tbuckley/cabot-search huggingface dataset:
Phase I study of sorafenib (S) with bevacizumab (B) and paclitaxel (P) in patients (pts) with refractory solid tumors.
Authors: E. G. Chiorean, D. Matei, A. Younger, J. M. Funke, M. J. Waddell, D. R. Jones, N. M. Hahn, S. M. Perkins, K. Sandrasegaran, C. Sweeney
Journal: Journal of Clinical Oncology (2010)

3043 Background: Prior data of dual VEGF-ligand/receptor blockade with B and S showed promising efficacy. P is active against many tumor types, and combined with B improves efficacy in breast and lung cancers. We conducted a phase I study to determine the safety and MTD of P with B and S. Methods: Eligible pts had good organ function, ECOG PS 0-1, and may have had prior therapy with P and either B or S. The study had a standard “3+3” design, using P 80 mg/m2 weekly × 3 q4wks cycle, B 5 mg/kg q2wks and escalating S from 200 mg BID, dosed 5 or 7 days/wk (5/7 or 7/7). The MTD cohort was expanded for further safety analysis. PK analyzes were performed for P and S at baseline and on cycle (C) 1 d15. Pharmacodynamic (PD) evaluations included dynamic contrast-enhanced magnetic resonance imaging. Results: 23 ptswere enrolled, M/F: 6/17, median age 55 yrs (29-75); PS: 0/1=16/7. The Table summarizes dose levels, DLTs, and the MTD. Ten pts at MTD required S dose reductions to 5/7 or QD dosing beyond C2. The most common toxicities were hand-foot skin reaction (HFSR) (17), alopecia (16), hypertension (HTN) (15), mucositis (12), and sensory neuropathy (10). Grade (Gr) 3/4 toxicities were HTN (7), HFSR (5), neutropenia (4), neuropathic pain (2) and mucositis (2), and 1 pt each with CVA, colon/bladder perforation, port-related DVT and P infusion reaction. Pts received a median of 5 cycles (1-19). One pt discontinued study in C1 due to CVA. Among 19 evaluable pts, 3 had CR (ovarian, endometrial, and urachal cancers), 8 PR (6 ovarian, 1 endometrial, 1 prostate), and 8 SD. Median response duration was 26 wks (10-58). PK analysis showed no significant interaction between P and S. Pretreatment Ktrans were higher in responders than nonresponders (p=0.03). Conclusions: While P+B+S was associated with increased toxicity, it demonstrated impressive efficacy across all dose levels. The recommended phase II dosing is P 80 mg/m2, B 5 mg/kg, and S 200 mg BID 5/7, based on data from the expansion cohort and long-term tolerability. Cohort (#pts) P (mg/m2) B (mg/kg) S (mg) # DLT DLT 1 (6) 80 5 200 BID 5/7 1 Gr 3 neutropenia > 7d 2 (MTD) (6) 80 5 200 BID 7/7 1 Gr 3 HTN 3 (2) 80 5 400 BID 5/7 2 Gr 3 HFSR × 2 2 (9) 80 5 200 BID 7/7 4 Gr 3 HFSR MTD expansion Gr 4 CVA + Gr 3 HTN Gr 3 neutropenia > 7 d S held >7d for Gr 2 HFSR Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Genentech, Roche Bayer, Genentech, Onyx
Noninvasive Assessment of Cardiopulmonary Reserve: Toward Early Detection of Pulmonary Vascular Disease
Authors: Timothy J. Baillie, Samuel Sidharta, Peter M. Steele, Stephen G. Worthley, Scott Willoughby, Karen Teo, Prashanthan Sanders, Stephen J. Nicholls, Matthew I. Worthley
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Gene expression in prostate tissue according to frequency of ejaculation.
Authors: Jennifer R. Rider, Jennifer A Sinnott, Lorelei A. Mucci
Journal: Journal of Clinical Oncology (2016)

