Citations

Abstract Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93–0.98; P = 5.2 × 10−4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92–0.97; P = 5.4 × 10−5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03–1.08; P = 3.3 × 10−5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01–1.07; P = 2.5 × 10−3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01–1.06; P = 1.2 × 10−2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

Abstract BACKGROUND Aneurysm recurrence after coiling has been associated with aneurysm growth, (re)hemorrhage, and a greater need for follow-up. The second-generation HydroCoil Embolic System (HES; MicroVention, Inc) consists of a platinum core with integrated hydrogel and was developed to reduce recurrence through enhancing packing density and healing within the aneurysm. OBJECTIVE To compare recurrence between the second-generation HES and bare platinum coil (BPC) in the new-generation Hydrogel Endovascular Aneurysm Treatment Trial (HEAT). METHODS HEAT is a randomized, controlled trial that enrolled subjects with ruptured or unruptured 3- to 14-mm intracranial aneurysms amenable to coiling. The primary endpoint was aneurysm recurrence using the Raymond-Roy scale. Secondary endpoints included minor and major recurrence, packing density, adverse events related to the procedure and/or device, mortality, initial complete occlusion, aneurysm retreatment, hemorrhage from target aneurysm during follow-up, aneurysm occlusion stability, and clinical outcome at final follow-up. RESULTS A total of 600 patients were randomized (HES, n = 297 and BPC, n = 303), including 28% with ruptured aneurysms. Recurrence occurred in 11 (4.4%) subjects in the HES arm and 44 (15.4%) subjects in the BPC arm ( P = .002). While the initial occlusion rate was higher with BPC, the packing density and both major and minor recurrence rates were in favor of HES. Secondary endpoints including adverse events, retreatment, hemorrhage, mortality, and clinical outcome did not differ between arms. CONCLUSION Coiling of small-to-medium aneurysms with second-generation HES resulted in less recurrence when compared to BPC, without increased harm. These data further support the use of the second-generation HES for the embolization of intracranial aneurysms. Video Abstract

Background: Balance assessment is used by clinicians as part of athlete concussion screening. The King-Devick (K-D) Balance app is designed to provide an objective balance assessment value. The purpose of this study was to investigate the responsiveness of a balance assessment using the K-D Balance app. Hypothesis: The K-D Balance app will demonstrate acceptable responsiveness for balance assessment. Study Design: Repeated-measures study. Level of Evidence: Level 5. Methods: A convenience sample of 25 participants between the ages of 20 and 25 years completed testing procedures. A battery of balance tests using the K-D Balance app on an iPhone were conducted 1 week apart. After a 5-minute warm-up, 3 stances were assessed: double leg, tandem right, and tandem left. The K-D Balance app guided the test positions and test times. A value representing movement was generated by the app algorithm. Analysis included descriptive statistics along with intraclass correlation coefficient and minimal detectable change (MDC). Results: The median score of the K-D test was 0.5 for session 1 and 0.4 for session 2. The ICC was 0.42 (95% CI, 0.04-0.70), and the MDC was 1.58. Conclusion: The MDC value of 1.58 represents the threshold of meaningful change in balance, as measured with the K-D Balance app. Clinical Relevance: Clinicians can use the results of this study to objectively assess changes in balance over time using the K-D Balance app.

PURPOSE Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes. METHODS Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach. RESULTS There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes. CONCLUSION Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Background and Purpose— The American Heart Association and the American Stroke Association guidelines for early management of patients with ischemic stroke offer guidance to physicians involved in acute stroke care and clarify endovascular treatment indications. The purpose of this study was to assess concordance of physicians’ endovascular treatment decision-making with current American Heart Association and the American Stroke Association stroke treatment guidelines using a survey-approach and to explore how decision-making in the absence of guideline recommendations is approached. Methods— In an international cross-sectional survey (UNMASK-EVT), physicians were randomly assigned 10 of 22 case scenarios (8 constructed with level 1A and 11 with level 2B evidence for endovascular treatment and 3 scenarios without guideline coverage) and asked to declare their treatment approach (1) under their current local resources and (2) assuming there were no external constraints. The proportion of physicians offering endovascular therapy (EVT) was calculated. Subgroup analysis was performed for different specialties, geographic regions, with regard to physicians’ age, endovascular, and general stroke treatment experience. Results— When facing level 1A evidence, participants decided in favor of EVT in 86.8% under current local resources and in 90.6% under assumed ideal conditions, that is, 9.4% decided against EVT even under assumed ideal conditions. In case scenarios with level 2B evidence, 66.3% decided to proceed with EVT under current local resources and 69.7% under assumed ideal conditions. Conclusions— There is potential for improving thinking around the decision to offer endovascular treatment, since physicians did not offer EVT even under assumed ideal conditions in 9.4% despite facing level 1A evidence. A majority of physicians would offer EVT even for level 2B evidence cases.

