Family history of liver cancer may modify the association between HBV infection and liver cancer in a Chinese population.

BACKGROUND & AIMS: The potential interaction between family history of liver cancer and HBV infection on liver cancer has not been fully examined. METHODS: We conducted a population-based case-control study composed of 2011 liver cancer cases and 7933 controls in Jiangsu province, China from 2003 to 2010. Data on major risk or protective factors were collected and HBV/HCV sero-markers were assayed using blood samples. Semi-Bayes (SB) adjustments were applied to provide posterior estimates. RESULTS: Both family history of liver cancer (adjusted odds ratios [OR]: 4.32, 95% confidence intervals [CI]: 3.25-5.73) and hepatitis B surface antigen (HBsAg) positivity (adjusted OR: 9.94, 95% CI: 8.33-11.87) were strongly associated with liver cancer development. For individuals with different combinations of serological markers, the adjusted ORs were 8.45 (95% CI: 5.16-13.82) for HBsAg- and HBcAb-positive; 7.57 (95% CI: 4.87-11.77) for HBsAg-, HBeAg- and HBcAb-positive; and 3.62 (95% CI: 2.47-5.31) for HBsAg-, HBeAb- and HBcAb-positive, compared to all negatives in HBV serological markers. One log increase in HBV DNA level was associated with 17% increased risk (adjusted OR: 1.17, 95% CI: 1.03-1.32). The SB-adjusted OR of HBV-positive individuals with family history of liver cancer was 41.34 (95% posterior interval [PI]: 23.69-72.12) compared with those HBV-negative without family history. Relative excess risk due to additive interaction, the attributable proportion and synergy index were 73.13, 0.87 and 8.04 respectively. Adjusted ratio of OR for multiplicative interaction was 2.84 (95% CI: 1.41-5.75). CONCLUSIONS: Super-additive and super-multiplicative interactions may exist between family history of liver cancer and HBV infection on the development of liver cancer.

Integrated multiomic predictors for ovarian cancer survival.

Increasingly affordable high-throughput molecular profiling technologies have made feasible the measurement of omics-wide interindividual variations for the purposes of predicting cancer prognosis. While multiple types of genetic, epigenetic and expression changes have been implicated in ovarian cancer, existing prognostic biomarker strategies are constrained to analyzing a single class of molecular variations. The extra predictive power afforded by the integration of multiple omics types remains largely unexplored. In this study, we performed integrative analysis on tumor-based exome-, transcriptome- and methylome-wide molecular profiles from The Cancer Genome Atlas (TCGA) for variations in cancer-relevant genes to construct robust, cross-validated multiomic predictors for ovarian cancer survival. These integrated polygenic survival scores (PSSs) were able to predict 5-year overall (OS) and progression-free survival in the Caucasian subsample with high accuracy (AUROC = 0.87 and 0.81, respectively). These findings suggest that the PSSs are able to predict long-term OS in TCGA patients with accuracy beyond that of previously proposed protein-based biomarker strategies. Our findings reveal the promise of an integrated omics-based approach in enhancing existing prognostic strategies. Future investigations should be aimed toward prospective external validation, strategies for standardizing application and the integration of germline variants.

Obesity and associated lifestyles modify the effect of glucose metabolism-related genetic variants on impaired glucose homeostasis among postmenopausal women.

PURPOSE: Impaired glucose metabolism-related genetic variants likely interact with obesity-modifiable factors in response to glucose intolerance, yet their interconnected pathways have not been fully characterized. METHODS: With data from 1,027 postmenopausal participants of the Genomics and Randomized Trials Network study and 15 single-nucleotide polymorphisms (SNPs) associated with glucose homeostasis, we assessed whether obesity, physical activity, and high dietary fat intake interact with the SNP-glucose variations. We used regression analysis plus stratification and graphic approaches. RESULTS: Across carriers of the 15 SNPs, fasting levels of glucose, insulin, and homeostatic model assessment-insulin resistance (HOMA-IR) were higher in obese, inactive, and high fat-diet women than in their respective counterparts. Carriers within subgroups differently demonstrated the direction and/or magnitude of the variants' effect on glucose-relevant traits. Variants in GCKR, GCK, DGKB/TMEM195 (P for interactions = 0.02, 0.02, and 0.01), especially, showed interactions with obesity: obese, inactive, and high fat-diet women had greater increases in fasting glucose, insulin, and HOMA-IR levels. Obese carriers at TCF7L2 variant had greater increases in fasting glucose levels than nonobese carriers (P for interaction = 0.04), whereas active women had greater decreases in insulin and HOMA-IR levels than inactive women (P for interaction = 0.02 in both levels). CONCLUSIONS: Our data support the important role of obesity in modifying glucose homeostasis in response to glucose metabolism-relevant variants. These findings may inform research on the role of glucose homeostasis in the etiology of chronic disease and the development of intervention strategies to reduce risk in postmenopausal women.

