tbuckley/cabot-search huggingface dataset:
EGFR ligands and ERCC1 mRNA expression to predict clinical outcome in Japanese (JPN) patients (pts) with metastatic colorectal cancer (mCRC) harboring overexpressed EGFR and <i>KRAS</i> exon 2 wild-type (<i>KRAS</i> wt) treated with cetuximab (cet) plus oxaliplatin-based chemotherapy (JACCRO CC-05/06 AR).
Authors: Yu Sunakawa, Wataru Ichikawa, Akihito Tsuji, Miriana Moran, Stephanie H. Astrow, Dongyun Yang, Wu Zhang, Takehiro Takahashi, Tadamichi Denda, Ken Shimada, Mitsugu Kochi, Masato Nakamura, Masahito Kotaka, Yoshihiko Segawa, Masahiro Takeuchi, Heinz-Josef Lenz, Masashi Fujii, Toshifusa Nakajima
Journal: Journal of Clinical Oncology (2015)

618 Background: Previous studies have reported that EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), are potential predictive markers for cet and high ERCC1 expression is associated with resistance to platinum-containing chemotherapy. However, there are still few studies to assess predictive values of these expression levels in JPN mCRC pts. The aim of this study was to evaluate the values in JPN mCRC pts treated with cet. Methods: This study enrolled 77 pts with tissue available from 2 prospective clinical trials evaluating combination of cet with oxaliplatin-based chemotherapy as first-line treatment in pts with KRAS wt and EGFR-expressing tumors, modified FOLFOX6 (n=28/57, UMIN000004197) and SOX (n=49/67, UMIN000007022). Total RNA isolated by macro-dissection from tissue was screened by RT-PCR for mRNA expression levels of AREG, EREG, and ERCC1, the cut-off values of which were based on the optimal cut-off value using the maximal chi-square approach on tumor response with adjusted p values. The same cut-off values were used to evaluate associations with progression-free survival (PFS) and overall survival (OS). Results: Median age and follow-up time were 63 (range: 39-79) years old and 24.7 (range: 5.5-39.3) months, respectively. In 73 evaluable pts, response rate (RR) was 77 % (95% CI, 67 to 86), but no significant association was seen in RR. Pts with high AREG expression (&gt;1.59) had significantly longer PFS (11.6 vs. 6.6 months, HR: 0.53, logrank p=0.047) but not OS in 67 assessable pts. Pts with low ERCC1 expression (≤1.35) had significantly longer OS (42.8 vs. 22.0 months, HR: 2.46, logrank p=0.014) but a trend toward longer PFS (11.6 vs. 8.9 months, HR: 1.63, logrank p=0.092) in 68 assessable pts. On the other hand, high EREG expression (&gt;3.21) was not associated with clinical outcome in 64 assessable pts. Conclusions: Our study identified predictive roles for AREG and ERCC1 mRNA expression in JPN mCRC pts treated with cet plus oxaliplatin. However, extended RAS mutations analysis is warranted (UMIN000010635).
Abstract P394: Health Literacy Within a Diverse Community-Based Cohort: The Multi-Ethnic Study of Atherosclerosis
Authors: Madison Anderson, Sharon Stein Merkin, Susan A. Everson Rose, Rachel Widome, Teresa Seeman, Carlos Rodriguez, Pamela L. Lutsey
Journal: Circulation (2019)

