Citations

Abstract Background: Acquired PARP inhibitor (PARPi) resistance in high-grade serous ovarian cancer (HGSOC) as a result of restored homologous recombination has been observed following secondary mutations that restore full-length protein in BRCA1, BRCA2, RAD51C, and RAD51D. Additionally, loss of BRCA1 methylation has also been shown to confer resistance. However, little is known about the role of RAD51C methylation in acquired PARPi resistance. In ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib in ovarian carcinoma, four (2%) tumors demonstrated RAD51C methylation. The present study utilizes HGSOC patient derived xenografts (PDXs) and recurrent samples from ARIEL2 to assess the role of RAD51C methylation in the development of PARPi resistance. Methods: To drive PARPi resistance, PDX039, an extremely PARPi-sensitive model lacking demonstrable mutations in DNA repair genes, was treated cyclically with niraparib (100 mg/kg) for 21 days, after which the tumor was allowed to regrow and re-established in new mice for the next treatment round. To evaluate the frequency of methylation change, RAD51C methylation was analyzed in 12 rucaparib-treated mice (300 or 450 mg/kg) harboring PDX183, a PARPi-sensitive model without mutations in DNA repair genes. Global changes in gene expression following development of PARPi resistance were assessed by RNA sequencing. RAD51C promoter methylation was evaluated by bisulfite sequencing. Subsequent functional analysis included qRT-PCR, IHC, and western blot. DNA damage response pathways are being evaluated by immunofluorescence ex vivo following niraparib, rucaparib, or IR. Results: PDX039 grew through PARPi treatment by the third and fourth cycle of therapy. RAD51C was the only DNA repair gene to show significant change in RNAseq analysis (log2 fold-change=8.43; p=2e-192), corresponding with a loss of RAD51C methylation. Moreover, after just one round of PARPi treatment, RAD51C methylation was lost in 1 of 12 PARPi-treated PDX183 xenografts. RAD51C methylation loss ultimately resulted in restoration of expression, for which functional analysis is ongoing. Analysis of patient samples is currently underway. Conclusions: In HGSOC PDX models, RAD51C methylation affords PARPi sensitivity in the absence of DNA repair gene mutations. Treatment pressure with PARPi can reverse RAD51C methylation and restore RAD51C expression. Isolated changes in methylation of the RAD51C locus are sufficient to restore HR and convey PARPi resistance. Citation Format: Rachel M. Hurley, Ksenija Nesic, Cordelia McGehee, Olga Kondrashova, Maria I. Harrell, Paula A. Schneider, Xiaonan Hou, Cristina Correia, Karen S. Flatten, Giada V. Zapparoli, Alexander Dobrovic, Kevin K. Lin, Thomas C. Harding, Andrea E. Wahner Hendrickson, Elizabeth M. Swisher, Matthew Wakefield, S. John Weroha, Clare L. Scott, Scott H. Kaufmann. Loss of RAD51C promoter hypermethylation confers PARP inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5885.

Abstract Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.

Objectives To define the elementary ultrasound (US) lesions in giant cell arteritis (GCA) and to evaluate the reliability of the assessment of US lesions according to these definitions in a web-based reliability exercise. Methods Potential definitions of normal and abnormal US findings of temporal and extracranial large arteries were retrieved by a systematic literature review. As a subsequent step, a structured Delphi exercise was conducted involving an expert panel of the Outcome Measures in Rheumatology (OMERACT) US Large Vessel Vasculitis Group to agree definitions of normal US appearance and key elementary US lesions of vasculitis of temporal and extracranial large arteries. The reliability of these definitions on normal and abnormal blood vessels was tested on 150 still images and videos in a web-based reliability exercise. Results Twenty-four experts participated in both Delphi rounds. From originally 25 statements, nine definitions were obtained for normal appearance, vasculitis and arteriosclerosis of cranial and extracranial vessels. The ‘halo’ and ‘compression’ signs were the key US lesions in GCA. The reliability of the definitions for normal temporal and axillary arteries, the ‘halo’ sign and the ‘compression’ sign was excellent with inter-rater agreements of 91–99% and mean kappa values of 0.83–0.98 for both inter-rater and intra-rater reliabilities of all 25 experts. Conclusions The ‘halo’ and the ‘compression’ signs are regarded as the most important US abnormalities for GCA. The inter-rater and intra-rater agreement of the new OMERACT definitions for US lesions in GCA was excellent.

Key PointsA new molecular assay identifies conventional and leukemic nonnodal MCL with differing clinicobiological features. The integration of the novel assay with genetic alterations identifies subsets of MCL patients with different management and outcome.