PIWI-interacting RNA 021285 is involved in breast tumorigenesis possibly by remodeling the cancer epigenome.

Although PIWI-interacting RNAs (piRNAs) account for the largest class of the small non-coding RNA superfamily, virtually nothing is known of their function in human carcinogenesis. Once thought to be expressed solely in the germ line where they safeguard the genome against transposon-induced insertional mutations, piRNAs are now believed to play an active role in somatic gene regulation through sequence-specific histone modification and DNA methylation. In the current study, we investigate the role of piRNA-021285 (piR-021285) in the regulation of the breast cancer methylome. Genotypic screening of a panel of single-nucleotide polymorphism (SNP)-containing piRNAs revealed a significant association between SNP rs1326306 G>T in piR-021285 and increased likelihood for breast cancer in a Connecticut-based population (441 cases and 479 controls). Given nascent but compelling evidence of piRNA-mediated gene-specific methylation in the soma, a genome-wide methylation screen was then carried out using wild type (WT) and variant piR-021285 mimic-transfected MCF7 cells to explore whether the observed association could be attributed in part to piR-021285-induced methylation at cancer-relevant genes. We found significant methylation differences at a number of experimentally implicated breast cancer-related genes, including attenuated 5' untranslated region (UTR)/first exon methylation at the proinvasive ARHGAP11A gene in variant mimic-transfected cells. Follow-up functional analyses revealed both concurrent increased ARHGAP11A mRNA expression and enhanced invasiveness in variant versus WT piR-021285 mimic-transfected breast cancer cell lines. Taken together, our findings demonstrate the first evidence supporting a role of piRNAs, a novel group of non-coding RNA, in human tumorigenesis via a piRNA-mediated epigenetic mechanism, which warrants further confirmation and investigation.

Aberrant methylation of miR-34b is associated with long-term shiftwork: a potential mechanism for increased breast cancer susceptibility.

PURPOSE: Although the evidence linking exposure to light at night (LAN) and breast cancer risk continues to accumulate, the molecular mechanisms driving this association remain to be fully elucidated. We have previously suggested that long-term exposure to LAN through shiftwork may result in dysregulated patterns of methylation genome-wide. In this study, we investigate the link between miR-34b, a miRNA suggested to be an important tumor suppressor, and shiftwork-related breast cancer. METHODS: Methylation states in the miR-34b promoter region were previously compared between 10 female long-term shiftworkers and 10 folate intake- and age-matched female dayworkers participating in the Danish "Diet, Cancer and Health" prospective cohort study. In order to further explore the functional role of miR-34b in breast tumorigenesis, a genome-wide expression microarray was carried out in miR-34b-overexpressed MCF-7 breast cancer cells and the identified transcripts were further analyzed for network and functional interrelatedness using Ingenuity Pathway Analysis software. RESULTS: We observed a 49.1 % increase in miR-34b promoter methylation among shiftworkers at a CpG site in this region (p = 0.016). Transfection of the miR-34b mimic in an MCF-7 breast cancer cell line induced differential expression of 230 transcripts that are involved in the interferon-mediated antiviral response as well as apoptotic and antiproliferative gene networks. CONCLUSIONS: Together, our results suggest that long-term shiftwork may increase the risk of breast cancer via methylation-based suppression of miR-34b and a consequent reduction in immunomediated anti-tumor capacity and support our previous findings that LAN may induce epigenetic alteration of cancer-relevant microRNAs.

The circadian gene CRY2 is associated with breast cancer aggressiveness possibly via epigenomic modifications.