Introduction: In 2018 the American Heart Association released a Scientific Statement on the importance of health literacy to cardiovascular disease (CVD) primary and secondary prevention. Health literacy has been defined as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.” However, most studies exploring the prevalence of health literacy have been conducted in populations that were demographically relatively homogeneous. Hypothesis: Using cross-sectional data from the race-ethnically diverse, sex-balanced and community-based Multi-Ethnic Study of Atherosclerosis (MESA), we tested the hypotheses that low health literacy was associated with older age, lower income and less acculturation. Methods: Four standard questions assessing health literacy were asked during annual phone follow up encounters which took place from August 2016 through August 2018. The questions assessed: 1) ability to read materials received from a doctor, 2) problems learning about health conditions, 3) confidence in filling out medical forms, and 4) understanding of medical statistics. Consistent with prior literature, responses to the 4 questions were combined into a composite score, and then a dichotomous variable was created to classify health literacy as low or adequate. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated, adjusted for age, sex, and race/ethnicity. Race/ethnicity-stratified associations were also explored. Results: Our sample consisted of 3,638 adults ages 53-94 years (median, 69), including 1,513 White, 445 Chinese, 936 Black, and 734 Hispanic participants. A total of 15.4% had low health literacy, which was more common among elderly [PR (95% CI) for ≥70 years vs. &lt;70 years: 2.24 (1.92, 2.61)], female [1.23 (1.07, 1.42)] and lower income [3.56 (2.82, 4.49)] participants, respectively. A higher prevalence of low health literacy was observed among participants who were Chinese, [PR (95% CI): 5.22 (4.15, 6.55)] Hispanic [4.94 (3.97, 6.14)], and Black [1.35 (1.01, 1.79)], relative to white participants. Acculturation factors such as non-US place of birth, fewer generations in the United States, and language other than English spoken in the home were all also associated with lower health literacy. When stratified by race/ethnicity, patterns of health literacy with age, sex, income and acculturation were similar to findings from the full study population. Conclusions: Within a diverse population low health literacy was more common among individuals who were older, female, had lower income, and were less acculturated. Since patients with low health literacy may need additional support to optimize their cardiovascular health, our results illustrate possible priority populations for health education intervention.
Racial disparities in late-stage prostate cancer: A SEER database analysis 2005–2015.
Authors: Jianqing Lin, Stephanie Rodriguez, Hanbing Zhou, Andrew D Sparks, Samuel J. Simmens, Richard Amdur
Journal: Journal of Clinical Oncology (2019)

115 Background: Incidence of metastatic prostate cancer in U.S. males has increased over the past ten years, but it is unknown how this trend varies over time within different racial and ethnic populations. Methods: We identified all men first diagnosed with prostate cancer from 2005-2015 in the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, which monitors 18 population-based cancer registries. Yearly cancer diagnosis frequency from 2005 to 2015 was categorized and analyzed by stage (in situ/localized, regional, and distant), race/ethnicity [White, Asian American/Pacific Islander (AAPI), Black], and age group (45-54, 55-69, 70-75). Chi-square tests, multivariable logistic regression models were used for data analysis with p &lt; 0.05 considered significant. Results: In the 10-year study period, the proportion of regional-stage prostate cancer increased from 14.2% to 16.6% of cases (p &lt; .0001) and distant-stage increased from 3.3% to 5.8% (p &lt; .0001). The odds of being diagnosed with regional-stage prostate cancer in 2013-2015 compared to 2005-2008 were 1.3 times higher for Black men (95% CI: 1.2-1.5), 1.3 times higher for AAPI men (95% CI: 1.1-1.5), and 1.2 times higher for White men (95% CI: 1.2-1.3). The odds of being diagnosed with distant-stage prostate cancer in 2013-2015 compared to 2005-2008 were 1.6 times higher for Black men (95% CI: 1.4-1.9), 1.8 times higher for AAPI men (95% CI: 1.5-2.3), and 2.1 times higher for White men (95% CI: 1.9-2.2). Conclusions: The incidence of late-stage prostate cancer has increased significantly in all US male despite race and ethnicity. However, reginal-stage prostate cancer increased the most over time in AAPI and Black men, while newly-diagnosed distant prostate cancer increased the most over time in White men.
Regulation of NGF Signaling by an Axonal Untranslated mRNA
Authors: Hamish Crerar, Emily Scott-Solomon, Chantal Bodkin-Clarke, Catia Andreassi, Maria Hazbon, Emilie Logie, Marifé Cano-Jaimez, Marco Gaspari, Rejji Kuruvilla, Antonella Riccio
Journal: Neuron (2019)

Neurons are extraordinarily large and highly polarized cells that require rapid and efficient communication between cell bodies and axons over long distances. In peripheral neurons, transcripts are transported along axons to growth cones, where they are rapidly translated in response to extrinsic signals. While studying Tp53inp2, a transcript highly expressed and enriched in sympathetic neuron axons, we unexpectedly discovered that Tp53inp2 is not translated. Instead, the transcript supports axon growth in a coding-independent manner. Increasing evidence indicates that mRNAs may function independently of their coding capacity; for example, acting as a scaffold for functionally related proteins. The Tp53inp2 transcript interacts with the nerve growth factor (NGF) receptor TrkA, regulating TrkA endocytosis and signaling. Deletion of Tp53inp2 inhibits axon growth in vivo, and the defects are rescued by a non-translatable form of the transcript. Tp53inp2 is an atypical mRNA that regulates axon growth by enhancing NGF-TrkA signaling in a translation-independent manner.
Prophylactic cranial irradiation (PCI) significantly decreases risk of brain metastases in patients with bulky, higher stage small-cell urothelial cancer.
Authors: Seungtaek Choi, Matthew T Campbell, Amishi Yogesh Shah, Neema Navai, Ashish M. Kamat, Colin P.N. Dinney, Quynh Nguyen, Arlene O. Siefker-Radtke
Journal: Journal of Clinical Oncology (2019)

