Citations

Abstract Background: Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. Methods: In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate–corrected P values (q values < 0.05) were considered statistically significant. Results: Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in BABAM1 were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)–negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR = 1.14; 95% confidence interval (CI) = 1.10–1.19; q = 6.87 × 10−5]. DPF1 rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95% CI = 0.91–0.96; q = 0.005). Variants in L3MBTL3 were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR = 1.06; 95% CI = 1.03–1.08; q = 0.02). Variants in TET2 were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility. Conclusions: Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology. Impact: This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes. Cancer Epidemiol Biomarkers Prev; 26(6); 816–25. ©2017 AACR.

Chronic administration of oestrogen and/or progesterone does not affect adrenergic neurotransmission or contractions initiated by sympathomimetic amines in the cutaneous venous smooth muscle of the dog. However, contractions initiated by the venotropic Ruscus-extract are enhanced following chronic exposure to progesterone, an affect that can be reversed by oestrogen. The contractions are mediated by an adrenergic and non-adrenergic component. The adrenergic component is enhanced by progesterone and decreased by oestrogen; the non-adrenergic component is most prominent when the serum-levels of the female steroid hormones are low.

Key Points HSCT after PD-1 blockade is feasible, although may be associated with increased early immune toxicity. PD-1 blockade may cause persistent depletion of PD1+ T cells and alterations in T-cell differentiation impacting subsequent treatment.

Abstract Background. We recently published and validated the new serum creatinine (Scr)-based full-age-spectrum equation (FAScrea) for estimating the glomerular filtration rate (GFR) for healthy and kidney–diseased subjects of all ages. The equation was based on the concept of normalized Scr and shows equivalent to superior prediction performance to the currently recommended equations for children, adolescents, adults and older adults. Methods. Based on an evaluation of the serum cystatin C (ScysC) distribution, we defined normalization constants for ScysC (QcysC = 0.82 mg/L for ages <70 years and QcysC = 0.95 mg/L for ages ≥70 years). By replacing Scr/Qcrea in the FAScrea equation with ScysC/QcysC, or with the average of both normalized biomarkers, we obtained new ScysC-based (FAScysC) and combined Scr-/ScysC-based FAS equations (FAScombi). To validate the new FAScysC and FAScombi we collected data on measured GFR, Scr, ScysC, age, gender, height and weight from 11 different cohorts including n = 6132 unique white subjects (368 children, aged ≤18 years, 4295 adults and 1469 older adults, aged ≥70 years). Results. In children and adolescents, the new FAScysC equation showed significantly better performance [percentage of patients within 30% of mGFR (P30) = 86.1%] than the Caucasian Asian Paediatric Adult Cohort equation (P30 = 76.6%; P < 0.0001), or the ScysC-based Schwartz equation (P30 = 68.8%; P < 0.0001) and the FAScombi equation outperformed all equations with P30 = 92.1% (P < 0.0001). In adults, the FAScysC equation (P30 = 82.6%) performed equally as well as the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPIcysC) (P30 = 80.4%) and the FAScombi equation (P30 = 89.9%) was also equal to the combined CKD-EPI equation (P30 = 88.2%). In older adults, FAScysC was superior (P30 = 88.2%) to CKD-EPIcysC (P30 = 84.4%; P < 0.0001) and the FAScombi equation (P30 = 91.2%) showed significantly higher performance than the combined CKD-EPI equation (P30 = 85.6%) (P < 0.0001). Conclusion. The FAS equation is not only applicable to all ages, but also for all recommended renal biomarkers and their combinations.

SummaryThe randomized, double‐blind, double‐dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)‐related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV‐related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm ‐symptom assessment form total symptom score cytokine symptom cluster (TSS‐C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib‐ and hydroxycarbamide‐treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82–4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13–16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening‐to‐baseline TSS‐C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV‐related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.

BACKGROUNDA new prostate cancer (PCa) grading system (namely, Gleason score‐GS‐ ≤6 vs. 3 + 4 vs. 4 + 3 vs. 8 vs. ≥9) was recently proposed and assessed on biochemical recurrence (BCR) showing improved predictive abilities compared to the commonly used three‐tier system (GS ≤6 vs. 7 vs. ≥8). We assessed the predictive ability of the five‐tier grade group (GG) system on harder clinical endpoint, namely clinical recurrence (CR).METHODSBetween 2005 and 2014, 9,728 clinically localized PCa patients were treated with radical prostatectomy (RP) at two tertiary referral centers. Kaplan–Meier curves, multivariable Cox regression analyses, and concordance index (C‐index) were used to assess CR after treatment according to four Gleason grade classifications at biopsy and RP: Group 1: ≤6 versus 7 versus ≥8; Group 2: ≤6 versus 3 + 4 vs. 4 + 3 versus ≥8; Group 3: ≤6 versus 7 versus 8 versus ≥9; Group 4: ≤6 versus 3 + 4 versus 4 + 3 versus 8 versus ≥9. Same analyses were repeated in patients who had BCR (n = 1,624). Decision curve analyses were performed to evaluate and compare the net benefit associated with the use of the four Gleason grade classifications.RESULTSOverall, 443 (4.6%) patients had CR. The hazard ratio of the GS 3 + 4, 4 + 3, 8, and ≥9 relative to GS ≤6 were 3.63, 5.93, 11.44, 18.08 and 4.93, 9.99, 15.31 and 25.12 in the pre‐ and post‐treatment models, respectively. The C‐index of the five‐tier GG system was slightly higher relative to the other 3 Gleason grade classifications both in the pre‐ (range: 0.001–0.006) and post‐treatment models (range: 0–0.008). Similar findings were observed when we focused our analyses in patients with BCR after RP. The use of the five‐tier GG system did not result into higher net‐benefit relative to the other three Gleason grade classifications.CONCLUSIONSThe difference in accuracy between the five‐tier GG system and the other Gleason grade classifications, using CR as an endpoint, is clinically negligible. Current evidence suggests that the five‐tier GG system represents a simplified user‐friendly scheme available for patient counseling rather than a new histopathological diagnostic system that improves the prediction of CR. Prostate 77:263–273, 2017. © 2016 Wiley Periodicals, Inc.