tbuckley/cabot-search huggingface dataset:
Alternative Splicing of APOBEC3D Generates Functional Diversity and Its Role As a DNA Mutator
Authors: Hisashi Takei, Masanori Fujii, Sohei Nakayama, Ikei Kobayashi, Keisuke Shindo, Kotaro Shirakawa, Akifumi Takaori-Kondo, Susumu Kobayashi
Journal: Blood (2016)
Acute Myeloid Leukemia Cells Export c-Myc in Extracellular Vesicles Driving a Proliferation of Immune-Suppressive Myeloid-Derived Suppressor Cells
Authors: Athalia Rachel Pyzer, Dina Stroopinsky, Hasan Rajabi, Abigail J. Washington, Leandra Cole, Salvia Jain, Ashujit Tagde, Arie Apel, Malgorzata McMasters, James D. Levine, Robin Joyce, Jon Arnason, Poorvi Somaiya, Rebecca Karp Leaf, Myrna R. Nahas, Donald Küfe, Jacalyn Rosenblatt, David E. Avigan
Journal: Blood (2016)
Prediction models for primary melanoma: an independent external validation study in an Australian population.
Authors: Kylie Vuong, Anne Elizabeth Cust, Bruce Konrad Armstrong, Kevin McGeechan
Journal: Journal of Clinical Oncology (2015)

1569 Background: There are a growing number of melanoma risk prediction models; however few assessed model external validity. External validation refers to the process of establishing model performance in an external, independent population and provides an indication of generalizability. Model performance tends to be poorer when measured in an external, independent data set compared with the data set that was used to develop the model. To help clinicians decide which models are potentially most useful, we assessed the external validity of six published melanoma models on an independent population. Methods: The Australian Melanoma Family Study, a population-based, case-control-family study with 629 population-based cases with first primary melanoma diagnosed before age 40 years and 535 controls from 2001 to 2005 were used to validate the models. We compared performance using discrimination (separation of those with and without melanoma) by calculating the area under the receiver operating curve (AUC). Results: Model performance ranged from fair to good. The models of Mar [AUC = 0.79 (95% CI 0.73 – 0.79)] and Fears for men [AUC = 0.79 (0.71 -0.86)] showed comparable discrimination. Other models yielded lower discrimination: Guther [AUC = 0.70 (0.67-0.72)], Williams [AUC = 0.66 (0.64-0.69)], Cho [AUC = 0.63 (0.61-0.65)] and Fears for women [AUC = 0.63 (0.56-0.69)]. Conclusions: The six models discriminate well between those with and without melanoma in the Australian population suggesting potential for these models to be developed for use in targeted melanoma prevention interventions. However further external validation in different populations and prospective evaluation of efficacy is required before they can be routinely used in clinical settings.
A phase I trial of pegylated liposomal anthracycline and lapatinib (L) combination in the treatment of metastatic breast cancer (MBC): First evaluation of an anthracycline and lapatinib combination in the treatment of MBC
Authors: M. E. Cianfrocca, S. T. Rosen, J. H. von Roenn, A. W. Rademaker, S. D. Rubin, R. A. Friedman, C. P. Rozario, W. J. Gradishar
Journal: Journal of Clinical Oncology (2007)