486 Background: Patients with bulky, higher-stage small cell urothelial cancer (≥T3b, N+, and/or M+) have a high risk of developing brain metastases. Siefker-Radtke et al reported a 50% risk of brain metastases in this patient population. Therefore, a prospective trial evaluating the potential benefit of PCI was undertaken. Methods: Thirty patients with stage ≥T3b, N+, and/or M+ disease (without brain metastases on MRI) were treated between 12/2008 and 5/2018 with PCI. Patients were treated to a total dose of 30 Gy in 2 Gy fractions over 3 weeks. The patient had baseline brain MRI and mini-mental status exam (MMSE) before the treatment began. After treatment, patients underwent MRI and MMSE every 3-4 months for one year and every 6 months thereafter. If the patients did not have M+ disease at diagnosis, they were also treated with neoadjuvant chemotherapy (usually consisting of cisplatin/etoposide alternating with Adriamycin/ifosfamide), followed by a radical cystectomy. The PCI was either given between the last cycle of chemotherapy and surgery or after the surgery. Both acute and chronic toxicity from PCI were measured using CTCAE 3.0. Change in the MMSE after PCI was evaluated using a t-test. Results: Twenty-nine patients were evaluable. Twenty-four patients had ≥T3b and/or N+ disease and 5 patients had M1 disease. Median follow-up was 22 months (range 8-103 months). Four patients have developed brain metastases with a median time of 11.5 months after PCI (range 3-23 months). Two of these patients have died. Nine other patients have died from progressive systemic disease, but they did not have evidence of brain metastases. PCI was well-tolerated, with no grade ≥2 toxicity seen. Acute grade 1 toxicity seen included headache, nausea, and dermatitis. MMSE were available for 19 patients with a median follow-up of 13 months (range 3-87 months). There was no significant change in the MMSE scores after the PCI when compared to baseline (p = 0.61). Conclusions: In this study, PCI decreased the risk of developing brain metastases in patients with bulky, higher-stage small cell urothelial cancer from 50% (historical) to 13.8% without significant toxicity. Clinical trial information: NCT00756639.
BL1 gene expression subtype to predict outcome in serous ovarian cancers.
Authors: Rob Seitz, David Richard Hout, Stephan Wade Morris, Brian Z Ring
Journal: Journal of Clinical Oncology (2015)

5574 Background: A new 2188-gene model classifies triple-negative breast cancer (TNBC) into six distinct subtypes: two basal-like, two mesenchymal-like, immunomodulatory and luminal androgen receptor subtypes. Among taxane-treated TNBC patients, significantly higher response rates were seen in patients with BL1 compared to BL2 tumors. Recently we showed that a “lean algorithm” of 101 genes could replicate this result in TNBC patients. As TNBC and serous ovarian cancer share many features, similar sub-classification of ovarian cancers may also be clinically important. Methods: A cohort of 592 patients with serous ovarian carcinoma (primarily platinum/taxane-treated) was analyzed. Patients were classified using both the original 2188-gene and 101-gene centroid models. Patients who had an insignificant or multiple statistically indistinguishable correlations with the subtype centroids were considered “unclassified.” Three-year survival was examined using log-rank test and Cox proportional hazard regression analysis. Results: While both models had a higher percentage of unclassified patients in ovarian as compared to TNBC, the 101-gene model classified more patients (60%) than the 2188-gene model (34%). In the subset classified by both models, the models showed 95% agreement. Ovarian cancer patients with BL1 tumors had significantly better 3-year overall survival compared to all other subtypes (hazard ratios of 0.48 and 0.41, p = 0.02 and 0.01, 2188 and 101-gene models respectively). If age and stage—both independent predictors of survival—were included as covariates, only the 101-gene model defined BL1 subtype had a significant association with outcome (HR 0.47, p = 0.02). Conclusions: There was excellent agreement between the original 2188-gene TNBC classifier and a streamlined 101-gene classifier when applied to an ovarian cancer cohort. BL1-classified ovarian cancer patients had significantly better 3-year survival outcomes than patients with tumors of other subtypes; however, only the 101-gene classification of the BL1 subtype was independent of age and stage. Studies aimed at the refinement of gene expression-defined serous ovarian carcinoma subtypes that can guide therapeutic management will be presented.
Drug development for breast (BC), colorectal (CRC), and non-small cell lung cancers (NSCLC) over the past 34 years.
Authors: Nancy Alice Nixon, Omar Farooq Khan, Patricia A. Tang, Jose Gerard Monzon, Haocheng Li, Hasiba Imam, Doreen Ezeife, Sunil Parimi, Scot D. Dowden, Vincent Channing Tam
Journal: Journal of Clinical Oncology (2015)

