Citations

Abstract Definitive radiotherapy combined with chemotherapy is associated with enhanced locoregional control and clinical outcomes in non-small cell lung cancer (NSCLC) patients who are not candidates for surgery. However, radiation-induced pneumonitis and esophagitis are common dose-limiting inflammatory conditions that occur in these patients. These events can compromise the effect of the overall treatment and reduce quality of life in these patients. It is not clear what factors contribute to differences in the development of toxicities among patients with same clinical or dosimetric parameters. In this study, we conducted a large scale pathway-based analysis to identify inflammation-related genetic variants associated with radiation-induced pneumonitis or esophagitis. In the initial discovery phase, 11,930 inflammation-related genetic variants were genotyped in 243 stage I-III NSCLC patients who were treated with definitive radiotherapy at MD Anderson Cancer Center. A fast-track validation was performed for the top candidate SNPs in an additional 212 NSCLC cases following the same criteria. A total of 14 SNPs and 12 SNPs were validated for pneumonitis and esophagitis, respectively. Meta-analysis was used to summarize the results from two phases. The most significant SNPs for esophagitis and pneumonitis mapped to chromosome 18p (OR=9.05, 95%CI=2.68-30.59, P-meta=3.90×10−4) and 14q (OR=4.75, 95%CI=2.17-10.41, P-meta =9.61×10−5), respectively. To explore the potential underlying mechanisms, we analyzed radiation sensitivity and eQTL relationships of the identified SNPs and their host genes in 277 ethnically defined human lymphoblastoid cell lines. Among the 24 host genes for the 26 identified SNPs, three genes (DDX58, GZMB, CDC2) showed significant association with radiation responses in these cell lines (P<0.05). Moreover, a significant eQTL relationship was identified between CDC2 expression and the genotype of the identified CDC2 SNP (P=0.022). Interestingly, this CDC2 SNP is predicted to create a new miRNA binding site. Luciferase reporter assays to test the influence of this SNP on miRNA regulation is currently ongoing. Our results provide evidence that inflammation-related genetic variants contribute to the development of radiation-induced pneumonitis and esophagitis. The results also suggest that gene expression changes through altered miRNA binding may be an underlying mechanism for these events. Citation Format: Xia Pu, Liewei Wang, Michelle AT Hildebrandt, Yuanqing Ye, Joe Y. Chang, Charles Lu, Heath D. Skinner, Nifang Niu, Gregory D. Jenkins, Ritsuko Komaki, John D. Minna, Jack A. Roth, Richard M. Weinshilboum, Xifeng Wu. Inflammation-related genetic variants predict radiation-induced toxicity following definitive radiotherapy for non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3626. doi:10.1158/1538-7445.AM2013-3626

Abstract The lysine deacetylase inhibitor suberoylanilide acid (SAHA) has shown promising but limited activity in the treatment of acute myeloid leukemia (AML). To identify potential targets for rational combination therapies that increase the efficacy of SAHA in AML, we used a functional RNA-interference (RNAi) screening approach to identify genes, that when inhibited, potentiate the in vitro anti-leukemic activity of SAHA. A total of 901 kinase, phosphatase and associated signaling genes were silenced, with four different siRNA sequences per gene, in combination with SAHA treatment. Log2 values of the ratio [(siRNA + SAHA)/(siRNA alone)] were calculated, with median and standard deviation determined on a per-plate basis. Hits were defined as ≥ 2 standard deviations from the log2 ratio median. Hit lists for each cell line were over-laid on an integrated functional relationship network. We applied a community detection algorithm to this sub-network and identified siRNA sensitive modules. Each module represents a highly connected set of genes in the integrated network. To identify the pathways represented by each module, we evaluated enrichment using the National Cancer Institute (NCI) Protein Interaction Database (PID) pathways. Several novel sensitizing targets, grouped into a small number of pathways, emerged from these screens. Some hits exhibit little to no anti-leukemic activity when silenced alone, indicative of synthetic lethal interaction with SAHA treatment. Initial validation experiments with siRNA and novel small molecule inhibitors confirm RNAi screen results and pharmacological sensitization is observed. The first reported large-scale HDAC inhibitor RNAi screen in leukemias has identified a novel rational combination that can be translated into design of a clinical trial. Citation Format: James M. Bogenberger, James E. Rudd, Donald Chow, Michelle Kassner, Holly Yin, Casey S. Greene, Raoul Tibes. Identification of HDAC inhibitor potentiating targets in acute myeloid leukemia cells by large-scale RNA-interference. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr A28.