1079 Background: Liposomal formulations such as pegylated liposomal doxorubicin (PLD) were developed to improve the therapeutic index and overall benefit of the anthracyclines (A). L is a selective and highly competitive inhibitor of ErbB1 and ErbB2 tyrosine kinases. The combination of conventional doxorubicin and an ErbB2 targeting agent (trastuzumab), while effective, led in a randomized phase III trial to an unacceptable risk of cardiac toxicity. The combination of PLD and L however may be effective with less cardiac risk Methods: This is an open-label, phase I, dose-escalation trial of PLD at 20, 30, 45 and 60 mg/m 2 IV every 4 weeks (maximum of 8 doses) and L, 1,500 mg po daily until progression in patients (pts) with MBC. EGFR and/or ErbB2 positivity was not required. Prior chemotherapy, endocrine therapy and trastuzumab were allowed however prior A use was limited to 240 mg/m 2 of doxorubicin or 600 mg/m 2 of epirubicin and prior EGFR targeting therapies were not allowed. Concomitant CYP3A4 inducers/ inhibitors were not allowed. A left ventricular ejection fraction (LVEF) of ≥ 50% was required. The primary objective was to evaluate the safety, tolerability and feasibility of the combination of PLD and L, particularly with respect to cardiac safety. MUGAs were performed at entry and every 8 weeks thereafter. Results: 7 patients (PLD: 20 mg/m 2 - 3 pts; 30 mg/m 2 - 3 pts; and 45 mg/m 2 - 1 pt) with a mean age of 43 yrs (range, 33–68) have been treated for a total of 14 treatment cycles. Dose-limiting toxicity (DLT) has not been reached. One pt experienced an LVEF drop to &lt; 50% after 4 cycles however this was accompanied by a pericardial effusion felt to be secondary to progressive disease. Adverse events observed include: grade III/IV- none; grade I/II in ≥2 pts- rash, nausea, and anorexia; grade II leukopenia, fatigue, alopecia, diarrhea, headache were also seen in 1 pt each. Preliminary response data in 4 evaluable pts reveals 1 PR, 1 SD, and 2 PD. Conclusions: In the first 7 pts treated, the combination of PLD and L has been well tolerated. One pt experienced an LVEF drop to &lt; 50%, however this was felt likely to be disease-related. DLT has not yet been reached and accrual is ongoing. No significant financial relationships to disclose.
Establishment of disease-specific graded prognostic assessment for patients with hepatocellular carcinoma and spinal metastasis.
Authors: Chai Hong Rim, Chiwhan Choi, Jinhyun Choi, Jinsil Seong
Journal: Journal of Clinical Oncology (2017)

433 Background: Spinal metastasis (SM) of hepatocellular carcinoma (HCC) is a crucial clinical problem. It shows heterogenous length of survival suggesting a need for predicting prognosis. In this study, we aimed to develop and propose a graded prognostic assessment of SM of HCC (HCC-SM GPA). Methods: We previously reported the outcomes of 192 HCC patients with SM who received radiotherapy from April 1992 to February 2012. Prognostic factors with significant effects on survival in that study were used to establish the HCC-SM GPA. Validation was performed using an independent cohort of 63 patients recruited from September 2011 to March 2016. Results: We developed HCC-SM GPA using the following factors: Eastern Cooperative Oncology Group performance status ( &lt; 2: 0, &gt; 3: 1 point), controlled primary HCC (Yes: 0, No: 2 points), and extrahepatic metastases other than bone (No: 0, Yes: 1 points). Patients were stratified into low (GPA = 0), intermediate (GPA = 1–2), and high risk (GPA = 3–4). When applied to the validation cohort, the HCC-SM GPA determined median survival durations of 13.6, 4.8, and 2.6 months and 1-year overall survival rates of 58.3%, 8.9%, and 7.3% for the low-, intermediate-, and high-risk patient groups, respectively (p &lt; 0.001). Conclusions: Our newly proposed HCC-SM GPA successfully predicted survival outcome. This index might be a useful tool for making treatment decision.
Assessment of cancer registries (CR) in low- and middle-income countries (LMCs).