e17789 Background: The purpose of this study was to delineate the drug development timeline and attrition rate of different drug classes for common cancer disease sites. Methods: A pharmaceutical business intelligence database (Citeline Pharmaprojects) was used to identify drugs entering clinical trials specifically for BC, CRC, and NSCLC from 1980 to 2014. Data regarding drug characteristics, clinical trials and approval dates were obtained from the database, clinical trial registries, PubMed and FDA website. Comparisons were made using Chi-squared and Fisher’s exact tests. Results: A total of 411 drugs met our inclusion criteria for BC, 246 for CRC and 315 for NSCLC (see table). A larger percentage of drugs reached phase II (P2) trials for NSCLC compared to BC (p = 0.02). Phase transition probabilities did not differ for the three tumor sites. Immuno-modulators/cancer vaccines were less likely to transition between phase I (P1) and P2 than other drug classes for BC (p < 0.001). Tyrosine kinase inhibitors were more likely to transition between P1 and P2 for BC (p = 0.001), but not for CRC or NSCLC. Cytotoxic chemotherapy and tyrosine kinase inhibitors were more likely to transition between P2 and phase III (P3) in NSCLC (p = 0.001). Conclusions: Specific drug classes have higher success rates in different cancer types. More research is required to determine whether this is due to differences in drug efficacy or limitations in preclinical models and trial design. BC (n = 411) CRC (n = 246) NSCLC (n = 315) Number of Drugs in Each Class (%) Chemotherapy Targeted antibody Tyrosine kinase inhibitor Immuno-modulator/Vaccine Other 100 (24%) 55 (13%) 86 (21%) 45 (11%) 125 (30%) 65 (26%) 49 (20%) 48 (20%) 34 (14%) 50 (20%) 80 (25%) 51 (16%) 74 (24%) 31 (10%) 79 (25%) Number of Drugs Reaching Each Phase of Development (%) P1 P2 P3 FDA Approval 411 (100%) 350 (85%) 92 (22%) 25 (6%) 246 (100%) 212 (86%) 43 (18%) 10 (4%) 315 (100%) 289 (92%) 80 (25%) 10 (3%) Phase Transition Probability (%) P1 - P2 P2 - P3 P3 - FDA Approval P1 - FDA Approval 91% 36% 38% 10% 92% 30% 33% 7% 94% 39% 19% 5% Mean Development Duration (Years) P1 P2 P3 2.8 2.6 3.6 2.8 3.2 4.4 2.8 2.7 3.0 Mean Time From P1 Start to P3 End (Years) 8.6 7.2 7.9
Implementation of a sequential screening process for depression in humanitarian crises: a validation study of the Patient Health Questionnaire in Syrian refugees
Authors: Danielle Poole, Shirley Liao, Elysia Larson, Bethany Hedt-Gauthier, Nathaniel Raymond, Till Börnighausen
Journal: The Lancet Global Health (2019)