Although the role of core circadian gene cryptochrome 2 (CRY2) in breast tumorigenesis has been demonstrated, the correlations of CRY2 with clinical parameters in breast cancer patients and its involvement in epigenetic processes such as DNA methylation remain relatively unexplored. In the current study, we first queried the Oncomine database and the Gene Expression-Based Outcome for Breast Cancer Online (GOBO) database to identify associations between CRY2 expression levels and clinical parameters in breast cancer patients. We then silenced CRY2 in vitro and performed a genome-wide methylation array to determine the epigenetic impact of CRY2 silencing. The Ingenuity Pathway Analysis software was used to further explore the genes exhibiting altered methylation identified using the array. We found that CRY2 was frequently down-regulated in breast cancer tissue compared to adjacent normal tissue or breast tissue from healthy controls. Lower CRY2 expression was associated with estrogen receptor (ER)-negativity (P < 0.0001), higher tumor grade (P < 0.0001), and shorter overall survival time in breast cancer patients (HR = 1.44, 95 % confidence interval (CI) 1.09-1.91). Genome-wide methylation analysis showed that a total of 515 CpG sites were hypermethylated following CRY2 knockdown, while 730 sites were hypomethylated. The pathway analysis revealed several cancer-relevant networks with genes exhibiting significantly altered methylation following CRY2 silencing. These findings suggest that the core circadian gene CRY2 is associated with breast cancer progression and prognosis, and that knockdown of CRY2 causes the epigenetic dysregulation of genes involved in cancer-relevant pathways, which provide further evidence supporting a role of the circadian system in breast tumorigenesis.

Epigenome-wide analysis of piRNAs in gene-specific DNA methylation.

PIWI-interacting RNAs (piRNAs) have long been associated with the silencing of transposable elements (TEs). However, over 20,000 unique species of piRNAs mapped to the human genome are more than the relatively few presumably required to regulate the known human transposon classes. Here, we present the results of the first genome-wide effort to study the effects of piRNAs on gene specific DNA methylation. We found that exon-derived piRNAs consist almost universally of species with 10 or fewer genomic copies, whereas piRNAs existing in high copies originate predominately from intronic and intergenic regions. Genome-wide methylation profiling following transfection of human somatic cells with piRNA mimics revealed methylation changes at numerous genic loci in single copy piRNA-transfected cells. Moreover, genomic regions directly adjacent to differentially methylated CpG sites were enriched for sequence matches to the transfected piRNAs. These findings suggest that a subset of single copy piRNAs may be able to induce DNA methylation at non-TE genic loci, a process that may be mediated in part by direct binding to either genomic DNA or nascent mRNA near target CpG sites.

Melatonin enhances DNA repair capacity possibly by affecting genes involved in DNA damage responsive pathways.

BACKGROUND: Melatonin, a hormone-like substance involved in the regulation of the circadian rhythm, has been demonstrated to protect cells against oxidative DNA damage and to inhibit tumorigenesis. RESULTS: In the current study, we investigated the effect of melatonin on DNA strand breaks using the alkaline DNA comet assay in breast cancer (MCF-7) and colon cancer (HCT-15) cell lines. Our results demonstrated that cells pretreated with melatonin had significantly shorter Olive tail moments compared to non-melatonin treated cells upon mutagen (methyl methanesulfonate, MMS) exposure, indicating an increased DNA repair capacity after melatonin treatment. We further examined the genome-wide gene expression in melatonin pretreated MCF-7 cells upon carcinogen exposure and detected altered expression of many genes involved in multiple DNA damage responsive pathways. Genes exhibiting altered expression were further analyzed for functional interrelatedness using network- and pathway-based bioinformatics analysis. The top functional network was defined as having relevance for "DNA Replication, Recombination, and Repair, Gene Expression, [and] Cancer". CONCLUSIONS: These findings suggest that melatonin may enhance DNA repair capacity by affecting several key genes involved in DNA damage responsive pathways.

Potential cancer-related role of circadian gene TIMELESS suggested by expression profiling and in vitro analyses.