Authors: Leah L. Zullig, Sky Vanderburg, Doug Johnson, Olola Oneko, Charles Muiruri, Moshi Ntabaye, Amy Pickar Abernethy, John Bartlett, Yousuf Zafar
Journal: Journal of Clinical Oncology (2012)

6102 Background: CRs are crucial for cancer control, yet few global standards exist. This study identifies characteristics of quality CRs in LMCs and globally. Methods: A Medline search was conducted in PubMed to identify peer-reviewed articles describing: 1) CR development and functionality 2) types of CRs and 3) implementation, development and utility of CRs in LMCs. We examined articles describing CRs and assessed benchmarking data that could be used to define quality characteristics. Full-text, English-language articles were reviewed. References cited were searched for additional articles. We categorized characteristics into 4 domains: comparability, completeness, validity and timeliness. Results: The literature search yielded 16 key characteristics within 4 domains that may define high quality CRs. In the “comparability” domain, the key characteristic was use of standard definitions. CRs in the US, Europe and China generally adhere to the International Classification of Diseases for Oncology and histological verification of disease; in 2007 only 40% of African registries did so. In the “completeness” domain the key characteristic was population coverage. African CRs monitor 8% of the population, the Costa Rican registry covers 90%, US and Madras cancer registries reach 96%. In the “validity” domain the key criterion was pathologic diagnosis confirmation. Most LMC CRs are not pathology-based. CRs in wealthier settings like Hong Kong report histologic confirmation in &gt;85% of cases. In the “timeliness” domain standards for timely data reporting are largely undocumented. Conclusions: No consensus exists on characteristics of quality CRs in a global context. The current study provides an initial set of metrics. A Delphi panel of international experts is planned to further address this. Based on this literature review, CRs in LMCs have limited reporting, validation and regional population coverage.
Exercise-induced changes in gene expression, muscular strength, and cancer-related fatigue in older prostate cancer patients.
Authors: Karen Michelle Mustian, Michelle Christine Janelsins, Supriya Gupta Mohile, Charles Stewart Kamen, Luke Joseph Peppone, Marie Anne Flannery, Mohamedtaki Abdulaziz Tejani, Anita Roselyn Peoples, Charles E. Heckler, Joachim Voss
Journal: Journal of Clinical Oncology (2014)

9538 Background: Radiation therapy (RT) and androgen deprivation therapy (ADT) impair muscular, mitochondrial and immune function, and result in muscle weakness and cancer-related fatigue (CRF) among prostate cancer patients. We investigated the influence of an exercise intervention (EXCAP), including resistance and aerobic training, on expression of 4825 mitochondrial and nuclear genes, muscular strength and CRF. Methods: In this phase II randomized clinical trial, older prostate cancer patients (N=58; mean age=67), receiving RT (47%) or ADT (53%), were randomized to 6 wks of EXCAP (7 days/wk) or standard care (RT or ADT with no exercise). RNA was isolated from muscle biopsies for microarray analyses of 4825 mitochondrial and nuclear genes (N=11). Muscular strength was assessed using multiple repetition maximum testing (chest press and leg extension). CRF was assessed via valid self-report questionnaires (BFI, MFSI). Assessments were pre- and post-intervention. Analyses included robust multi-array average normalization, analyses of covariance (ANCOVA), correlations and partial least squares (PLS) with cross-validation. Results: MYH8, MYL5, ACTN3, XIRP1, MTTM, and HLA-DQB1 were significantly correlated with muscular strength and CRF (all p<0.05). Analyses revealed >2-fold down regulation in MYH8 and XIRP1 in the exercise group, no >2-fold changes in expression in the control group, and a >2-fold difference between groups on MTTM where MTTM was down-regulated >1.5-fold in controls with no change in exercisers (all p<0.05). ANCOVAs revealed a trend for group differences in muscular strength (all p<0.10) with significant group differences in CRF on the BFI (p<0.05) and a trend on the MFSI (p<0.10): exercisers improved while controls worsened. PLS suggested down-regulation of MYL5, ACTN3, and HLA-DQB1 may optimally predict increases in CRF. Conclusions: Results suggest exercise improves muscular strength and CRF and these improvements may be mediated via exercise-induced expression changes in genes involved in muscle generation and contraction (MYH8, MYL5, ACTN3, XIRP1), mitochondrial function (MT-TM) and immune function (HLA-DQB1). Funding DOD W81XWH-07-1-0341. Clinical trial information: NCT00815672.
Epidermal growth factor receptor mutation status and adjuvant chemotherapy in resected advanced non-small cell lung cancer.
