Citations

Abstract Introduction: Epidemiologic data support an inverse association between statin use and risk of lethal prostate cancer, but contributing mechanisms have not been elucidated. Herein, using data from the Health Professionals Follow-up Study (HPFS), we updated our previous analysis of statins and lethal prostate cancer with a decade of additional follow-up, and incorporated immunohistochemistry (IHC)-based biomarkers and gene expression profiling to identify putative molecular mechanisms contributing to the association. Methods: We included data from 44,076 HPFS participants who were cancer free in 1990, with follow-up through 2012. Participants reported prediagnostic statin use on biennial questionnaires. Statin use was categorized as current vs. never/past use, with current users further categorized as long-term vs. short-term users (≥6 vs. <6 years). To classify prostate cancer molecular subtypes, genetically validated IHC assays for TMPRSS2:ERG fusion and PTEN loss were conducted on tissue microarrays for 891 and 660 cases, respectively. Whole-genome mRNA profiling of tumor and adjacent normal tissue was completed for 237 and 114 cases, respectively, using Affymetrix GeneChip Human Gene 1.0 ST arrays. We used Cox proportional hazards analysis to generate hazard ratios (HR) and 95% confidence intervals (CI) for associations between statin use and risk of overall, advanced (stage T3b or higher at diagnosis, metastatic or fatal), and lethal (metastatic or fatal) prostate cancer, as well as molecular subtypes, adjusted for PSA testing behavior and potential confounders including obesity and smoking. Moreover, we explored gene expression pathways in tumor and adjacent normal prostate tissue of statin users vs. nonusers using gene set enrichment analysis (GSEA). Results: During 22 years of follow-up, 6,144 men were diagnosed with prostate cancer; 1,051 (17%) had advanced disease and 827 (13%) developed lethal prostate cancer. Of cases with molecular subtype available, 48% were ERG-positive and 14% PTEN-null. In multivariable analysis, relative to never/past use, current statin use was inversely associated with risk of advanced (HR 0.84; 95% CI 0.68-1.04) and lethal (HR 0.78; 95% CI 0.68-1.01) prostate cancer. These associations were more pronounced in long-term users, where ≥6 years of prediagnosis statin use was significantly associated with a lower risk of advanced (HR 0.72; 95% CI 0.53-0.97) and lethal prostate cancer (HR 0.64; 95% CI 0.45-0.92), relative to nonuse. Long-term statin use was not associated with overall prostate cancer risk, whether ERG-positive (HR 0.89; 95% CI 0.59-1.35) or ERG-negative (HR 1.06; 95% CI 0.74-1.50). However, relative to nonuse, a longer duration of prediagnosis statin use was associated with reduced risk of PTEN-null cancers (HR 0.42; 95% CI 0.20-0.90), but not PTEN-intact disease (HR 1.18; 95% CI 0.95-1.46; p-heterogeneity=0.01). In GSEA, we identified T cell, B cell, and phosphatidylinositol (PI3K) signaling among the top pathways enriched in tumor-adjacent normal prostate tissue of current statin users, relative to never users. Intriguingly, no gene sets were differentially expressed by statin use in the tumor. Discussion: Our updated findings from the HPFS are consistent with our prior findings and other epidemiologic data supporting a role for statins in lethal prostate cancer prevention. Molecular classification of tumors identified PTEN/PI3K signaling and inflammation/immune activation as two potential mechanisms contributing to this association. Elucidating molecular mechanisms mediating the association between statin use and lower risk of lethal prostate cancer will provide support for a causal effect of statins on lethal prostate cancer risk and could inform statin clinical trials with appropriate intermediate endpoints. Citation Format: Emma H. Allott, Ericka M. Ebot, Amparo G. Gonzalez-Feliciano, Sarah C. Markt, Kathryn M. Wilson, Thomas U. Ahearn, Travis A. Gerke, Mary K. Downer, Konrad H. Stopsack, Jennifer R. Rider, Stephen J. Freedland, Elizabeth A. Platz, Meir J. Stampfer, Edward L. Giovannucci, Christopher J. Sweeney, Stephen P. Finn, Lorelei A. Mucci. Molecular tumor profiling to identify mechanisms linking statin use with lower risk of lethal prostate cancer: Results from the Health Professionals Follow-up Study [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A015.