Background: Catamenial epilepsy refers to cyclic seizure exacerbation in relation to the menstrual cycle. Three distinct patterns have been described: C1-perimenstrual, C2-periovulatory, and C3-inadequate luteal. There is experimental and clinical evidence that gonadal steroid hormones affect neuronal excitability with estrogens being mainly proconvulsant and progesterone anticonvulsant. If reproductive steroids have a role in seizure occurrence, they may also have a role in treatment. Objective: The objective of this study was to critically assess current evidence regarding the efficacy of progesterone as adjunctive therapy in women with intractable catamenial epilepsy. Methods: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, medical librarian, and content experts in the fields of epilepsy and gynecology. Results: A randomized, placebo-controlled clinical trial was selected for critical appraisal. This trial compared the efficacy of adjunctive cyclic natural progesterone therapy versus placebo for seizures in women with intractable partial epilepsy, stratified by catamenial and noncatamenial status. There was no significant difference in proportions of responders between progesterone and placebo in the catamenial and noncatamenial strata. Prespecified secondary analysis showed that the level of perimenstrual seizure exacerbation is a significant predictor of the responder rate for progesterone therapy. Conclusions: Cyclic natural progesterone is not superior to placebo in reducing seizure frequency in women with intractable partial epilepsy. Posthoc findings suggest that progesterone may benefit a subset of women with perimenstrually exacerbated seizures.

Abstract Diastolic dysfunction causes close to half of congestive heart failures and is associated with increased stiffness in left-ventricular myocardium. A clinical tool capable of measuring viscoelasticity of the myocardium could be beneficial in clinical settings. We used Lamb wave Dispersion Ultrasound Vibrometry (LDUV) for assessing the feasibility of making in vivo non-invasive measurements of myocardial elasticity and viscosity in pigs. In vivo open-chest measurements of myocardial elasticity and viscosity obtained using a Fourier space based analysis of Lamb wave dispersion are reported. The approach was used to perform ECG-gated transthoracic in vivo measurements of group velocity, elasticity and viscosity throughout a single heart cycle. Group velocity, elasticity and viscosity in the frequency range 50–500 Hz increased from diastole to systole, consistent with contraction and relaxation of the myocardium. Systolic group velocity, elasticity and viscosity were 5.0 m s −1 , 19.1 kPa, 6.8 Pa · s, respectively. In diastole, the measured group velocity, elasticity and viscosity were 1.5 m s −1 , 5.1 kPa and 3.2 Pa · s, respectively.

Background Studies have shown that chronic total occlusion ( CTO ) in a noninfarct‐related artery in patients with ST‐segment–elevation myocardial infarction is linked to increased mortality. It remains unclear whether staged revascularization of a noninfarct‐related artery CTO in patients with ST‐segment–elevation myocardial infarction translates to improved outcomes. We performed a meta‐analysis to compare outcomes between patients presenting with ST‐segment–elevation myocardial infarction with concurrent CTO who underwent percutaneous coronary intervention of noninfarct‐related artery CTO versus those who did not. Method and Results We conducted an electronic database search of all published data. The primary end point was major adverse cardiovascular events. Secondary end points were all‐cause mortality, cardiovascular mortality, myocardial infarction, repeat revascularization with either percutaneous coronary intervention or coronary artery bypass grafting, stroke, and heart failure readmission. Odds ratios ( ORs ) and 95% confidence intervals ( CIs ) were computed. Random effects model was used and heterogeneity was considered if I 2 >25. Six studies (n=1253 patients) were included in the analysis. There was a significant difference in major adverse cardiovascular events ( OR , 0.54; 95% CI , 0.32–0.91), cardiovascular mortality ( OR , 0.43; 95% CI , 0.20–0.95), and heart failure readmissions ( OR , 0.57; 95% CI , 0.36–0.89), favoring the patients in the CTO percutaneous coronary intervention group. No significant differences were observed between the 2 groups for all‐cause mortality ( OR , 0.47; 95% CI , 0.22–1.00), myocardial infarction ( OR , 0.78; 95% CI , 0.41–1.46), repeat revascularization ( OR , 1.13; 95% CI , 0.56–2.27), and stroke ( OR , 0.51; 95% CI , 0.20–1.33). Conclusions In this meta‐analysis, CTO percutaneous coronary intervention of the noninfarct‐related artery in patients presenting with ST‐segment–elevation myocardial infarction was associated with a significant reduction in major adverse cardiovascular events, cardiovascular mortality, and heart failure readmissions.