Authors: Si-Yu Wang, Haibo Sun, Wei Ou, Qin Fang
Journal: Journal of Clinical Oncology (2012)

7034 Background: Mutations in the epidermal growth factor receptor (EGFR) are associated with response to chemotherapy in patients with advance NSCLC. The purpose of this study was to assess the association of mutations in the EGFR tyrosine kinase domain and the efficacy of adjuvant chemotherapy in patients with fully resected IIIA-N2 NSCLC tumors. Methods: Tumor samples (n =150) from patients in our prior trial with IIIA-N2 NSCLC who either had or had not received paclitaxel/vinorelbine plus carboplatin chemotherapy following removal of the tumor were analyzed for EGFR mutations in exons 19 and 21. The association of the presence of EGFR mutations and survival following treatment was assessed. Results: Mutations were identified in 33 (22%) patients (n=13 in the no chemotherapy [observation] arm and n=20 in the chemotherapy arm). Fourteen patients (9.3%) had deletion mutations in exon 19, and 19 patients (12.7%) had a substitution mutation in exon 21. Compared with patients wild-type for EGFR, patients with EGFR mutations had numerical but not statistically significant improved disease-free survival (35 months [95% CI, 14.6-55.4] versus 23 months [95% CI, 17.3-28.7], respectively, P=0.339) and overall survival (36 months [95% CI, 27.9 to 44.1] versus 26 months [95% CI, 20.1 to 31.9], respectively p=0.271) regardless of treatment. Patients with wild-type EGFR had greater overall survival with chemotherapy compared to no adjuvant therapy (HR=1.920; 95%CI, 1.245-2.963; p=0.003). In contrast, EGFR mutant patients in the observation group compared to the chemotherapy group had longer median disease-free survival (35 months [95% CI, 20.9 to 49.1] versus 27 months [95% CI, 5.3 to 48.7], respectively, p=0.671) and overall survival (33 months [95% CI, 24.2 to 41.8] versus 40 months [95% CI, 31.8 to 48.2] respectively, p =0.360). Conclusions: In this study, the status of mutations in exons 19 and 21 of EGFR was associated with different clinical outcomes in patients with resected IIIA-N2 NSCLC tumors either treated with or without adjuvant chemotherapy. These findings suggest that a patient’s treatment should be customized to their EGFR mutational status.
Adjuvant therapy in stage II pancreatic cancer: A National Cancer Database analysis.
Authors: Aabra Ahmed, Ryan W Walters, Timothy Dean Malouff, Mridula Krishnan, Javaneh Jabbari, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2017)

283 Background: Oldfield et al (2015) showed the conflicting evidence regarding the effect of adjuvant chemotherapy vs. chemoradiation in pancreatic cancer. Using patients identified by the National Cancer Database (NCDB), we are the largest study to compare survival in stage II pancreatic cancer patients who received adjuvant chemotherapy, chemoradiation, radiation, or no adjuvant therapy. Methods: We identified 65,091 patients with stage II pancreatic cancer who received surgery only or surgery in combination with chemotherapy, radiation, or chemoradiation. Between-therapy survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p &lt; .05 indicated statistical significance. Results: Patient characteristics were similar between groups; although, patients receiving chemoradiation were younger, had fewer comorbidities, and were more likely to have private insurance compared to all other therapy groups. Statistically significant survival differences were indicated between all therapy groups (all adjusted p&lt; 0.05), as patients receiving chemoradiation had the longest survival followed by patients receiving chemotherapy, patients receiving radiation therapy, and patients receiving no adjuvant therapy (median survival = 22.5, 19.6, 16.9, 14.8 months, respectively). When examining other variables, patients living in an area with a median income &lt; $43,000 were 14% more likely to die compared to patients in an area with a median income ≥ $63,000 (p &lt; 0.001) and those with no comorbidities were 19% less likely to die than patients with two or more comorbidities (p &lt; 0.001). Conclusions: Our data suggests that adjuvant therapy improves median and 3-year survival compared to no adjuvant therapy. Of all adjuvant therapies examined, adjuvant chemoradiation was associated with the greatest increase in survival, followed by adjuvant chemotherapy. Table 1: Median survival and survival rates of stage II pancreatic cancer [Table: see text]
The LIMD1-MYBL1 index as a composite marker for subtype classification and survival prediction for diffuse large B-cell lymphoma patients.