BACKGROUND: The circadian clock and cell cycle are two global regulatory systems that have pervasive behavioral and physiological effects on eukaryotic cells, and both play a role in cancer development. Recent studies have indicated that the circadian and cell cycle regulator, TIMELESS, may serve as a molecular bridge between these two regulatory systems. METHODS: To assess the role of TIMELESS in tumorigenesis, we analyzed TIMELESS expression data from publically accessible online databases. A loss-of-function analysis was then performed using TIMELESS-targeting siRNA oligos followed by a whole-genome expression microarray and network analysis. We further tested the effect of TIMELESS down-regulation on cell proliferation rates of a breast and cervical cancer cell line, as suggested by the results of our network analysis. RESULTS: TIMELESS was found to be frequently overexpressed in different tumor types compared to normal controls. Elevated expression of TIMELESS was significantly associated with more advanced tumor stage and poorer breast cancer prognosis. We identified a cancer-relevant network of transcripts with altered expression following TIMELESS knockdown which contained many genes with known functions in cancer development and progression. Furthermore, we observed that TIMELESS knockdown significantly decreased cell proliferation rate. CONCLUSIONS: Our results suggest a potential role for TIMELESS in tumorigenesis, which warrants further investigation of TIMELESS expression as a potential biomarker of cancer susceptibility and prognostic outcome.

Dysregulated methylation at imprinted genes in prostate tumor tissue detected by methylation microarray.

BACKGROUND: Imprinting is an important epigenetic regulator of gene expression that is often disrupted in cancer. While loss of imprinting (LOI) has been reported for two genes in prostate cancer (IGF2 and TFPI2), disease-related changes in methylation across all imprinted gene regions has not been investigated. METHODS: Using an Illumina Infinium Methylation Assay, we analyzed methylation of 396 CpG sites in the promoter regions of 56 genes in a pooled sample of 12 pairs of prostate tumor and adjacent normal tissue. Selected LOI identified from the array was validated using the Sequenom EpiTYPER assay for individual samples and further confirmed by expression data from publicly available datasets. RESULTS: Methylation significantly increased in 52 sites and significantly decreased in 17 sites across 28 unique genes (P < 0.05), and the strongest evidence for loss of imprinting was demonstrated in tumor suppressor genes DLK1, PLAGL1, SLC22A18, TP73, and WT1. Differential expression of these five genes in prostate tumor versus normal tissue using array data from a publicly available database were consistent with the observed LOI patterns, and WT1 hypermethylation was confirmed using quantitative DNA methylation analysis. CONCLUSIONS: Together, these findings suggest a more widespread dysregulation of genetic imprinting in prostate cancer than previously reported and warrant further investigation.

Heart Failure Among Patients with Multiple Myeloma Treated with Carfilzomib-Based Versus Non-Carfilzomib-Based Regimens in the United States by Race.

BACKGROUND: Carfilzomib treatment for multiple myeloma (MM) can increase heart failure risk. Whether this risk differs by race is unknown. PATIENTS AND METHODS: We sought to estimate the incidence rates (IRs) of heart failure hospitalization among mostly 65-years-and-older US patients with MM by race treated with carfilzomib- and non-carfilzomib-based regimens in the real-world using Centers for Medicare & Medicaid Services Medicare Fee-for-Service data, Optum Clinformatics Data Mart, and Humana Research Database. The risk of heart failure hospitalization associated with a carfilzomib-based regimen was evaluated using propensity score matching among Black and White patients receiving second or later lines of therapy. RESULTS: Most patient-episodes (88%) were in persons 65 years or older for the 3 cohorts combined. The IR (95% CI) of heart failure hospitalization was higher for patient-episodes treated with a carfilzomib-based regimen than those with a non-carfilzomib-based regimen for both White (14.5 [12.2-17.0] vs. 10.7 [10.3-11.2] events per person-years) and Black patients (15.8 [10.1-23.5] vs. 12.1 [10.9-13.4] events per person-years) in the Medicare cohort. After propensity score matching, the hazard ratio (95% CI) of increased heart failure hospitalization comparing carfilzomib-based to non-carfilzomib-based regimens for White patients (1.6 [1.3-2.0]) was similar to that of Black patients (1.7 [1.0-2.9]) in the Medicare Database, and in the Humana Database (1.4 [0.8-2.6] and 1.2 [0.4-3.5], respectively). CONCLUSION: Although the IR of heart failure among patients with MM treated with a carfilzomib-based regimen was slightly higher, no evidence suggested the relative risk was different between White and Black patients with MM.