Abstract Background: Imaging biomarkers of cellular division offer promise as non-invasive measures of tumor response. 3’-deoxy-3’[18F]-fluorothymidine ([18F]-FLT) positron emission tomography (PET) imaging generally correlates with pathology-based measurements of cancer proliferation, especially the Ki67 score. Though clinical studies have associated changes in [18F]-FLT uptake with therapeutic response, clinical studies validating its ability to assess cell proliferation are comparatively lacking. The goal of this study was to determine quantitative relationships between [18F]-FLT compared with molecular and cellular metrics of proliferation during treatment for locally advanced breast cancer (LABC). Methods: Baseline [18F]−FLT-PET scans were obtained prior to the initiation of chemotherapy for LABC from patients enrolled at several academic oncology study sites. MRI scans, and transmission CT scans were obtained. Core needle biopsies were obtained to determine Ki-67 indices using immuno-histochemistry and to assess an mRNA signature based measurement of proliferation. Prospectively specified quantitative relationships between PET, Ki67 immunohistochemistry and the mRNA signature were evaluated using image-matched tumor specimens. Correlations between volumetric MRI changes and pathologic responses were evaluated in a post-hoc exploratory analysis. Results: Motivated by the hypothesis that effective chemotherapies should decrease tumor cell proliferation, FLT-PET was compared with biomarkers of proliferation including Ki67 and the mRNA signature during neoadjuvant treatment for LABC. [18F]-FLT correlated both with the Ki67 labeling index (SUVmean r = 0.53) and with the proliferation signature (SUVmean r = 0.7), validating the principle of thymidine analogue imaging. However, variability in the [18F]-FLT PET and tumor cell proliferation measures likely contributed to correlations less than pre-specified target values considered appropriate for clinical use (r > 0.78). Moreover, none of the proliferation biomarkers predicted pathologic complete responses at the end of neoadjuvant therapy ∼16 weeks after the 3 week response scan. In contrast, an evaluation of change in tumor volume measured by MRI after 3 weeks of therapy confirmed its superior ability to predict pCR and tumor re-staging. Conclusion: With large numbers of cancer drugs entering therapeutic pipelines, early efficacy measures remain critical for drug development. The 3-4 month neoadjuvant treatment paradigm for LABC offers unique opportunities for drug evaluation. Functional imaging using [18F]-FLT has been advanced as an assessor of cellular proliferation, potentially offering a non-invasive approach to response evaluation. While [18F]-FLT generally correlated with proliferation, its lack of association with patient responses likely limit its clinical utility. On the other hand, the predictive value of MRI offers unique opportunities for future trial designs and confirms previous reports (1). 1. N. M. Hylton et al., Locally advanced breast cancer: MR imaging for prediction of response to neoadjuvant chemotherapy. Radiology 263, 663 (2012). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-11.

Objectives. We examined whether a proactive care smoking cessation intervention designed to overcome barriers to treatment would be especially effective at increasing cessation among African Americans receiving care in the Veterans Health Administration. Methods. We analyzed data from a randomized controlled trial, the Veterans Victory over Tobacco study, involving a population-based electronic registry of current smokers (702 African Americans, 1569 Whites) and assessed 6-month prolonged smoking abstinence at 1 year via a follow-up survey of all current smokers. We also examined candidate risk adjustors for the race effect on smoking abstinence. Results. The interaction between patient race and intervention condition (proactive care vs usual care) was not significant. Overall, African Americans had higher quit rates than Whites (13% vs 9%; P < .006) regardless of condition. Conclusions. African Americans quit at higher rates than Whites. These findings may be a result of the large number of veterans receiving smoking cessation services and the lack of racial differences in receipt of these services as well as racial differences in smoking history, self-efficacy, and motivation to quit that favor African Americans.