Authors: Qinghua Xu, Cong Tan, Shujuan Ni, Lin Yuan, Fei Wu, Fang Liu, Xun Ye, Xia Meng, Weiqi Sheng, Xiang Du
Journal: Journal of Clinical Oncology (2013)

8547 Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphomas with wide variations in patient survival. Through gene expression profiling, DLBCL can be stratified into two major cell-of-origin subtypes with distinct prognoses: the favorable germinal center B-cell-like (GCB) and the unfavorable activated B-cell-like (ABC) DLBCLs. However, the current cell-of-origin signatures are not suitable for use in routine clinical practice. Our study aimed to identify a novel biomarker to facilitate the translation of research into clinical practice. Methods: We performed an integrative analysis of seven independent cohorts comprising 1,682 patients. The DLBCL-1 cohort was used for signature identification. The identified signature was then tested in the DLBCL-2 to DLBCL-7 cohorts. Results: Two genes (LIMD1 and MYBL1) were significantly differentially expressed between the ABC and GCB subtypes. We integrated these genes into a composite marker, the LIMD1-MYBL1 Index. In seven independent cohorts, the average concordance rate between the LIMD1-MYBL1 Index and the cell-of-origin signature classification was 87% (range, 77% to 94%). Furthermore, the LIMD1-MYBL1 index is an independent prognostic factor for patients from different populations and for patients treated with a variety of therapies (Table). Conclusions: We identified the LIMD1-MYBL1 Index that has clinical value for DLBCL subtype classification and prognosis. Although little is known about the oncogenic roles of these genes, our findings prompt further research on the molecular mechanisms of DLBCL. [Table: see text]
Docetaxel pharmacogenetics: The influence of <i>RXR</i><i>α</i> and <i>HNF4</i><i>α</i> genetic variations on docetaxel disposition in Asian nasopharyngeal carcinoma patients.
Authors: Sin Chi Chew, Onkar Singh, Xiangai Chen, Wan-Teck Lim, Eng-Huat Tan, Edmund Jon Deoon Lee, Balram Chowbay
Journal: Journal of Clinical Oncology (2012)

2598 Background: The transactivations of the metabolism enzymes (CYP3A4/5) and efflux transporters (ABCB1/ABCC2) involved in docetaxel disposition are regulated by the orphan nuclear receptors such as PXR, CAR, RXRα and HNF4α. This study aimed to explore the associations between the genetic variations present in the genes encoding the orphan nuclear receptors, RXRα and HNF4α, on docetaxel disposition. Methods: The DNAs from healthy Chinese, Malay and Indian subjects (n=56 each) were screened for RXRα and HNF4α SNPs in exons and intronic/exonic boundaries by direct sequencing. The high frequency SNPs (&gt;1%) were profiled in a cohort of local nasopharyngeal cancer patients (n=54). Genotypic-phenotypic correlations were conducted using Mann-Whitney U-test and Kruskal-Wallis test. Results: Eighty-eight and sixty-nine SNPs were identified from the healthy screening of RXRα and HNF4α, respectively, across 3 populations. A total of 30 and 35 high frequency SNPs in RXRα and HNF4α, respectively, were profiled in the patients. Six RXRα SNPs [IVS2+33G&gt;A (rs2234753), IVS7+70A&gt;G (rs1536475),*846G&gt;A (rs4240711), *+4458G&gt;A (rs3132291), *+4768C&gt;A (rs4842196) and *+4988A&gt;G (rs4842198)] and 6 HNF4α SNPs [-728A&gt;C (rs1800963), IVS2-278A&gt;G (rs55934816), IVS6+141A&gt;G (rs6103731), IVS7-88T&gt;C (rs2273618), IVS9–145T&gt;C (rs3746574) and IVS9-67C&gt;G (rs3746575)] were significantly associated with higher clearance and lower AUC 0-∞ and/or C max of docetaxel (P&lt;0.05). Conversely, HNF4α SNP [IVS9+354G&gt;T (rs3818247)] was associated with lower clearance and higher AUC 0-∞ and C max of docetaxel (p&lt;0.05). A high linkage pattern was observed among the abovementioned RXRα SNPs except for IVS2+33G&gt;A (rs2234753) (D'≥0.74). Similarly, HNF4α SNPs were found to be highly linked, except for -728A&gt;C (rs1800963) (D'≥0.62). Conclusions: The results highlight the contributions of RXRα and HNF4α pharmacogenetics in influencing the inter-individual variability in docetaxel disposition in Asian nasopharyngeal patients.
