Citations

Abstract Background: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits. Methods: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. Results: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. Conclusions: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures. Impact: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126–35. ©2016 AACR.

De novo progressive aortic insufficiency (AI) is a side effect frequently related to prolonged support with continuous-flow left ventricular assist devices (CF-LVAD). Its progression can result in recurrent clinical heart failure symptoms and significantly increased mortality. Recently, percutaneous intervention methods, such as transcatheter aortic valve replacement (TAVR) and percutaneous occluder devices, have emerged. However, given the very scarce global experience with these approaches, evidence in the literature is lacking. We sought to assess the outcomes of CF-LVAD patients who had undergone percutaneous intervention for AI. A systematic search of six databases from inception to April 2016 was performed by two independent reviewers. Eligible studies were those that included series or cases where patients had percutaneous transcatheter interventions for AI in CF-LVAD patients. Data were extracted and meta-analyzed from the identified studies. A total of 29 patients from 15 published studies and 3 unpublished records were included in the analysis. Mean patient age was 56.6 ± 13.7 years, and 72.4% were male. The etiology of heart failure resulting in LVAD placement was ischemic cardiomyopathy in 17.2%. The two intervention groups were TAVR (27.6%) and occluder devices (72.4%). A transfemoral approach (69%), apical approach (10%), brachial approach (7%), subclavian approach (3%), and mini-sternotomy (3%) were used. The preintervention AI grade was severe with a median grade of 4 (interquartile range, 4–4). Postoperatively, the AI grade improved significantly to a median grade of 0 (0–2). At long-term follow-up AI grade was still trivial with a median AI grade of 1 (0–1). Subgrouping the treatments into the occluder device and TAVR, it was found that both interventional techniques were similarly effective in reducing the AI grade from severe to trivial. In terms of complications, from the occluder group, two patients were complicated with device migration and another two with transient hemolysis. In the TAVR cohort, two patients experienced device migration and another had significant postimplant perivalvular leakage. Our results indicate that percutaneous interventions for AI in CF-LVAD patients with TAVR, and closure devices demonstrate similar efficacy in significantly reducing severe AI. Current results are encouraging, potentiating viability as a treatment option, particularly in nonsurgical candidates. Future research with larger patient cohorts and comparative controls is required to sufficiently evaluate the efficacy of this technique and promote its widespread acceptance as a mainstay treatment.

Abstract Purpose: The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone. Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML). Results: A total of 99 patients received veliparib 10–100 mg orally twice daily on days 1–8, 1–14, or 1–21 along with continuous infusion topotecan 1.0–1.2 mg/m2/d + carboplatin 120–150 mg/m2/d on days 3–7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m2/d + carboplatin 150 mg/m2/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage–induced FANCD2 monoubiquitination, had improved survival [HR = 0.56 (95% confidence interval, 0.27–0.92)]. A single 80-mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34+ leukemia cells, with greater phosphorylation in cells from responders. Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias. Clin Cancer Res; 23(4); 899–907. ©2016 AACR.

Abstract Purpose: In preclinical studies, the PARP inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arising from aggressive myeloid malignancies. Experimental Design: Patients received veliparib [20–200 mg once a day on day 1 and twice daily on days 4–12 in cycle 1 (days 1–8 in cycle ≥2)] and temozolomide [150–200 mg/m2 daily on days 3–9 in cycle 1 (days 1–5 in cycle ≥2)] every 28 to 56 days. Veliparib pharmacokinetics and pharmacodynamics [ability to inhibit poly(ADP-ribose) polymer (PAR) formation and induce H2AX phosphorylation] were assessed. Pretreatment levels of MGMT and PARP1 protein, methylation of the MGMT promoter, and integrity of the Fanconi anemia pathway were also examined. Results: Forty-eight patients were treated at seven dose levels. Dose-limiting toxicities were oral mucositis and esophagitis lasting >7 days. The MTD was veliparib 150 mg twice daily with temozolomide 200 mg/m2 daily. The complete response (CR) rate was 17% (8/48 patients). Veliparib exposure as well as inhibition of PAR polymer formation increased dose proportionately. A veliparib-induced increase in H2AX phosphorylation in CD34+ cells was observed in responders. Three of 4 patients with MGMT promoter methylation achieved CR. Conclusions: Veliparib plus temozolomide is well tolerated, with activity in advanced AML. Further evaluation of this regimen and of treatment-induced phosphorylation of H2AX and MGMT methylation as potential response predictors appears warranted. Clin Cancer Res; 23(3); 697–706. ©2016 AACR.