ScopeWe reevaluated previously reported associations between variants in pathways of one‐carbon (1‐C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13 410 OC cases and 22 635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10−5) and rs828054 (OR = 1.06; p = 1 × 10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1‐C transfer, previously reported with OC, suggested lower risk at higher folate (pinteraction = 0.03–0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP‐by‐folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Anomalies in the course and drainage of the Inferior Vena Cava (IVC) may complicate normal functioning, correct diagnosis, and therapeutic interventions within the abdomen. Development of the IVC occurs during the 4th to 8th week of gestation, and due to its developmental complexity, there are many opportunities for malformations to occur. Although most IVC anomalies are clinically silent and are usually discovered incidentally on abdominal imaging, aberrations may be responsible for formation of thrombosis, back pain, and anomalous circulation of blood to the heart. In this review, we will discuss the most common variations and abnormalities of the IVC, which include the posterior cardinal veins, the subcardinal veins, the supracardinal veins, persistent left IVC, IVC duplication, situs inversus, left retroaortic renal vein, left circumaortic renal collar, scimitar syndrome, and IVC agenesis. For each abnormality outlined above, we aim to discuss relevant embryology and potential clinical significance with regards to presentation, diagnosis, and treatment as is important for radiologists, surgeons, and clinicians in current clinical practice. Clin. Anat. 27:1234–1243, 2014. © 2014 Wiley Periodicals, Inc.

Object Traditionally, hemisacrectomy and internal hemipelvectomy procedures have required both an anterior and a posterior approach. A posterior-only approach has the potential to complete an en bloc tumor resection and spinopelvic reconstruction while reducing surgical morbidity. Methods The authors describe 3 cases in which en bloc resection of the hemisacrum and ilium and subsequent lumbopelvic and pelvic ring reconstruction were performed from a posterior-only approach. Two more traditional anterior and posterior staged procedures are also included for comparison. Results In all 3 cases, an oncologically appropriate surgery and spinopelvic reconstruction were performed through a posterior-only approach. Conclusions The advantage of a midline posterior approach is the ability to perform a lumbosacral reconstruction, necessary in cases in which the S-1 body is iatrogenically disrupted during tumor resection.

SummaryObjectiveTo evaluate safety, tolerability, seizure frequency, and regional variations in treatment responses with the AMPA antagonist, perampanel, in a large extension study during up to 3 years of treatment.MethodsPatients ≥12 years old with partial‐onset seizures despite treatment with 1–3 antiepileptic drugs at baseline completed a perampanel phase III trial and entered extension study 307 (NCT00735397). Patients were titrated to 12 mg/day (or their individual maximum tolerated dose) during the blinded conversion period, followed by open‐label maintenance. Exposure, safety (adverse events [AEs], vital signs, weight, electrocardiography [ECG], laboratory values) and seizure outcomes were analyzed; key measures were assessed by geographic regions.ResultsAmong 1,216 patients, median exposure was 1.5 years (range 1 week to 3.3 years), with >300 patients treated for >2 years. Treatment retention was 58.5% at cutoff. AEs reported in ≥10% of patients were dizziness, somnolence, headache, fatigue, irritability, and weight increase. Only dizziness and irritability caused discontinuation in >1% of patients (3.9% and 1.3%, respectively). The only serious AEs reported in >1% of patients were epilepsy‐related (convulsion, 3.0%; status epilepticus, 1.1%). No clinically relevant changes in vital signs, ECG or laboratory parameters were seen. After titration/conversion, responder rate and median percentage change from baseline in seizure frequency were stable: 46% for both measures at 9 months (in 980 patients with ≥9 months' exposure) and 58% and 60%, respectively, at 2 years (in the 337 patients with 2 years' exposure). Median percentage reduction in frequency of secondarily generalized (SG) seizures ranged from 77% at 9 months (N = 422) to 90% at 2 years (N = 141). Among the 694 patients with maintenance data ≥1 year, 5.3% were seizure‐free for the entire year.SignificanceNo new safety signals emerged during up to 3 years of perampanel exposure in 39 countries. Seizure responses remained stable, with marked reductions, particularly in SG seizures.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.