Survey of patients and physicians on shared decision-making in treatment selection in relapsed/refractory multiple myeloma.

Shared decision-making (SDM) is a key component of patient-centered healthcare. SDM is particularly pertinent in the relapsed and/or refractory multiple myeloma (RRMM) setting, in which numerous treatment options can present challenges for identifying optimal care. However, few studies have assessed the extent and relevance of SDM and patient-centered communication (PCC) in RRMM. To describe treatment decision-making patterns between physicians and patients in the RRMM setting, we conducted online surveys of patients and physicians in the USA to compare their perspectives on the process of treatment decision-making. We analyzed the surveys descriptively. Two hundred hematologists/oncologists and 200 patients with RRMM receiving second-line (n = 89), third-line (n = 65), and fourth-line (n = 46) therapy participated. Top treatment goals for physicians and patients included extending overall survival (among 76% and 83% of physicians and patients, respectively) and progression-free survival (among 54% and 77% of physicians and patients, respectively), regardless of the number of prior relapses. Thirty percent of physicians believed patients preferred a shared approach to treatment decision-making, while 40% of patients reported most often preferring a shared role in treatment decision-making. One-fourth of patients most often preferred physicians to make the final treatment decision after seriously considering their opinion. Thirty-two percent of physicians and 16% of patients recalled ≥3 treatment options presented at first relapse. Efficacy was a primary treatment goal for patients and physicians. Discrepancies in their perceptions during RRMM treatment decision-making exist, indicating that communication tools are needed to facilitate SDM and PCC.

Shared decision-making (SDM) is an important facet of patient-centered healthcare. Multiple myeloma (MM) is a cancer of the bone marrow that can return (relapse) after treatment. SDM may be especially pertinent for relapsed MM as there is no uniform standard of care and treatment selection can be complex. Few studies have examined the extent and relevance of SDM and patient-centered communication (PCC) in this relapsed and/or refractory (RRMM) setting. We conducted online surveys of 200 patients who had received 1­3 previous therapies and 200 physicians to compare treatment decision-making patterns in RRMM in the USA. Both physicians and patients felt that extending patient survival was a top treatment goal, regardless of the number of prior relapses. A lower percentage of physicians believed patients preferred a shared approach to treatment decision-making than patients who reported preferring such a shared role. Twice as many physicians than patients recalled ≥3 treatment options presented at first relapse. In conclusion, while improving survival was an important treatment goal for physicians and patients, there are discrepancies in physician and patient perceptions during RRMM treatment decision-making. Thus, communication tools are needed to facilitate SDM and PCC.

Genetic and epigenetic associations of circadian gene TIMELESS and breast cancer risk.

Results from recent molecular epidemiologic studies suggest that the core circadian genes play a role in breast tumorigenesis, possibly by influencing hormone regulation or other pathways relevant to cancer. In order to further evaluate this hypothesis, we conducted a genetic and epigenetic association study of the circadian regulator TIMELESS in breast carcinogenesis. We detected significant associations between two tagging SNPs (rs2291738 and rs7302060) in the TIMELESS gene and breast cancer among 441 breast cancer cases and 479 cancer-free controls, with apparent effect modification by ER/PR status. The presence of the C allele of rs7302060 was found to be associated with reduced breast cancer risk (OR, 0.54; 95% CI, 0.54-0.99). In addition, both the G/G genotype of rs2291738 and the C/C genotype of rs7302060 were associated with reduced risk of breast cancer among ER- or PR-positive breast cancer cases (OR, 0.46; 95% CI, 0.22-0.97 and OR, 0.36; 95% CI, 0.17-0.78, respectively). We also observed a significant association between stage II, III, and IV breast cancers and TIMELESS promoter hypomethylation in peripheral blood lymphocytes (OR, 0.35; 95% CI, 0.13-0.96) in 80 breast cancer cases and 80 age-matched controls, which is corroborated by documented overexpression of TIMELESS in breast tumor tissue compared to adjacent normal tissue. Our findings support the hypothesized role of circadian genes in breast tumorigenesis, and identify a set of circadian biomarkers for breast cancer susceptibility.

