 2.0). Low quality data were identified using 'simpleaffy' and 'ffpe', and removed; all tools were from the R package unless otherwise noted. Remaining data were normalized using 'frma'. Genes differentially expressed between early (≤3 years) and late (≥ 5 years) were selected using limma. Unsupervised hierarchical clustering and PCA explored the structure of the data. A similar molecular analysis was done on the 2nd dataset. A classification scheme that robustly separated early from late recurrences was validated in an independent public dataset of comparable patients, array platform, and frozen tissues. We also explored features in pretreatment samples that predetermined response duration. Results: Genes that separated pretreatment specimens by recurrence time did not separate posttreatment specimens. Specimens did not cluster in patient pairs or by site of recurrence. 8245 genes were differentially expressed between early and late recurrences in the FFPE samples, while 2400 genes were significantly different in the same comparison in the frozen samples. Initial pathway analysis was done on each dataset independently using IPA (Ingenuity® Systems, www.ingenuity.com). 70 canonical pathways were identified in common between the two datasets (pretreatment). We then looked for genes regulated in both datasets (ignores FFPE and frozen tissue as source). There were 279 genes in common that differentially regulated in the same direction (upregulated; downregulated). IPA analysis of these genes identified 49 canonical pathways. We also explored the differentially expressed gene sets using 'GSEA' (www.software.broadinstitute.org/gsea/index.jsp). Pathways consistently associated with early vs. late recurrence include integrin signaling, the unfolded protein response, endoplasmic reticulum stress, actin-based motility, and estrogen biosynthesis. Conclusion: Analysis of pretreatment tumors can predict early recurrences from those that will remain dormant and recur much later. Recurrent tumors exhibit a remodeled molecular landscape that likely reflects the effects of treatments and/or a recreation of a niche with potentially common features at the site of recurrence. Changes in molecular signaling associated with duration of recurrence are consistent with our experimental model studies in vitro implicating UPR signaling as a major integrator of response to endocrine therapy and duration of survival. Additional data sets are being arrayed and more detailed molecular signaling studies are in progress. Citation Format: Clarke R, Dixon MJ, Jin L, Turnbull A, Hu R, Zwart A, Wang Y, Xuan J, Sengupta S, Renshaw L, Sims A, Liu MC. Molecular features of dormancy in ER+ breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-10.