Association of Calcium Channel Blocker Use With Intradialytic Hypotension in Maintenance Hemodialysis.

Introduction: Calcium channel blockers (CCBs) are common antihypertensive agents among patients receiving hemodialysis (HD). Despite this, the association of CCBs with intradialytic hypotension (IDH), an important adverse outcome that is associated with cardiovascular morbidity and mortality, remains largely unexplored. Methods: Using kinetic modeling sessions data from the Hemodialysis (HEMO) Study, random effects regression models were fit to assess the association of CCB use versus nonuse with IDH (defined as systolic blood pressure [SBP] < 90 mm Hg if pre-HD SBP < 160 mm Hg or < 100 mm Hg if pre-HD SBP ≥160 mm Hg). Models were adjusted for age, biological sex (distinguishing between males and females), race, randomized Kt/V and flux assignments, heart failure, ischemic heart disease, peripheral vascular disease, diabetes mellitus, blood urea nitrogen, ultrafiltration rate, access type, pre-HD SBP, and other antihypertensives. Results: Data were available for 1838 patients and 64,538 sessions. At baseline, 49% of patients were prescribed CCBs. The overall frequency of IDH was 14% with a mean decline from pre- to nadir-SBP of 33 ± 15 mm Hg. CCB use was associated with lower adjusted risk of IDH, compared with no use (incidence rate ratio [IRR]: 0.84; 95% confidence interval [CI]: 0.78-0.89). The association was most pronounced for those in the pre-HD SBP lowest quartile (IRR: 0.77; 95% CI: 0.70-0.85); compared with the highest quartile (IRR: 0.86; 95% CI: 0.77-0.97; P-interaction < 0.001). Conclusion: Among patients receiving HD, CCB use was associated with a lower risk of developing IDH, independent of pre-HD SBP and other antihypertensives use. Mechanistic studies are needed to better understand the effects of CCB and other antihypertensives on peridialytic blood pressure (BP) parameters among patients receiving HD.

Inferring early genetic progression in cancers with unobtainable premalignant disease.

Analysis of premalignant tissue has identified the typical order of somatic events leading to invasive tumors in several cancer types. For other cancers, premalignant tissue is unobtainable, leaving genetic progression unknown. Here, we demonstrate how to infer progression from exome sequencing of primary tumors. Our computational method, PhylogicNDT, recapitulated the previous experimentally determined genetic progression of human papillomavirus-negative (HPV-) head and neck squamous cell carcinoma (HNSCC). We then evaluated HPV+ HNSCC, which lacks premalignant tissue, and uncovered its previously unknown progression, identifying early drivers. We converted relative timing estimates of driver mutations and HPV integration to years before diagnosis based on a clock-like mutational signature. We associated the timing of transitions to aneuploidy with increased intratumor genetic heterogeneity and shorter overall survival. Our approach can establish previously unknown early genetic progression of cancers with unobtainable premalignant tissue, supporting development of experimental models and methods for early detection, interception and prognostication.

Single-cell RNA sequencing identifies a paracrine interaction that may drive oncogenic notch signaling in human adenoid cystic carcinoma.

Salivary adenoid cystic carcinoma (ACC) is a rare, biologically unique biphasic tumor that consists of malignant myoepithelial and luminal cells. MYB and Notch signaling have been implicated in ACC pathophysiology, but in vivo descriptions of these two programs in human tumors and investigation into their active coordination remain incomplete. We utilize single-cell RNA sequencing to profile human head and neck ACC, including a comparison of primary ACC with a matched local recurrence. We define expression heterogeneity in these rare tumors, uncovering diversity in myoepithelial and luminal cell expression. We find differential expression of Notch ligands DLL1, JAG1, and JAG2 in myoepithelial cells, suggesting a paracrine interaction that may support oncogenic Notch signaling. We validate this selective expression in three published cohorts of patients with ACC. Our data provide a potential explanation for the biphasic nature of low- and intermediate-grade ACC and may help direct new therapeutic strategies against these tumors.

Association of Estrogen Receptor Alpha Expression With Survival in Oropharyngeal Cancer Following Chemoradiation Therapy.

BACKGROUND: Oropharyngeal squamous carcinoma (OPSC) continues to increase in incidence secondary to human papillomavirus (HPV) infection. Despite the good overall prognosis for these patients, treatment with chemoradiation is associated with morbidity and treatment failure. Better predictors for disease outcome are needed to guide de-intensification regimens. We hypothesized that estrogen receptor α (ERα), a prognostic biomarker in oncology with therapeutic implications, might have similar utility in OPSC. METHODS: To investigate associations among ERα and demographics, HPV status, and survival, we analyzed ERα mRNA expression of head and neck squamous carcinomas (HNSC) from The Cancer Genome Atlas (TCGA) and immunohistochemistry (IHC) of pretreatment biopsy specimens from an independent group of 215 OPSC patients subsequently treated with primary chemoradiation (OPSC-CR). Associations among variables were evaluated with Fisher exact tests and logistic regression; associations with survival were evaluated with log-rank tests and Cox proportional hazards regression. RESULTS: Among 515 patients in TCGA, ERα mRNA expression was highest in HPV-positive OPSC. High ERα mRNA expression was associated with improved survival among those receiving chemoradiation (hazard ratio adjusted for HPV status = 0.44, 95% confidence interval = 0.21 to 0.92). In OPSC-CR, ERα was positive by IHC in 51.6% of tumors and was associated with improved overall, disease-specific, progression-free, and relapse-free survival (log-rank tests: P < .001, P < .001, P = .002, P = .003, respectively); statistically significant associations of ERα positivity with improved survival were maintained after adjusting for clinical risk factors including HPV status. CONCLUSION: In two independent cohorts, ERα is a potential biomarker for improved survival that also may represent a therapeutic target in OPSC.

PD-1 Expression in Head and Neck Squamous Cell Carcinomas Derives Primarily from Functionally Anergic CD4+ TILs in the Presence of PD-L1+ TAMs.

Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cavity tumor. In this study, we examined the basis for the activity of programmed cell death protein (PD-1)-based immune checkpoint therapy that is being explored widely in head and neck cancers. Using multispectral imaging, we systematically investigated the OTSCC tumor microenvironment (TME) by evaluating the frequency of PD-1 expression in CD8+, CD4+, and FoxP3+ tumor-infiltrating lymphocytes (TIL). We also defined the cellular sources of PD-1 ligand (PD-L1) to evaluate the utility of PD-1:PD-L1 blocking antibody therapy in this patient population. PD-L1 was expressed in 79% of the OTSCC specimens examined within the TME. Expression of PD-L1 was associated with moderate to high levels of CD4+ and CD8+ TILs. We found that CD4+ TILs were present in equal or greater frequencies than CD8+ TILs in 94% of OTSCC and that CD4+FOXP3neg TILs were colocalized with PD-1/PD-L1/CD68 more frequently than CD8+ TILs. Both CD4+PD1+ and CD8+PD1+ TILs were anergic in the setting of PD-L1 expression. Overall, our results highlight the importance of CD4+ TILs as pivotal regulators of PD-L1 levels and in determining the responsiveness of OTSCC to PD1-based immune checkpoint therapy. Cancer Res; 77(22); 6365-74. ©2017 AACR.