Introduction Under certain circumstances, e-consultations can substitute for a face-to-face consultation. A basic requirement for a successful e-consultation is that the e-consultant has access to important medical history and exam findings along with laboratory and imaging results. Knowing just what information the specialist needs to complete an e-consultation is a major challenge. This paper examines differences between specialties in their need for past information from laboratory, imaging and clinical notes. Methods This is a retrospective study of patients who had an internal e-consultation performed at an academic medical centre. We reviewed a random sample of e-consultations that occurred in the first half of 2013 for the indication for the e-consultation and whether the e-consultant reviewed data in the medical record that was older than one year to perform the e-consultation. Results Out of 3008 total e-consultations we reviewed 360 (12%) randomly selected e-consultations from 12 specialties. Questions on management (35.8%), image results (27.2%) and laboratory results (25%) were the three most common indications for e-consultation. E-consultants reviewed medical records in existence more than one year prior to the e-consultation 146 (40.6%) of the time with e-consultants in the specialties of endocrinology, haematology and rheumatology, reviewing records older than one year more than half the time. Labs (20.3%), office notes (20%) and imaging (17.8%) were the types of medical data older than one year that were reviewed the most frequently overall. Discussion Management questions appear to be the most common reason for e-consultation. E-consultants frequently reviewed historical medical data that is older than one year at the time of the e-consultation, especially in endocrinology, haematology and rheumatology specialties. Practices engaging in e-consultations that require transfer of data may want to include longer time frames of historical information for those specialties.

Abstract Purpose: DNA methylation is a heritable covalent modification that is developmentally regulated and is critical in tissue-type definition. Although genotype–phenotype correlations have been described for different subtypes of renal cell carcinoma (RCC), it is unknown if DNA methylation profiles correlate with morphological or ontology based phenotypes. Here, we test the hypothesis that DNA methylation signatures can discriminate between putative precursor cells in the nephron. Experimental Designs: We performed deep profiling of DNA methylation and transcriptome in diverse histopathological RCC subtypes and validated DNA methylation in an independent dataset as well as in The Cancer Genome Atlas Clear Cell and Chromophobe Renal Cell Carcinoma Datasets. Results: Our data provide the first mapping of methylome epi-signature and indicate that RCC subtypes can be grouped into two major epi-clusters: C1, which encompasses clear-cell RCC, papillary RCC, mucinous and spindle cell carcinomas and translocation RCC; C2, which comprises oncocytoma and chromophobe RCC. Interestingly, C1 epi-cluster displayed 3-fold more hypermethylation as compared with C2 epi-cluster. Of note, differentially methylated regions between C1 and C2 epi-clusters occur in gene bodies and intergenic regions, instead of gene promoters. Transcriptome analysis of C1 epi-cluster suggests a functional convergence on Polycomb targets, whereas C2 epi-cluster displays DNA methylation defects. Furthermore, we find that our epigenetic ontogeny signature is associated with worse outcomes of patients with clear-cell RCC. Conclusions: Our data define the epi-clusters that can discriminate between distinct RCC subtypes and for the first time define the epigenetic basis for proximal versus distal tubule derived kidney tumors. Clin Cancer Res; 22(24); 6236–46. ©2016 AACR.