Implementing Real-World RECIST-based Tumor Response Assessment in Patients With Metastatic Non-small Cell Lung Cancer.

BACKGROUND: To accelerate drug approvals while maintaining scientific rigor in the evaluation of a therapeutic's efficacy and safety, the United States Food and Drug Administration now considers real-world data (RWD) to support New Drug Applications and expanded indications. Response Evaluation Criteria in Solid Tumors (RECIST) are the gold standard in clinical trials, but the derivation of RECIST-based treatment response from RWD is unproven. This study investigated the feasibility of implementing RECIST criteria in RWD by comparing lung cancer response assessments from RECIST-based measurement of lesions on archived radiologic films with results from medical oncologist and radiologist narratives recorded in electronic health records (EHR). MATERIALS AND METHODS: Response to index treatment via different assessment approaches was compared among 30 metastatic non-small cell lung cancer (mNSCLC) patients receiving systemic treatment (index) after progression on a platinum or anti-PD(L)-1-containing regimen. Specifically, responses based on assessments documented in the medical oncologists' narratives were compared to a radiologist's assessments of archived images using RECIST v1.1 criteria. Each patient's best overall response was characterized as complete or partial (CR/PR), stable disease (SD), progressive disease (PD), or not evaluable (NE). RESULTS: Similar distributions of best overall response and substantial concordance (77%) between medical oncologist-reported and radiologist re-assessed responses were observed. There were no instances of CR/PR to PD or PD to CR/PR discordance. CONCLUSIONS: Results suggest that accurate treatment responses, similar to RECIST, may be derived using RWD. Further validation and improvement of real-world response assessment are needed to develop a scalable real-world approach for response assessment.

Circulating phosphorus concentration and risk of prostate cancer: a Mendelian randomization study.

BACKGROUND: Recent observational studies have suggested that circulating phosphorus concentrations are positively associated with the risk of prostate cancer. However, little is known about the causal direction of the association. OBJECTIVES: To explore the potential causal relation between circulating phosphorus and risk of prostate cancer, we conducted a Mendelian randomization (MR) study. METHODS: Summary statistics of prostate cancer were obtained from a meta-analysis of genome-wide association studies (GWASs) consisting of 79,148 cases and 61,106 controls. Single-nucleotide polymorphisms (SNPs) associated with serum phosphorus concentration were selected from a GWAS of 291,408 individuals from the UK Biobank. MR analysis was performed using the inverse variance weighted (IVW) method, supplemented with simple median method, weighted median method, maximum likelihood-based method, MR-Egger regression, and the MR pleiotropy residual sum and outlier test. We also performed a meta-analysis of observational studies to assess the associations of dietary phosphorus intake and serum phosphorus concentration with risk of prostate cancer. RESULTS: In the MR analysis, a total of 125 independent SNPs associated with serum phosphorus concentrations were used as instrumental variables. Genetically predicted serum phosphorus concentrations were associated with a 19% increased risk of prostate cancer (95% CI: 9%, 31%) per 1-SD increment of serum phosphorus by IVW (P = 1.82 × 10-4). Sensitivity analyses using alternative MR methods produced similar positive associations, and no evidence of pleiotropy was detected by MR-Egger regression (P = 0.422). For meta-analysis, 8 studies for dietary phosphorus intake and 4 for serum phosphorus concentrations were included involving a total of 669,080 participants. Consistently, high dietary phosphorus intake and serum phosphorus concentrations were associated with an 8% (95% CI: 4%, 12%) and 7% (95% CI: 1%, 14%) increase in prostate cancer risk, respectively. CONCLUSIONS: Our study suggested a potential causal relation between circulating phosphorus and risk of prostate cancer. Further studies are warranted to elucidate the underlying mechanism of phosphorus in the development of prostate cancer.

Renal response in real-world carfilzomib- vs bortezomib-treated patients with relapsed or refractory multiple myeloma.

