Citations

Abstract Introduction. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel treatment. There is conflicting data on the benefits and harms of supplement use for the treatment and prevention of CIPN. We examined dietary supplement use before diagnosis and during treatment in relation to CIPN among breast cancer patients registered to a clinical trial (SWOG 0221; ClinicalTrials.gov Identifier: NCT00070564) before diagnosis and during treatment in relation to CIPN. Methods. At trial registration (baseline), breast cancer patients (n = 1,225) completed questionnaires to capture use before and at diagnosis of multivitamins and other dietary supplements. Of these patients, 1,068 completed a 6-month follow-up questionnaire to capture use during treatment. We examined the use of multivitamins, vitamins C, D, E, B6, and B12, folic acid, iron, calcium, glucosamine, and combined fish oil, eicosapentaenoic acid (EPA), omega-3, flaxseed and cod liver oil at these timepoints in relation to CIPN. CIPN was assessed via the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale. Odds ratios and 95% confidence intervals were computed using unconditional logistic regression. Results. Multivitamin use before diagnosis was associated with reduced symptoms of CIPN (CTCAE adjusted OR = 0.60, 95% CI = 0.42-0.87; FACT/GOG-Ntx adjusted OR = 0.78, 95% CI = 0.61-1.00). Although in a similar direction as use prior to diagnosis, multivitamin use during treatment was less strongly associated with CIPN (CTCAE adjusted OR = 0.73, 95% CI = 0.49-1.08; FACT/GOG-Ntx 0.77, 95% CI = 0.60-0.99). Other supplement use, either before diagnosis or during treatment, was not associated with CIPN. Conclusions. Our results indicate that supplement use during treatment may not appreciably affect experience of CIPN symptoms. Future analyses of the relationships between supplement use and survival outcomes will better inform patient decision making. Acknowledgments: supported by R01 CA116395 (CBA); S0221 supported, in part, by National Cancer Institute/Division of Cancer Prevention SWOG NCORP Research Base grant 5UG1CA189974-02; National Cancer Institute (NCI), National Clinical Trials Network (NCTN): CA180888, CA180819; and in part by Amgen, Inc. Citation Format: Gary R. Zirpoli, Susan E. McCann, Lara E. Sucheston-Campbell, Dawn L. Hershman, Gregory Ciupak, Warren Davis, Joseph M. Unger, Halle C.F. Moore, James A. Stewart, Claudine Isaacs, Timothy J. Hobday, Muhammad Salim, Robert B. Livingston, Gabriel N. Hortobagyi, Julie R. Gralow, Daniel F. Hayes, G. Thomas Budd, Kathy S. Albain, Christine B. Ambrosone. Supplement use and chemotherapy-induced peripheral neuropathy in breast cancer patients treated on SWOG study S0221. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3413.

Background Intracranial aneurysms ( IAs ), abdominal aortic aneurysms ( AAAs ), and thoracic aortic aneurysms ( TAAs ) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs , AAAs, and TAAs . Methods and Results We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study ( GWAS ) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA , AAA , and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA ‐, AAA ‐, and TAA ‐associated SNP s and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls ( IA ) and 4391 cases and 37 904 controls ( AAA ), and found nominally significant associations for IA risk locus 18q11 near RBBP 8 to AAA (odds ratio [ OR ]=1.11; P =4.1×10 −5 ) and for TAA risk locus 15q21 near FBN 1 to AAA ( OR =1.07; P =1.1×10 −3 ). Conclusions Although there was no evidence for polygenic overlap between IAs , AAAs , and TAAs , we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs . These two loci will require further replication.