25 Background: Long-term prospective data from within the Health Professionals Follow-up Study (HPFS) suggest more frequent ejaculation throughout adult life may be protective against future development of prostate cancer (PCa). Compared to men with an average monthly ejaculation frequency (EF) of 4-7 times/month during adulthood, men who ejaculated at least 21 times per month were 30% less likely to be diagnosed with PCa after adjustment for a number of potential confounders and PCa screening. We sought to explore mechanisms through which EF may influence PCa development utilizing gene expression data assessed on tumor and adjacent normal tissue. Methods: In 1992, 31,925 HPFS participants were questioned on their average monthly EF at ages 20-29, 40-49, and in the previous year; 3,839 of these men were later diagnosed with PCa. Expression of 20,254 genes was available from archival tumor tissue from 156 cases; 84 of these cases also had data from adjacent normal tissue. We regressed each gene expression value as a continuous outcome on EF, age at diagnosis, and year at diagnosis. We calculated the p value associated with the coefficient for the EF variable as a measure of the strength of the trend test. We then used t values for the coefficients to rank the genes, and ran a gene set enrichment analysis to identify pathways with genes associated with EF. Results: We observed that while there was not much signal in the tumor tissue, there was enrichment of smaller p values in the adjacent normal tissue. EF in the time period most proximal to diagnosis is most strongly associated with gene expression in normal tissue. Focusing on the association between gene expression in normal tissue and EF in the year prior to the questionnaire (1991), the top six differentially expressed genes were OR4K1, CCDC138, SERPINA9, TRMT61B, ZNF302, and ASB4. Gene set enrichment analysis revealed a substantial number of pathways differentially expressed at the FDR &lt;0.05 threshold. Conclusions: Identifying changes in gene expression associated with EF in normal prostate tissue provides further support for a biological role of ejaculation frequency in the etiology of PCa. Notably, pathways downregulated with increasing ejaculation frequency were primarily immune related.
Improving the prediction of colon cancer survival after curative resection.
Authors: Aliyah Pabani, Winson Y. Cheung, Matthew Mazurek, Jennifer L. Spratlin, Karen E. Mulder, Sunita Ghosh, Julie A. Price Hiller, Leah Jean Standeven, Maria Yi Ho
Journal: Journal of Clinical Oncology (2015)

552 Background: Cancer staging systems convey valuable prognostic information to both clinicians and patients. Currently, colon cancer is staged according to the American Joint Committee on Cancer (AJCC) TNM classification system. However, survival estimates for patients with the same stage of colon cancer may vary considerably due to other factors including age, sex, grade, and number of lymph nodes sampled. The objectives of this study are to 1) assess the accuracy of the seventh edition of the TNM classification system in predicting survival of patients with primary colon cancer after curative-intent surgery, and 2) evaluate the utility of incorporating additional demographic and tumor variables beyond TNM staging in improving prognostic accuracy. Methods: Patients with curative-intent resection of a first primary adenocarcinoma of the colon at the time of referral to the Cross Cancer Institute between 2004 and 2007 were identified from the Alberta Cancer Registry. We constructed three multivariate Cox’s proportional hazard models to explore the effect of supplementing TNM staging with additional demographic and tumor variables in predicting overall survival (OS). Results: 559 consecutive patients with complete chart records were identified. 52 % (n=290) were male; median age was 74. In the first model based only on T and N elements, N2 disease was correlated with increased mortality (hazard ratio [HR], 2.546; p&lt;0.0001). When the number of lymph nodes examined (HR, 0.980; p=0.034) and number of metastatic lymph nodes detected (HR, 1.094; p&lt;0.0001) were substituted for the N-staging element, both variables correlated positively and negatively with outcome, respectively. Finally, when tumor grade, sex and age were incorporated into the model, number of examined lymph nodes (HR, 0.980; p=0.029) and those containing tumor (HR, 1.093; p&lt;0.0001) remained independent predictors of OS. Conclusions: Incorporating readily available demographic and tumor variables, such as age, sex and number of lymph nodes examined, can enhance the current TNM staging system and improve prognostication in early stage colon cancer.
Patterns of adjuvant systemic therapy in elderly with breast cancer (BC)
Authors: R. Yelamanchili, T. Koru-Sengul, V. Pavlova, C. Phillips, A. Ali, B. Dhesy
Journal: Journal of Clinical Oncology (2008)