ABSTRACTThe MLLT10 (formerly AF10) gene is the fourth most common KMT2A fusion partner across all acute leukemias and requires at least 3 breaks to form an in‐frame KMT2A/MLLT10 fusion due to the opposite orientation of each gene. A 10‐year retrospective review was performed to identify individuals from all age groups that harbor KMT2A/MLLT10 fusion obtained by our KMT2A/MLLT10 dual‐color dual‐fusion fluorescence in situ hybridization (D‐FISH) assay. Of the 60 unique individuals identified, 31 were male and 29 were female (M:F ratio, 1.1:1) with ages ranging from 3 days to 86 years (mean 21.5 years, median 5.5 years). The diagnoses included acute myeloid leukemia (AML) (49 patients, 82%), B‐ or T‐lymphoblastic leukemia/lymphoma (7 patients, 12%), myeloid sarcoma (3 patients, 5%), and a single case (2%) of undifferentiated leukemia. Twenty‐seven of 49 patients (55%) with AML were in the infant or pediatric age group. Fifty‐three of 60 patients (88%) had KMT2A/MLLT10 D‐FISH signal patterns mostly consisting of single fusions. In addition, 10 (26%) of 38 patients with conventional chromosome studies had “normal” (5 patients) or abnormal (5 patients) chromosome studies that lacked structural or numeric abnormalities involving chromosomes 10 or 11, implying cryptic cytogenetic mechanisms for KMT2A/MLLT10 fusion. Lastly, mate‐pair sequencing was performed on 4 AML cases, 2 of which had “normal” chromosome studies and cryptic KMT2A/MLLT10 fusion as detected by KMT2A/MLLT10 D‐FISH studies, and verified the multiple breaks required to generate KMT2A/MLLT10 fusion.

Background The authors conducted a cluster randomized study to determine the effect of an exportable educational intervention for young women with breast cancer (YWI) on improving care. Methods Sites were randomized 1:1 to the YWI or a contact time control physical activity intervention (PAI) stratified by academic or community site. Up to 15 women aged ≤45 years with newly diagnosed breast cancer were enrolled at each of 14 academic sites and 10 were enrolled at each of 40 community sites. The primary endpoint, attention to fertility, was ascertained by medical record review. Statistical inferences concerning the effect of the intervention used general estimating equations for clustered data. Results A total of 467 patients across 54 sites were enrolled between July 2012 and December 2013. The median age of the patients at the time of diagnosis was 40 years (range, 22‐45 years). Attention to fertility by 3 months was observed in 55% of patients in the YWI and 58% of patients in the PAI ( P = .88). Rates were found to be strongly correlated with age ( P < .0001), and were highest in patients aged <30 years. Attention to genetics was similar (80% in the YWI and 81% in the PAI), whereas attention to emotional health was higher in patients in the YWI (87% vs 76%; estimated odds ratio, 2.63 [95% confidence interval, 1.20‐5.76; P = .016]). Patients rated both interventions as valuable in providing education (64% in the YWI and 63% in the PAI). Conclusions The current study failed to demonstrate differences in attention to fertility with an intervention to improve care for women with breast cancer, although attention to fertility was found to be higher than expected in both groups and emotional health was improved in the YWI group. Greater attention to young women with breast cancer in general may promote more comprehensive care for this population.