AbstractMany clinical trials have been conducted on the treatment of pityriasis rosea (PR). Our aim was to establish a position statement for the management of adults withPRbased on the best available evidence. We searchedPubMedfor all reports on randomized controlled trials for the treatment ofPRpublished in the past 30 years. We retrieved 14 articles reporting randomized controlled trials, and found five which met our quality requirements for in‐depth analyses. Erythromycin was found in a well‐conducted triple‐blind study to cast significant impacts on clinical outcomes. However, adverse gastrointestinal effects were fairly common. Another well‐conducted study on azithromycin reported no significant benefit. It was reported in three well‐conducted studies on oral acyclovir in low dose (400 mg three times daily for 7 days or 400 mg five times daily for 7 days) and high dose (800 mg five times daily for 7 days), that acyclovir is effective in attaining rash regression and lessening the pruritus. When compared against each other, the high‐dose regimen demonstrated no benefit over the low‐dose regimens. Our statement comprises the follows: (i) The diagnosis ofPRshould be ascertained; (ii) The patients should be assessed for rash severity and impacts on quality of life; (iii)PRis a self‐limiting disease, and most patients do not necessitate any treatment; (iv) For patients necessitating active treatment, oral acyclovir as 400 mg three times daily for 7 days can be considered; (v) Attention should be given to adverse effects and contraindications of acyclovir; (vi) WhenPRoccurs in early pregnancy, oral antiviral therapy could be considered after consulting experienced clinicians; (vii) Inadequate information exists in the use of acyclovir to treatmentPRin children and breastfeeding women; and (viii) TreatingPRis an off‐label use of acyclovir, and this has to be discussed with experienced colleagues and the patients.

AbstractObjectivesTo investigate whether Gianotti–Crosti syndrome (GCS) in children is associated with atopy.MethodsThe setting was two outpatient clinic. Diagnoses of asthma and atopic dermatitis (AD) were made according to internationally accepted diagnostic criteria. Allergic rhinitis, atopic urticaria, and allergic conjunctivitis were diagnosed clinically. Participants were children with GCS diagnosed over the previous 5 years. For any child with GCS, we extracted the record of the subsequent age and sex pair‐matched child seen for problems unrelated to the skin as controls.ResultsWe retrieved the records of 37 pairs of study and control subjects; 28 (76%) children with GCS and 9 (24%) controls had AD (risk ratio [RR] = 3.11[95% confidence interval {CI} 1.73, 5.73]), 31 (84%) children with GCS and 19 (51%) controls had at least one atopic condition (RR = 1.63 [95% CI 1.13, 2.18]) and 11 (30%) children with GCS and 2 (5%) controls had at least three atopic conditions (RR = 5.50 [95% CI 1.29, 35.35]).ConclusionGCS is significantly associated with AD and the presence of atopic conditions.

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.

Genome engineering has gone mainstream because of breakthroughs in defining and harnessing naturally occurring, customizable DNA recognition cursors (protein or RNA-guided). At present, most gene editing relies on these cursors to direct custom DNA endonucleases to a specific genomic sequence to induce a double-strand break. New tools for genome engineering are continuously being explored, and another advance in DNA targeting has recently been described. Argonaute isolated from Natronobacterium gregoryi (NgAgo) is an ssDNA-based cursor that thus far has no known limitations in sequence recognition, shows promise for high specificity, and for many applications may represent a potentially more accessible genome-editing system over prior tools as it requires only a single, 24-base, 5′ phosphorylated ssDNA for DNA targeting. Genome engineering is in a remarkable moment of unprecedented growth with exponential reduction in costs reminiscent of Moore's law in electronics. Many questions remain with regard to Argonaute utility in specific systems, but there is no doubt that genome engineering is expanding into new and exciting areas from synthetic biology to gene therapy.