Outcome Disparities in T-Cell Non-Hodgkin Lymphoma and the Lack of Significant Improvement over the Years: A SEER Database Review
Authors: Jennifer A Crozier, Taimur Sher, Dongyun Yang, Abhisek Swaika, James M. Foran, Han W Tun, Gerardo Colon-Otero, Asher Alban Chanan-Khan, Sikander Ailawadhi
Journal: Blood (2014)
Reliability of ER, PR, and HER2 status in core needle biopsy.
Authors: Hee-Chul Shin, Heeju Sohn, Hee Sung Kim, Sung Jun Park
Journal: Journal of Clinical Oncology (2015)

e11503 Background: It has become important in the preoperative work up of breast cancer patients to analyze estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki67 in core needle biopsy (CNB). These factors reflect response or resistance to endocrine therapy, chemotherapy and target therapy. Furthermore, factors help to select adjuvant or neoadjuvant treatment. For accuracy of ER, PR, HER2, and Ki67 in CNB, we compared the results of CNB and those of surgical specimen. Methods: We retrospectively reviewed data from 161 breast cancer patients whose ER, PR, HER2, and Ki67 were analyzed in both CNB and surgical specimen between 2013 and 2014. Patients who received neoadjuvant chemotherapy were exclued in this study. ER, PR, and Ki67 were determined by immunohistochemistry (IHC) and reported as percentage. The cut-off point for ER and PR was 1%, and for Ki67 was 14%. HER2 was determined by IHC and/or fluorescence in situ hybridization (FISH). HER2 positive was defined as IHC 3+ or FISH (+). Results: The mean percentage in CNB and surgical specimen were 59.4% and 58.9% for ER, 46.1% and 44.6% for PR, and 24.0% and 26.8% for Ki67. The expression difference between CNB and surgical specimen for ER and PR were not statistically significant (P = 0.681 and P = 0.455, respectively). However, Ki67 level in surgical specimen was higher than that in CNB with statisticall significant (P = 0.038). According to cut off value, ER, PR, HER2, and Ki67 were divided into positive and negative. The sensitivity of ER, PR, HER2 and Ki67 in CNB were 92.4%, 96.3%, 100%, and 81.7%, respectively. The specificity of ER, PR, HER2 and Ki67 in CNB were 85.7%, 81.7%, 97.9%, and 91.2%, respectively. The positive predictive value(PPV) and negative predictive value(NPV) of CNB were 94.8% and 80.0% for ER, 91.2% and 91.7% for PR, 93.5% and 100% for HER2, and 94.5% and 72.9% for Ki67, respectively. Conclusions: The ER, PR, HER2 in CNB were generally well correlated with those in surgical specimen. Especially, HER2 status of CNB was the most accurate factor compared with surgical specimen. When we consider neoadjuvant HER2-targeted agents, HER2 status based on CNB can be very useful and reliable result. Ki67 level in CNB was slightly lower than that in surgical specimen.