Study Design: Retrospective cohort study. Objective: To evaluate inpatient outcomes in dialysis dependent patients undergoing elective cervical spine surgery. Methods: A total of 1605 dialysis dependent patients undergoing elective primary or revision cervical spine surgery for degenerative conditions were identified from the National Inpatient sample from 2002 to 2012 and compared to 1 450 642 nondialysis-dependent patients undergoing the same procedures. The National Inpatient Sample is a de-identified database; thus, no institutional review board approval was needed. Results: Dialysis dependence was associated with higher inpatient mortality rates (7.5% vs 1.9%; P < .001) as well as both major (17.3% vs 0.6%; P < .001) and minor (36.8% vs 10.5%; P < .001) complication rates as compared with nondialysis-dependent patients. Dialysis-dependent patients had substantially increased mean lengths of stay (9.8 days compared with 2.0 days; P < .001) and total hospital charges ($141 790 compared with $46 562; P < .001). Conclusion: Dialysis-dependence is associated with drastically increased complication rates, risk of mortality, and represent a significant financial and psychosocial burden to patients undergoing elective cervical spine surgery. Both surgeons and patients should be aware of these risks while planning elective surgeries.

Multiple organizations around the world have issued evidence‐based exercise guidance for patients with cancer and cancer survivors. Recently, the American College of Sports Medicine has updated its exercise guidance for cancer prevention as well as for the prevention and treatment of a variety of cancer health‐related outcomes (eg, fatigue, anxiety, depression, function, and quality of life). Despite these guidelines, the majority of people living with and beyond cancer are not regularly physically active. Among the reasons for this is a lack of clarity on the part of those who work in oncology clinical settings of their role in assessing, advising, and referring patients to exercise. The authors propose using the American College of Sports Medicine's Exercise Is Medicine initiative to address this practice gap. The simple proposal is for clinicians to assess, advise, and refer patients to either home‐based or community‐based exercise or for further evaluation and intervention in outpatient rehabilitation. To do this will require care coordination with appropriate professionals as well as change in the behaviors of clinicians, patients, and those who deliver the rehabilitation and exercise programming. Behavior change is one of many challenges to enacting the proposed practice changes. Other implementation challenges include capacity for triage and referral, the need for a program registry, costs and compensation, and workforce development. In conclusion, there is a call to action for key stakeholders to create the infrastructure and cultural adaptations needed so that all people living with and beyond cancer can be as active as is possible for them.