BackgroundFactors associated with dissection from inflammatory aortic aneurysms may be different from those in the general population.ObjectiveThe aim of this study was to evaluate the risk factors for aortic dissection/rupture in patients with giant cell arteritis (GCA) and aortic aneurysms.MethodsA population-based incident cohort of patients with a diagnosis of GCA from 1950 to 2004 was used. All patients with aortic aneurysms diagnosed 1 year prior to GCA diagnosis or any time thereafter were included. Cox proportional hazard models were used to evaluate risk factors for aortic dissection/rupture.ResultsThe study included 33 patients (91% women) with GCA and aortic aneurysms. Mean age at diagnosis of aortic aneurysm was 83.6 years. There were 27 thoracic aneurysms and 19 abdominal aneurysms. Eight patients developed aortic dissection/rupture (both thoracic and abdominal aorta in 5 cases, thoracic aorta only in 2 cases, and isolated abdominal aorta in 1 case).Older age (hazard ratio [HR], 0.27 per 10 years; 95% confidence interval [CI], 0.09–0.86) and later calendar year at diagnosis of aortic aneurysm (HR, 0.29 per 10 years; 95% CI, 0.13–0.69) were associated with decreased risk of dissection/rupture. Size of the thoracic aneurysm (HR, 1.17; 95% CI, 0.69–1.99) was not associated with dissection/rupture. Histopathology showed active aortitis in 4 of 7 patients with aortic dissection/rupture compared with 0 of 7 patients with aortic aneurysm without dissection/rupture.ConclusionsAneurysm size was not a predictor of aortic dissection/rupture in this cohort of patients with GCA. The higher frequency of active aortitis in patients with dissection suggests that active inflammation may play a role.

Abstract Breast cancer diagnosis and death has risen in low to middle income countries (LMIC) in the past 20 years. Early detection, diagnosis and treatment in the LMIC setting are thought to impact morbidity and survivorship. The population of South Florida is composed of a significant portion of Afro-Caribbean immigrants from LMICs. We compared a cohort of recent Haitian immigrants with residents in Haiti who had a diagnosis of breast cancer to evaluate the effects of geographical location on presentation, treatment and outcomes. Methods: Retrospective cohort study. Participants were Haitian females with breast cancer that were living in Miami and presented to the University of Miami/Jackson Memorial Hospital (UM/JMH) between 2008 and 2014 and patients living in Haiti and presented to the Breast Cancer Treatment program at the Hospital Bernard Mevs Project Medishare (HBMPM) from 2013 to 2015 with a new diagnosis or who had been diagnosed as far back as 2008 and were presenting for continuation of care. The main outcome was the relationship between cohort location and breast cancer characteristics and cancer–specific survival by log-rank. Cox proportional hazards regression was used to compare breast cancer–specific survival overall and analyzed by stage and other significant explanatory factors. Results: 102 patients from UM/JMH and 94 patients from HBMPM were included in the analysis. The cohort in Haiti presented after longer median duration of symptoms (20 vs 3 months, p<0.001) and more advanced stage (31% Vs 20% with locally advance and 27% vs 19% with metastatic disease). The median age of diagnosis was 55 years in Miami compared to 50 years in Haiti (p=0.03). In Miami all patients had estrogen receptor (ER) and her-2 status ascertained at diagnosis, whereas only 52% and 27% of the Haitian cohort had them. Tumor characteristics in Miami vs Haiti in patients with reported status: ER + 74% (n=102) vs 55% (n=49), p=0.02, her-2+ 20% (n=102) vs 28% (n=25), p=0.36, triple negative 27% (n=102) vs 28% (n=25),p=0.49. Treatment modalities and censoring was available for all the patients in Miami and 72 patients in Haiti. In Haiti, radiation therapy was not widely available compared to Miami. Once patients had known ER and her-2 status, there was no difference in treatment with hormonal therapy (p=0.97) but none of the patients in Haiti received her-2 directed therapy (p<0.001). 50% of the patients with unknown ER status in Haiti received Tamoxifen. Twice as many Haitian women died after a median follow-up of 23 months (12% vs 24%), with median survival of 53 months for Haitians in Haiti (not reached for Miami cohort). Breast cancer specific survival was significantly different in the two cohorts (p<0.000). After exploratory analysis, the risk of death was higher for Haitians in Haiti than Haitians in Miami [HR 3.13 (CI 1.50-6.51)] and was higher for more advanced disease [HR 2.58 (CI 1.67-3.99)]. No other variable or interaction reached statistical significance in our model. Conclusion: Haitian women diagnosed with breast cancer in Haiti experience a significantly worse outcome than Haitians living in Miami that appears to be related to a more advanced stage, younger age, more ER negative tumors and lack of timely effective treatments including restricted access to trastuzumab and radiation. In addition there is a difference in the age of breast cancer onset (Caucasian 62, African American 58, Haitian American 55, Haitian 50) and ER positivity (Caucasian 70%, African American 48%, Haitian American 74%, Haitian 55%) depending on race and ethnic group that raises the question of whether there are disparities within subgroups of women of African origin who have breast cancer. Confounding epigenetic-related variables may impact survival and they need further exploration in these populations. Citation Format: Alexandra Gomez, Vincent DeGennaro, Jr., Sophia George, Estefania Santamaria, Gustavo Westin, Gabriel Dieudina, Judith Hurley. Presentation, treatment, and outcomes of Haitian women with breast cancer in Miami and Haiti: Disparities in breast cancer. A retrospective cohort study. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C55.