BackgroundDespite the urgency of mental health surveillance and treatment in humanitarian emergencies, there has been little evaluation of instruments that keep response burden to a minimum. We aimed to evaluate a sequential screening process for the detection of major depressive disorder that improves the efficiency of screening-confirmation procedures using the two-item and eight-item Patient Health Questionnaires (PHQ-2 and PHQ-8, respectively) in a refugee population.MethodsWe analysed data from a cross-sectional survey completed by Syrian refugees in a camp in Greece between January and February, 2017. All survey items were translated to and back-translated from Arabic. Face-to-face interviews took place in an area with audio privacy. We used logistic regression to measure the correlation between the PHQ-2 classification and the summed score of the remaining six items of the PHQ-8, and used empirical data to simulate the sequential screening process for major depressive disorder. The sequential process replicates the diagnoses captured if the PHQ-2 were used to narrow the population who would complete the full PHQ-8 assessment. First, respondents complete the PHQ-2; next, only respondents who score above a threshold are considered at risk for depression and complete the remaining six items. We compared the positive and negative percent agreement of the PHQ-2 and sequential screening process. Response burden was assessed through item and instrument completion.FindingsWe included data from 135 respondents, representing 40% of the adult population in the refugee camp at the time of the survey. Mean age was 30 years (range 18–61 years); 41% of respondents were women. The PHQ-2 and PHQ-8 instruments were completed by 123 (91%) and 113 (84%) respondents, respectively (p=0·014). The scores of the PHQ-2 and remaining six items of the PHQ-8 were significantly correlated (p<0·001). Using a cut-off score of ≥2, the sequential screening process is 90% sensitive using the PHQ-8 classification as the reference standard with a 100% negative agreement, meaning there were no false negative classifications. The sequential screening process eliminated the completion of the full PHQ-8 instrument for 34 respondents (25%). The PHQ-2 model did not lack a predictor explaining a significant proportion of the variation (deviance information criterion: p=0·395).InterpretationThe sequential screening process detected 90% of people who had symptoms consistent with major depressive disorder. Concurrent validity of the PHQ-2 and PHQ-8 was shown. Our results suggest that this sequential screening approach is a useful strategy to streamline surveillance of major depressive disorder in humanitarian contexts with a scarcity of mental health specialists while simultaneously reducing the response burden.FundingNone.
Abstract 018: New York City Youth Cardiovascular Fitness and Subsequent School Absenteeism Have an Inverse, Dose-Response Relationship, Regardless of How Poverty is Measured
Authors: Emily M D’Agostino, Sophia E Day, Kevin J Konty, Katarzyna Wyka
Journal: Circulation (2019)

Introduction: Recent research demonstrates that cardiovascular fitness improvements are associated with lower absenteeism, particularly for girls attending schools located in high poverty neighborhoods. Poverty at the student, school, and neighborhood levels may each have unique effects on both cardiovascular fitness and school absenteeism. There is a need to simultaneously explore the effects of poverty measures collected at different levels of observation on the longitudinal fitness-absenteeism relationship and across gender in order to inform policy targeting reduced school absenteeism. Hypothesis: It was hypothesized that poverty measured at the neighborhood level would have the strongest magnitude of effects on the cardiovascular fitness-absenteeism relationship compared with poverty measured at the school and student levels. Methods: Data for this study were drawn from the New York City Fitnessgram dataset. Inclusion criteria were enrollment in a New York City public school for at least 2 consecutive years in grades 6-8 (2006-2013) while attending a school that collected Fitnessgram measurements. Negative binomial longitudinal mixed models with random-intercepts were run to test the association between the exposure, child-specific change in cardiovascular fitness from the year prior, and the outcome, days absent the subsequent year. Separate crude and adjusted models were run stratified by student (individual household), school (percent of students living in poverty or qualifying for free/reduced price school meals) and neighborhood (home- and school-area) poverty measures, and also by gender. Models were adjusted for individual- and group-level confounders (time, grade, race/ethnicity, place of birth, change in obesity status, and school size), and clustering by individual student and school. Results: The sample included 360,743 students (67% black or Hispanic, 51% male, 69% qualifying for free/reduced price school meals). Adjusted estimates showed an inverse-dose response fitness-absenteeism relationship across all poverty measures, with the highest magnitude of effects for youth attending schools in high poverty neighborhoods (IRR= -0.12, 95%CI: -0.20, -0.04 in girls; IRR= -.13, 95%CI: -.29, .03 in boys), and in girls attending schools with a high proportion of students qualifying for free/reduced school meals (IRR= -.11, 95%CI: -.23, -.01). Conclusions: In conclusion, there is an inverse, dose-response trend between cardiovascular fitness and subsequent absenteeism in high poverty youth, regardless of how poverty is measured, and particularly among girls. Future research should examine the potential for distinct youth physical activity interventions tailored to the individual, school and neighborhood levels to reduce school absenteeism associated with poverty.
Evolutionary Rates of Bumblebee Genomes Are Faster at Lower Elevations
Authors: Gonghua Lin, Zuhao Huang, Lei Wang, Zhenhua Chen, Tongzuo Zhang, Lennard N Gillman, Fang Zhao
Journal: Molecular Biology and Evolution (2019)

The importance of climate in determining biodiversity patterns has been well documented. However, the relationship between climate and rates of genetic evolution remains controversial. Latitude and elevation have been associated with rates of change in genetic markers such as cytochrome b. What is not known, however, is the strength of such associations and whether patterns found among these genes apply across entire genomes. Here, using bumblebee genetic data from seven subgenera of Bombus, we demonstrate that all species occupying warmer elevations have undergone faster genome-wide evolution than those in the same subgenera occupying cooler elevations. Our findings point to a critical biogeographic role in the relative rates of whole species evolution, potentially influencing global biodiversity patterns.