Abstract The first two authors and last two authors contributed equally. Genome-wide association studies (GWAS) have identified risk loci for Acute Lymphoblastic Leukemia (ALL), Chronic Lymphoblastic Leukemia (CLL) and Non-Hodgkin Lymphoma, however an Acute Myeloid Leukemia (AML) GWAS has not been published to date. We performed a GWAS to identify AML and Myelodysplastic Syndrome (MDS) risk loci using a nested case-control study design in the DISCOVeRY-BMT cohorts which includes almost 2000 AML and MDS patients as cases and 2813 unrelated donors as controls. Genotyping was performed using the Illumina Human OmniExpress BeadChip and imputed using the Haplotype Reference Consortium, yielding > 8 million high-quality variants for statistical analysis. Logistic regression models with AML (de novo AML with normal cytogenetics, de novo AML with abnormal cytogenetics and therapy-related AML) and MDS cases and European American healthy donor controls adjusted for age and sex were used to test the association of each SNP with disease status. To identify the strongest association signal with disease we conducted a summary statistic SNP-based association analysis (ASSET) using non-overlapping AML and MDS cases implemented in R statistical software. ASSET uses an exhaustive search for SNPs with small but common pleiotropic effects across groups of traits while accounting for the multiple tests required by the subset search, as well as any shared controls between groups. This approach allowed us to further investigate the heterogeneity within AML subtypes and to gain increased power by pooling subtypes that show pleiotropic effects. ASSET genome wide (GW) significance is defined as P<5.0x10-8, however, we present results of each subset analysis. ASSET analyses identified an association of T allele at rs12203592, Interferon Regulatory Factor 4 (IRF4), with increased risk of de novo AML and MDS (Figure 1) (OR=1.37; 95% CI, 1.25-1.51, Pmeta=1.59x10-10). The variant has been reported significant in GWAS of skin pigmentation, hair color, non-melanoma skin cancer, squamous cell carcinoma, actinic keratosis, and childhood ALL; GW case-control studies of neuroblastoma and breast cancer show suggestive association signals (P<5 x 10-6). IRF4 belongs to the IRF family of transcription factors and is a key regulator of differentiation stages in hematopoiesis. The T allele at rs12203592 is associated with significantly increased expression of IRF4 in whole blood and lung tissue and in vitro mouse studies have shown the T allele to be associated with higher levels of IRF4 transcription. rs12203592 is <80bp from an IRF4 transcription start site and in an important position within NF-κB motifs in multiple blood and immune cell lines, supporting the hypothesis that this SNP modulates NF-κB repression of IRF4 expression. Another variant in the IRF4 regulatory region, rs62389423 (A allele), showed a putative association with subsets of de novo AML and MDS (OR=1.36; 95% CI,1.21-1.52, Pmeta=1.2x10-7). Although not in linkage disequilibrium with rs12203592, the A allele has also been previously associated with susceptibility to skin cancer and melanoma in multiple GWAS. Analysis of 596 UKbiobank CLL cases and >300,000 controls, shows the A allele correlates with a 50% increased risk of CLL (95% CI, 1.32-1.73, P= 2.4x10-9).Several other GWAS also show an association between additional IRF4 variants and CLL. Analyses in individual subtypes also revealed an intronic variant, rs10098598, in RAD21 to be associated with de novo AML (OR=2.18; 95% CI, 1.60-2.97; Pmeta=8.9x10-7). RAD21, on8q24, a region known to be associated with multiple cancer types, is involved in DNA double-stranded break repair and in chromatid cohesion in mitotic cells. Loss of function would theoretically lead to chromosomal instability and tumorigenesis. Components of the cohesion complex (including RAD21) are somatically mutated in ~12% of de novo AML and MDS patients, where it is frequently an early event. We provide the first GW evidence of association between a common variant and AML susceptibility. This SNP has been shown to be associated with multiple phenotypes, suggesting that there are pleiotropic effects at work. Our RAD21 finding is consistent with the role of cohesion in leukemogenesis and provides some evidence of its role in de novo AML susceptibility. Replication and further subset analyses with genome-wide data in >2000 AML cases are ongoing. Disclosures Griffiths: Alexion Inc.: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Celgene, Inc: Honoraria, Research Funding; Novartis, Inc.: Research Funding; Pfizer, Inc.: Research Funding. McCarthy:Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Abstract Introduction: Rearrangements of the MLL (mixed lineage leukemia) gene on chromosome 11q23 are present in 5-10% of either acute myeloid (AML) or acute lymphoblastic leukemia (ALL), and are associated with a poor prognosis. Fusion proteins involving the MLL histone methyltransferase (HMT) result in recruitment of another HMT, DOT1L, to a multi-protein complex leading to aberrant