Citations

Abstract Individuals from pancreatic cancer families are at increased risk, not only of pancreatic cancer, but also of melanoma, breast, ovarian, and colon cancers. While some of the increased risk may be due to mutations in high-penetrance genes (i.e., BRCA2, PALB2, ATM, p16/CDKN2A or DNA mismatch repair genes), common genetic variants may also be involved. In a high-risk population of cases with either a family history of pancreatic cancer or early-onset pancreatic cancer (diagnosis before the age of 50 years), we examined the role of genetic variants previously associated with risk of pancreatic, breast, ovarian, or prostate cancer. We genotyped 985 cases (79 early-onset cases, 906 cases with a family history of pancreatic cancer) and 877 controls for 215,389 SNPs using the iSelect Collaborative Oncological Gene-Environment Study (iCOGS) array with custom content. Logistic regression was performed using a log-linear additive model. We replicated several previously reported pancreatic cancer susceptibility loci, including recently identified variants on 2p13.3 and 7p13 (2p13.3, rs1486134: OR = 1.36; 95% CI, 1.13–1.63; P = 9.29 × 10−4; 7p13, rs17688601: OR = 0.76; 95% CI, 0.63–0.93; P = 6.59 × 10−3). For the replicated loci, the magnitude of association observed in these high-risk patients was similar to that observed in studies of unselected patients. In addition to the established pancreatic cancer loci, we also found suggestive evidence of association (P < 5 × 10−5) to pancreatic cancer for SNPs at HDAC9 (7p21.1) and COL6A2 (21q22.3). Even in high-risk populations, common variants influence pancreatic cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 25(7); 1185–91. ©2016 AACR.

OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein–protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein–protein interactions.

AbstractObjectivesCoronary computerized tomography angiography (CCTA) is a rapidly emerging technology for the evaluation of chest pain in the emergency department (ED). We assessed trends in CCTA use and compared downstream healthcare utilization between CCTA and cardiac stress testing modalities.MethodsUsing administrative claims data (Optum Labs Data Warehouse) from over 100 million geographically diverse privately insured and Medicare Advantage enrollees across the United States, we identified 2,047,799 ED patients from January 2006 to December 2013 who presented with chest pain and had a CCTA or cardiac stress test within 72 hours. Cohorts were established based on CCTA or functional stress testing (myocardial perfusion scintigraphy [MPS], stress echocardiogram [SE], or treadmill exercise electrocardiogram [TMET]) performed within 72 hours of the ED visit. We tracked subsequent invasive cardiac procedures (invasive coronary angiography [ICA], percutaneous coronary intervention [PCI], and coronary artery bypass grafting [CABG]), repeat noninvasive testing, return ED visits, hospitalization, and the rate of acute myocardial infarction (AMI) within 30 days. We used propensity‐score matching to adjust for coronary artery disease (CAD) risk factors, Charlson‐Deyo comorbidity index, and baseline differences between patients selected for CCTA or cardiac stress testing. Logistic regression was used to measure adjusted associations between testing modality and outcomes.ResultsDuring the study period, CCTA use increased from 0.8% to 4.5% of all cardiac testing within 72 hours, a change of 434% (p‐value for trend < 0.001), while rates of other cardiac stress testing modalities decreased (–22% for TMET [p < 0.001]; –11% for SE [p = 0.11]; –6% for MPS [p = 0.04]. After matching, there was no difference in the 30‐day rate of AMI between testing modalities. Compared to MPS, CCTA was associated with higher rates of PCI (odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.04 to 1.51), and CABG (OR = 1.47; 95% CI = 1.03 to 2.13). Compared to SE and treadmill stress testing, CCTA was associated with more invasive procedures, hospitalizations, return ED visits, and repeat noninvasive testing.ConclusionsCCTA use increased fourfold during the study period and was associated with higher rates of PCI, CABG, repeat noninvasive testing, hospitalization, and return ED visits.The authors have no relevant financial information or potential conflicts to disclose.

Objective The main objective of this pilot study was to investigate the safety of administering onabotulinumtoxinA towards the sphenopalatine ganglion in 10 patients with intractable chronic migraine with an open, uncontrolled design. We also collected efficacy data to provide an indication as to whether future placebo-controlled studies should be performed. Method In a prospective, open-label, uncontrolled study after one-month baseline, we performed bilateral injections of 25 IU onabotulinumtoxinA (total dose 50 IU) toward the sphenopalatine ganglion in a single outpatient session in 10 patients with intractable migraine with a follow-up of 12 weeks. The primary outcome was adverse events and the main efficacy outcome was frequency of moderate and severe headache days in month 2 post-treatment compared to baseline. Results All 10 patients experienced a total of 25 adverse events. The majority of these were different types of local discomfort in the face and jaw, and none were classified as serious. In an intention-to-treat analysis of the main efficacy outcome, a statistically significant reduction of moderate and severe headache days in baseline versus month 2 was observed (16.3 ± 6.2 days baseline versus 7.6 ± 7.6 days month 2, p = 0.009). Eight out of 10 patients experienced an at least 50% reduction of moderate and severe headache days compared to baseline. Conclusion The result warrants randomised, placebo-controlled studies to establish both safety and efficacy of this potential novel treatment of chronic migraine.