Caring for the growing elderly population will require specialty and subspecialty physicians who have not completed geriatric medicine fellowship training to participate actively in patient care. To meet this workforce demand, a sustainable approach to integrating geriatrics into specialty and subspecialty graduate medical education training is needed. This article describes the use of a geriatrics education team ( GET ) model to develop, implement, and sustain specialty‐specific geriatrics curricula using a systematic process of team formation and needs assessment through evaluation, with a unique focus on developing curricular interventions that are meaningful to each specialty and satisfy training, scholarship, and regulatory requirements. The GET model and associated results from 15 specialty residency and fellowship training programs over a 4‐year period include 93% curriculum sustainability after initial implementation, more than half of the programs introducing additional geriatrics education, and more than 80% of specialty GET s fulfilling their scholarship requirements through their curriculum dissemination. Win–wins and barriers encountered in using the GET model, along with the model's efficacy in curriculum development, sustainability, and dissemination, are summarized.

Abstract Purpose: APOBEC3 DNA cytosine deaminase family members normally defend against viruses and transposons. However, deregulated APOBEC3 activity causes mutations in cancer. Because of broad expression profiles and varying mixtures of normal and cancer cells in tumors, including immune cell infiltration, it is difficult to determine where different APOBEC3s are expressed. Here, we ask whether correlations exist between APOBEC3 expression and T-cell infiltration in high-grade serous ovarian cancer (HGSOC), and assess whether these correlations have prognostic value. Experimental Design: Transcripts for APOBEC3G, APOBEC3B, and the T-cell markers, CD3D, CD4, CD8A, GZMB, PRF1, and RNF128 were quantified by RT-qPCR for a cohort of 354 HGSOC patients. Expression values were correlated with each other and clinical parameters. Two additional cohorts were used to extend HGSOC clinical results. Immunoimaging was used to colocalize APOBEC3G and the T-cell marker CD3. TCGA data extended expression analyses to additional cancer types. Results: A surprising positive correlation was found for expression of APOBEC3G and several T cell genes in HGSOC. Immunohistochemistry and immunofluorescent imaging showed protein colocalization in tumor-infiltrating T lymphocytes. High APOBEC3G expression correlated with improved outcomes in multiple HGSOC cohorts. TCGA data analyses revealed that expression of APOBEC3D and APOBEC3H also correlates with CD3D across multiple cancer types. Conclusions: Our results identify APOBEC3G as a new candidate biomarker for tumor-infiltrating T lymphocytes and favorable prognoses for HGSOC. Our data also highlight the complexity of the tumor environment with respect to differential APOBEC family gene expression in both tumor and surrounding normal cell types. Clin Cancer Res; 22(18); 4746–55. ©2016 AACR.