In the phase 3 ENDEAVOR study, carfilzomib-dexamethasone (Kd) improved survival over bortezomib-dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM), regardless of baseline renal function. This real-world study compared renal response in patients with RRMM (1-3 prior lines) and renal impairment (estimated glomerular filtration rate ≤50 mL/min) treated with Kd vs Vd. Electronic medical records data from the Oncology Services Comprehensive Electronic Records database were assessed (from January 2012 through February 2018). Time to renal response (defined according to International Myeloma Working Group criteria) was evaluated using the Kaplan-Meier method and log-rank test. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for renal overall response (ROR) and renal complete response (RCR) using Cox proportional hazard models adjusted for baseline covariates. Included were 543 Kd-treated and 1005 Vd-treated patients. In line 2 (2L), compared with Vd, Kd achieved significantly higher ROR (51.4% vs 39.6%; P < .0001) and RCR (26.6% vs 22.2%; P = .0229). After baseline covariate adjustment, 2L patients receiving Kd vs Vd were 45% more likely to achieve ROR (IRR, 1.45; 95% CI, 1.18-1.78), and 68% were more likely to achieve RCR (IRR, 1.68; 95% CI, 1.24-2.28). The renal response benefit with Kd remained consistent in 2L to line 4 (4L). In a combined analysis of patients receiving Kd and Vd (2L and 2L-4L), renal responders had longer overall survival and time to next treatment than renal nonresponders. These results demonstrate improved real-world effectiveness of Kd over Vd in RRMM renal rescue, and the positive association between renal response and improved survival.

Clinical Outcomes Associated With Chronic Kidney Disease in Elderly Medicare Patients With Multiple Myeloma.

BACKGROUND: Chronic kidney disease (CKD) is common in patients with multiple myeloma (MM) and is associated with a poor prognosis. We assessed CKD-associated clinical outcomes among elderly patients with MM initiating chemotherapy in the United States. MATERIALS AND METHODS: We identified elderly Medicare beneficiaries (≥66 years) diagnosed with MM who initiated first-line therapy from 2008 to 2014. We identified CKD using diagnosis codes. We followed patients for death, time to next treatment (TTNT), and myeloma-defining events (anemia, hypercalcemia, skeletal-related events, progression to/of CKD) until September 30, 2015. We estimated overall survival, TTNT, and cumulative incidence of myeloma-defining events using the Kaplan-Meier method and risk of CKD-associated outcomes using Cox proportional hazards models, adjusting for demographics and comorbid conditions. RESULTS: Of 22,484 included patients, 8704 (39%) had CKD at first-line therapy initiation. Compared with patients without CKD, patients with CKD had shorter median overall survival (2.1 vs. 3.6 years) and median TTNT (10.0 vs. 12.4, 9.7 vs. 11.2, 8.3 vs. 9.2, and 6.9 vs. 8.3 months at first- to fourth-line therapy). Probability of CKD progression for patients at stages 1 to 5 was higher than the probability of developing CKD for patients without CKD (3-year cumulative incidence [95% confidence interval, CI], 47% [45-48%] vs. 27% [24-26%]). Adjusted hazard ratios for CKD versus non-CKD were: all-cause death, 1.23 (95% CI, 1.18-1.28); anemia, 1.34 (95% CI, 1.24-1.45); hypercalcemia, 1.23 (95% CI, 1.09-1.38); skeletal-related events, 0.85 (95% CI, 0.90-0.91); and TTNT, from 1.03 (95% CI, 0.96-1.10) at third-line therapy to 1.15 (95% CI, 1.04-1.27) at fourth-line therapy. CONCLUSION: Data from the study suggest that CKD-associated clinical burden is substantial in elderly patients with MM.

Valerian and valeric acid inhibit growth of breast cancer cells possibly by mediating epigenetic modifications.