Abstract Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.

ObjectiveTo describe the clinical presentation and management of patients with cholesterol granulomas (CGs) that develop following temporal bone surgery.Study DesignCase series with chart review.SettingTwo independent tertiary academic referral centers.Subjects and MethodsA multicenter retrospective review was performed to identify all patients between 2001 and 2014 who were diagnosed with a CG that developed following temporal bone surgery. Patients with a history of idiopathic petrous apex CGs were excluded, as were those with <6 months of follow‐up after diagnosis. Demographic and clinical data were recorded at presentation, and the main outcome measure was symptom evolution over time.ResultsA total of 20 patients met inclusion criteria (median age, 55.0 years; 70.0% female), and their cases were analyzed. Diagnosis was made, on average, 149.5 months (median, 94.5; range, 13.0‐480.0) following a temporal bone operation, which was for chronic ear disease in 75.0% of cases. The most common presenting symptoms were otalgia (55.0%) and otorrhea (40.0%). In patients initially managed with observation, 71.4% required no surgical intervention through a mean of 56.8 months (median, 30; range, 12.0‐178.0) of follow‐up. For those who initially underwent surgical excision, durable symptom relief was achieved in 66.7% of cases.ConclusionPostoperative CG formation in the temporal bone is a rare occurrence that can be encountered years following surgery. The present study suggests that conservative management can be appropriate for many cases in which patients are relatively asymptomatic.

ObjectivesTo analyze factors that influence hearing preservation over time in cochlear implant recipients with conventional‐length electrode arrays located entirely within the scala tympani.Study DesignCase series with planned chart review.SettingSingle tertiary academic referral center.Subjects and MethodsA retrospective review was performed to analyze a subgroup of cochlear implant recipients with residual acoustic hearing. Patients were included in the study only if their electrode arrays remained fully in the scala tympani after insertion and serviceable acoustic hearing (≤80 dB at 250 Hz) was preserved. Electrode array location was verified through a validated radiographic assessment tool. Patients with <6 months of audiologic follow‐up were excluded. The main outcome measure was change in acoustic hearing thresholds from implant activation to the last available follow‐up.ResultsA total of 16 cases met inclusion criteria (median age, 70.6 years; range, 29.4‐82.2; 50% female). The average follow‐up was 18.0 months (median, 16.1; range, 6.2‐36.4). Patients with a lateral wall electrode array were more likely to have stable acoustic thresholds over time (P <. 05). Positive correlations were seen between continued hearing loss following activation and larger initial postoperative acoustic threshold shifts, though statistical significance was not achieved. Age, sex, and noise exposure had no significant influence on continued hearing preservation over time.ConclusionsTo control for hearing loss associated with interscalar excursion during cochlear implantation, the present study evaluated patients only with conventional electrode arrays located entirely within the scala tympani. In this group, the style of electrode array may influence residual hearing preservation over time.

Context: Differences among patient populations that present to consultative palliative care are not known. Such an appreciation would inform health-care delivery tailored to unique populations. Objectives: We aimed to compare characteristics and palliative care needs of African Americans (AAs) and whites during initial palliative care consultation. Methods: We analyzed patient-reported, clinician-entered clinical encounter data from a large, multisite community-based, nonhospice palliative care collaborative. We included first specialty palliative care consultations from January 1, 2014, to July 2, 2015, across 15 sites within the Global Palliative Care Quality Alliance registry. Demographics, disease, performance status, advance care planning, and symptom prevalence/severity were compared. Results: Of 775 patients, 12.9% (N = 100) were AA. African Americans were younger (63 vs 75.4 years, P < .0001). A larger proportion of AAs had a diagnosis of cancer (45.0% vs 36.3%, P = .09) and in the hospital (71% vs 61.8%, P = .07). African Americans were more likely to have a Palliative Performance Score of 0 to 30 (35.6% vs 23.7%, P = .049). Around 50% in both racial groups were full code; slightly more than 40% had an advance directive. Nearly two-thirds in both racial groups reported 3 or more symptoms of any severity; one-third reported 3 or more moderate or severe symptoms. A larger proportion of Africans than whites reported pain of any severity (66.0% vs 56.1%, P = .06). Conclusion: All patients present to palliative care consultations with significant symptom and advance care planning needs. Further research is needed to identify how to deliver palliative care: earlier, in noncancer conditions, and improve pain management in AA populations.