methylation of Histone H3 lysine 79 (H3K79) at MLL target genes and enhanced expression of leukemogenic genes such as HOXA9 and MEIS1. EPZ-5676 is a small molecule inhibitor of DOT1L with sub-nanomolar affinity and >37,000 fold selectivity against additional HMTs. EPZ-5676 treatment of cultured cells reduced histone H3K79 methylation, decreased MLL target gene expression and resulted in selective killing of MLL-rearranged (MLL-r) leukemia cells by inducing apoptosis and differentiation. EPZ-5676 administration led to tumor regression in an MLL-r leukemia xenograft model. We report preliminary results of an ongoing Phase 1 trial of EPZ-5676 in patients with advanced hematologic malignancies, including acute leukemia with MLL-r. Methods: This is a 2-part phase 1 open label dose escalation study investigating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and anti-leukemic activity of EPZ-5676 in adult patients (pts) with relapsed/refractory leukemia (CT.gov: NCT01684150). In the dose-escalation phase, patients with AML, ALL, acute mixed lineage leukemia, myelodysplastic syndrome, myeloproliferative neoplasia (MPN) or chronic myeloid leukemia were eligible. Eligibility in the expansion phase of the study was restricted to pts with MLL-r or partial tandem duplication of MLL (MLL-PTD). EPZ-5676 was administered via continuous intravenous infusion (CIV) for 21 days of a 28 day cycle in the dose escalation phase and CIV for all 28 days of a 28 day cycle in the expansion phase, until disease progression or unacceptable toxicity. Results: Between October 2012 and July 2014, 37 pts have enrolled; 36 are evaluable for safety (received at least 1 dose of EPZ-5676) and 28 pts (19 MLL-r, 4 MLL-PTD) are evaluable for anti-leukemia activity (completed at least one post baseline marrow evaluation). The median age at time of enrollment was 53 years (range: 20 to 81 years); the median number of prior systemic therapies was 2 (range: 1 to 6) and 14 pts had a prior allogeneic stem cell transplant. Of the treated pts, disease characteristics were: 31 pts with AML (21 MLL-r, 5 MLL-PTD), 4 pts with ALL (3 MLL-r) and 1 pt with MPN (MLL-r). Table 1: Number of evaluable pts per cohort Dose (mg/m2/day) 12 24 36 54 80 90 21 day CIV 1 5 4 6 3 - 28 day CIV - - - - - 17 The median time on study was 29 days (range: 5-196 days). Adverse events (AEs) reported in >15% of pts were: anemia, fever/neutropenia, thrombocytopenia, constipation, diarrhea, nausea, chills, fatigue, mucosal inflammation, peripheral edema, hypomagnesemia, dyspnea and sepsis; of which leukocytosis, nausea and hypomagnesemia were assessed by the investigator as drug related. Grade I PR interval prolongation, without associated QTc changes, was observed in 2 pts. There were no deaths attributed to study drug treatment, and there were 2 pts with treatment discontinuation for potentially drug-related AEs. Dose proportional PK was observed with rapid attainment of steady-state plasma concentrations on Day 1 of treatment. Preliminary PD data demonstrated inhibition of H3K79 methylation from baseline in marrow (median: 52%, range 0-81%) and peripheral blood mononuclear cells (median: 43%, range 25-67%) at doses above 36 mg/m2/day. PD effects were observed by day 8. The 21 day CIV pts recovered H3K79 methylation towards baseline by day 28, and the 28 day CIV pts maintained methyl-mark inhibition throughout cycle 1. To date, best responses for pts with MLL-r are morphologic CR (1 pt.), cytogenetic CR (1 pt), and resolution of leukemia cutis (2 pts). In addition, a treatment-related increase in neutrophils (PMN) and/or monocytes was observed in 6 pts with a median day of onset of 15 days (range 8-28 days). The identification of the MLL-r by split signal FISH in mature PMN suggests a differentiation effect on the leukemic clone. Conclusions: EPZ-5676 is well tolerated and exhibits anti-leukemic activity in MLL-rearranged acute leukemia. These data provide rationale for continued clinical investigation of potential utility of EPZ-5676 in patients with rearrangements of the MLL gene. Disclosures Stein: Janssen Pharmaceuticals: Consultancy. Garcia-Manero:Epizyme, Inc: Research Funding. Rizzieri:Novartis, Inc: Consultancy, Speakers Bureau; Ariad, Inc: Speakers Bureau. Savona:Karyopharm: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Altman:Astellas: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Membership on an entity's Board of Directors or advisory committees. Armstrong:Epizyme, Inc: Consultancy. Pollock:Epizyme: Employment, Equity Ownership. Waters:Epizyme, Inc: Employment, Equity Ownership. Legler:Epizyme, Inc: Employment. Thomson:Epizyme, Inc: Employment. Daigle:Epizyme, Inc: Employment, Equity Ownership. McDonald:Epizyme, Inc: Employment. Campbell:Epizyme, Inc: Employment, Equity Ownership. Olhava:Epizyme, Inc: Employment. Hedrick:Epizyme, Inc: Employment; Pharmacyclics, Inc: Equity Ownership. Copeland:New Enterprise Associates: Ad hoc consultant, Ad hoc consultant Other; Mersana: Membership on an entity's Board of Directors or advisory committees; Epizyme, Inc: Employment, Equity Ownership.