Abstract Background: Activation of the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor receptor (MET) pathway promotes tumor growth, invasion and dissemination. Emibetuzumab is a humanized IgG4 monoclonal antibody that binds to and inhibits ligand-dependent and ligand-independent activation of MET. In the first-in-human dose escalation study NCT0128756, emibetuzumab demonstrated favorable tolerability when administered up to 2000mg Q2W IV in unselected patients. The study was expanded to evaluate emibetuzumab in expansion cohorts for patients with tumors positive for MET expression. Methods: Patients with locally advanced or metastatic castration-resistant prostate cancer (CRPC) with bone metastasis, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and hepatocellular carcinoma (HCC) received 2000 mg emibetuzumab Q2W IV on a 28-day cycle. RCC, NSCLC, and HCC patients were required to have measurable disease as defined by RECIST v1.1 and have MET positive tumors (≥50% of cells to be ≥2+ for MET expression) as determined by a MET IHC assay (Ventana). The objectives were to evaluate the safety and activity of emibetuzumab in patients with MET positive tumors. Additional objectives included pharmacokinetics (PK) and pharmacodynamics (PD). Results: A total of 62 patients received emibetuzumab across the 4 cohorts: CRPC n = 15, RCC n = 19, NSCLC n = 19,and HCC n = 9, with a median of prior systemic oncology therapies of 6, 3, 5, and 3, respectively. Common possibly related treatment-emergent adverse events included fatigue (29% all grades, 3% Gr3/4), nausea (13% all grades, no Gr3/4), edema of limbs (8% all grades, 2% Gr3/4), and anorexia (8%, no Gr3/4) and were similar among cohorts. No evidence of clinical activity was observed in CRPC patients. For RCC, NSCLC, and HCC patients with MET positive tumors, an overall disease control rate (DCR = partial response [PR] + stable disease [SD]) of 32% (15/47) was observed. In the individual cohorts, DCR was 26% (5/19) in RCC, 26% (5/19) in NSCLC, and 56% (5/9) in HCC. The median duration of disease stabilization in the 3 cohorts was: 4.2 months (range 1.6-24.6) in RCC, 3.9 months (range 2.5-6.4) in NSCLC, and 3.7 months (range 1.2-6.6) in HCC. One PR was observed in an HCC patient with MET amplification. After a single dose of 2000 mg emibetuzumab, PK parameters were similar among these cohorts and also comparable to patients treated at this dose during dose escalation. Conclusions: In cohorts enriched for tumor MET expression, limited single-agent activity of emibetuzumab was observed indicating that MET positivity by IHC (Ventana assay) at the cut-point employed here might not be a sufficient predictive biomarker to select patients receiving benefit from emibetuzumab monotherapy for the tumor types studied. Further evaluation of biomarkers/assays to identify patients who may benefit from treatment with emibetuzumab may be warranted. Citation Format: Michaela S. Banck, Rashmi Chugh, Ronald B. Natale, Alain Algazi, Bradley C. Carthon, Lee S. Rosen, Michael E. Menefee, Andrew Xiuxuan Zhu, Takami Sato, Brian Moser, P. Kellie Turner, Jay Tuttle, Xuejing Aimee Wang, Volker Wacheck, Frederick E. Millard. Phase 1 results of emibetuzumab (LY2875358), a bivalent MET antibody, in patients with advanced castration-resistant prostate cancer, and MET positive renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A55.

Background: The Apple (Cupertino, CA) HealthKit is a new telemonitoring platform that promises to make it easier for patients and healthcare institutions to collect, transmit, and store data from devices that monitor common conditions such as diabetes, hypertension, and asthma. To assess the potential use for this platform in primary care, we need to know how many Apple Healthkit users there are and if they have conditions that could benefit from telemonitoring. Materials and Methods: We examined patients in the Mayo Clinic primary care practice in Rochester, MN, who registered to connect to their Mayo Clinic medical record with Apple HealthKit. We used the primary care registry to identify users with chronic conditions of diabetes, hypertension, asthma, and depression. We also examined users for recent measurements of blood pressure, glucose, hemoglobin A1C, and cholesterol. Results: Of 98,151 patients there were 503 registrants of HealthKit. There were 95 (19%) who had hypertension, 37 (7.4%) who had diabetes, 125 (25%) who had depression, and 56 (11%) who had asthma. Overall, there were 245 (49%) who had readily telemonitorable conditions. Conclusions: Almost half of primary care Apple HealthKit registrants have conditions that could benefit from telemonitoring. This pre-installed telemonitoring platform, available on every new iPhone ® (Apple), can be used to monitor a significant number of primary care patients. However, it also has continued provider and informatics barriers that need to be addressed.