651 Background: Oxaliplatin (OX), used primarily in gastrointestinal cancers, is considered moderately emetogenic while multiple guidelines classify carboplatin and cisplatin as highly emetogenic chemotherapy (HEC). The new oncology outcome measure (OP-35) from the US Centers for Medicare and Medicaid Services (CMS) deems 30-day post-chemotherapy inpatient (IP) and emergency room (ED) events “potentially avoidable” if involving nausea or emesis (NV) or any of eight other toxicities. We lack data comparing avoidable IP/ED and NV events for OX relative to platinums classified as HEC. Methods: We assessed OX, cisplatin, and carboplatin courses of therapy from 4Q 2012 to 1Q 2018 using the IBM Watson Explorys database. We identified IP/ED and OP-35 toxicities (anemia, dehydration, diarrhea, fever, NV, neutropenia, pain, pneumonia, or sepsis) by diagnosis and procedure codes, and stratified results by sex and age < 70 (median age at diagnosis for colorectal cancer). An IP/ED event could involve ≥ 1 OP-35 toxicity. We also evaluated a FOLFIRINOX subgroup (receiving irinotecan ≤ 3 days after OX). Results: In sum, we identified 4,231 OX courses (382 FOLFIRINOX) (Table). OP-35 toxicities occurred in 75% of IP/ED events; of these, 34% OX and 42% FOLFIRINOX involved NV. Rates of IP/ED, IP/ED OP-35-defined toxicity, and NV after OX were consistent with cisplatin and carboplatin. Among patients receiving OX, women age < 70 (n = 1388) had higher NV rates vs. others (p < 0.001). Conclusions: Roughly one-third of patients receiving OX experienced IP/ED events ≤ 30 days post chemotherapy. Most involved ≥ 1 of 10 OP-35 toxicities, meeting CMS’ criteria as potentially avoidable acute care. OX IP/ED rates and NV rates were similar to other platinums and were worse among women age < 70, suggesting more aggressive antiemetic prophylaxis should be evaluated. [Table: see text]

Level of Evidence : 5 Technical Efficacy : Stage 5 J. Magn. Reson. Imaging 2019.

We present the use of transtracheal jet ventilation in two uncooperative patients with a difficult airway. Although transtracheal jet ventilation is considered as a last resort option in the difficult airway algorithm, its use can be a valuable tool in selected difficult airway situations. Transtracheal jet ventilation can effectively maintain arterial oxygenation and provide extra time for attempts to intubate the trachea, either directly or fibreoptically.

BackgroundOlfactory nerve fibers are at risk of injury during transnasal endoscopic skull‐base approaches. Olfactory outcomes for various techniques have not been thoroughly investigated. This study aims to report long‐term olfactory outcomes when a cold knife upper septal limb incision technique is used compared to monopolar cautery.MethodsA prospective cohort study was performed at a tertiary referral center. Adult patients undergoing endoscopic approaches with septal incisions were randomized to cold knife or monopolar cautery groups. Patient demographics, clinical history, surgical data, and outcomes were collected. Preoperative, 3‐month, and 12‐month postoperative scores on the University of Pennsylvania Smell Inventory Test (UPSIT) and 22‐item Sino‐Nasal Outcome Test (SNOT‐22) were measured. Fisher's exact tests were performed for categorical variables and t tests were performed for continuous variables.ResultsTwenty‐two (22) patients (10 cold knife, 12 cautery) were enrolled between March 2016 and August 2017. The average age ± standard deviation was 50.2 ± 14.0 years (p = 0.59), 54% (p = 0.69) were female, and the primary pathology was pituitary adenoma (73%, p = 1.00). Preoperative, 3‐month, and 12‐month postoperative UPSIT scores were similar between the cold knife and cautery groups (32.8 vs 32.4, p = 0.80; 33.1 vs 33.0, p = 0.96; 33.6 vs 33.3, p = 0.84). On the “sense of smell/taste” question of the SNOT‐22, there was also no difference at all time points (p > 0.22).ConclusionThere was no significant change in patient UPSIT scores 1 year after transnasal skull‐base approaches, and no short‐term or long‐term differences between cold knife and cautery upper septal limb incision techniques. Our study supports an individualized approach based on surgeon preference.

Use of gadoxetate disodium, a hepatobiliary gadolinium‐based agent, in patients with chronic parenchymal liver disease offers the advantage of improved sensitivity for detecting hepatocellular carcinoma (HCC). Imaging features of liver observations on gadoxetate‐enhanced MRI may also serve as biomarkers of recurrence‐free and overall survival following definitive treatment of HCC. A number of technical and interpretative pitfalls specific to gadoxetate exist, however, and needs to be recognized when protocoling and interpreting MRI exams with this agent. This article reviews the advantages and pitfalls of gadoxetate use in patients at risk for HCC, and the potential impact on Liver Imaging Reporting and Data System (LI‐RADS) imaging feature assessment and categorization.Level of Evidence: 5Technical Efficacy Stage: 2J. Magn. Reson. Imaging 2019;49:1236–1252.