Valerian root (Valeriana officinalis) is a popular and widely available herbal supplement used to treat sleeping disorders and insomnia. The herb's ability to ameliorate sleep dysfunction may signify an unexplored anti-tumorigenic effect due to the connection between circadian factors and tumorigenesis. Of particular interest are the structural similarities shared between valeric acid, valerian's active chemical ingredient, and certain histone deacteylase (HDAC) inhibitors, which imply that valerian may play a role in epigenetic gene regulation. In this study, we tested the hypothesis that the circadian-related herb valerian can inhibit breast cancer cell growth and explored epigenetic changes associated with valeric acid treatment. Our results showed that aqueous valerian extract reduced growth of breast cancer cells. In addition, treatment of valeric acid was associated with decreased breast cancer cell proliferation, migration, colony formation and 3D formation in vitro in a dose- and time-dependent manner, as well as reduced HDAC activity and a global DNA hypomethylation. Overall, these findings demonstrate that valeric acid can decrease the breast cancer cell proliferation possibly by mediating epigenetic modifications such as the inhibition of histone deacetylases and alterations of DNA methylation. This study highlights a potential utility of valeric acid as a novel HDAC inhibitor and a therapeutic agent in the treatment of breast cancer.

Discharge status and post-discharge healthcare costs after skeletal-related event hospitalizations among medicare patients with bone metastatic solid tumors or multiple myeloma.

BACKGROUND: Previous studies have quantified direct inpatient costs of skeletal-related events (SREs); however, costs associated with subsequent post-SRE care have not been examined. METHODS: We identified two study cohorts using 2011-2015 Medicare 20% sample data: patients diagnosed with 1) bone metastases from solid tumors or 2) multiple myeloma (MM), both with SRE-related hospitalization discharge dates January 1, 2011-September 30, 2015. We assessed discharge status and costs from discharge to the earliest of death, end of Medicare enrollment, or December 31, 2015. Discharge status was defined as: skilled nursing facility (SNF), rehabilitation facility, hospice, home health agency (HHA), long-term care (LTC) nursing home, LTC hospital, or rehospitalization within or after 30 days. Percentage, stay duration, and Medicare costs were calculated for each setting. All analyses were descriptive. RESULTS: We identified 7988 bone metastases patients and 4277 MM patients discharged from index SRE-related hospitalizations; corresponding mean ages were 76.9 and 76.6 years. The largest proportion of bone metastases patients were discharged to SNF (32.9%), then HHA (13.7%), hospice (13.5%), and LTC (11.3%); the pattern was similar for MM patients (SNF, 35.9%; HHA, 18.2%; hospice, 7.2%; LTC, 1.5%). Almost 10% of patients in both cohorts were re-hospitalized within 30 days. Mean Medicare cost per patient per facility stay was < $10,000 for hospice, and from $15,517 for LTC nursing home to $49,729 for LTC hospital for MM patients. CONCLUSION: Most elderly cancer patients (>75%) require healthcare facility support after SRE-related hospitalization, with substantial associated costs. Post-discharge management is clinically and economically important.

Surface smoothness effect for the direct growth of carbon nanotubes on bulk FeCrAl metal substrates.

We investigate effects of surface smoothness and surface chemistry on the nature of multi-walled CNTs (MWCNTs) grown directly on FeCrAl substrates. A single sample was grown that contained a gradation in surface morphologies ranging from 2.9 nm to 30.2 nm RMS. The MWCNTs were grown using ethylene and H2 gases. Characterization was done using atomic force microscopy (AFM), scanning electron microscopy (SEM), and Auger elemental surface analysis. In smooth regions, MWCNTs demonstrated high-density vertical aligned growths; however, patches of approximately 10-20 microm where poor MWCNT growth occurred. In contrast, rough regions of the surface exhibited a continuous blanket layer of MWCNTs, albeit growth was spaghetti-like throughout this layer. The variation in nature of MWCNT growths was directly dependent on the surface roughness, which can affect surface growth chemistry of MWCNTs. Auger elemental analysis determined carbon was observed everywhere on the surface, but carbon was strongest over the smooth regions of high density growth; while relatively less carbon was detected over the patches with poor MWCNT growth, as well as over the blanket layer of the rough region. Oxygen was also measured, which was detected both within the patches of poor MWCNT growth in the smooth regions and over the blanket layer of the rough region. However, measurements of Cr and Al were exhibiting mixed trends: Cr was detected more strongly than Al over the rough region; whereas the opposite was observed in the patches of poor MWCNT growth in the smooth region. The surface smoothness affects the surface chemistry involving the nature of MWCNT growth and may also affect the surface chemistry involving the metal substrate itself; therefore, comparisons on the nature of MWCNT growths must also take careful consideration of the surface smoothness.