11597 Background: Studies indicate that elderly BC patients are undertreated with adjuvant systemic therapy. Methods: We conducted a retrospective chart review of women over 70 yrs of age, with stages I-III BC, referred to Juravinski Cancer Centre, Ontario, Canada, in 2004. Primary objective was to determine the proportion of patients (pts) receiving adjuvant systemic treatment, reasons for non- receipt and correlation with Charlson’s comorbidity score. Results: One hundred twenty-two charts met the inclusion criteria. Median follow-up was 31 months. Median age was 76 yrs, 83.6% (102) were hormone receptor (HR) positive, 28.6% (35) lymph node (LN) positive, 41.8% (51) LN negative, 29.5% (36) had no LN dissection.15.5% (19) had chemotherapy (CT), 57.4% (70) had hormone therapy (HT), 66.39% (81) received CT, HT or both. Among the 103 patients who did not receive CT, 36.8% (38) were considered low risk (low grade, LN negative), 15.5% (13) pts declined CT. 47.5% (49) were deemed ineligible by physicians (due to comorbidities [10], age [10], no lymph node dissection with otherwise low-risk features [18] and no reason mentioned in 11 pts). 31.3% (32) HR positive pts did not receive HT. 50% (10) HR negative pts received CT. 11.4% (14) had recurrence, 8 systemic, 4 local, 2 both. There were 20 (16.3%) deaths and 7.4% (9) were due to BC, with no deaths due to treatment toxicity. NCI Grade 3 or 4, toxicity was seen in 9.8% (8). No correlations were found between treatment decisions, survival, recurrence, toxicity and Charlson’s comorbidity score. In pts with LN positive, HR positive disease, CT+HT improved OS (HR=0.04; 95% CI: 0.007, 0.247), and DFS (HR=0.028; 95% CI: 0.002, 0.327). HT alone, also improved OS (HR=0.069; 95% CI: 0.011, 0.425) and DFS (HR=0.048; 95% CI: 0.004, 0.559) in this subgroup. Similar benefits were not seen with CT alone (HR=0.33; 95% CI: 0.07, 1.58). Conclusions: One third of elderly BC patients over 70 yrs of age did not receive adjuvant systemic therapy, primarily due to low perceived benefit-risk ratio. The benefits of adjuvant treatment were limited to LN positive, HR positive pts. Numbers may have been too small to detect effects in HR negative pts. No significant financial relationships to disclose.
Estimation of the likelihood of epidermal growth factor receptor (EGFR) mutations based on cigarette smoking history in patients with adenocarcinoma of the lung
Authors: D. Pham, M. G. Kris, T. McDonough, G. J. Riely, E. S. Venkatraman, W. Pao, R. K. Wilson, V. A. Miller, B. Singh, V. W. Rusch
Journal: Journal of Clinical Oncology (2005)

7069 Background: Lung adenocarcinomas with EGFR mutations demonstrate sensitivity to gefitinib or erlotinib. Unfortunately, the majority of patients with lung adenocarcinoma have inadequate tumor specimens to permit EGFR sequencing prior to treatment. Pao (Pao W. PNAS 2004) and others reported a higher incidence of EGFR mutations in never smokers. In this study we characterized features of a smoking history that predict for the presence of EGFR mutations. Methods: EGFR exons 18–24 were sequenced in 127 tumor samples using standard polymerase chain reaction techniques. Smoking histories with age at first cigarette, packs per day, number of smoking and smoke-free years were obtained. Patients were categorized as never smokers (<100 lifetime cigarettes), former smokers (quit ≥1 year ago), or current smokers (quit <1 year ago). The Fisher’s exact and Wilcoxon’s rank tests were used. The receiver operating characteristic (ROC) curve methodology assessed the ability of smoking history parameters to predict the likelihood of a mutation in EGFR. Results: We detected EGFR mutations in 17/32 never smokers (53%, 95% CI 35–71%), 8/62 former smokers (13%, 95% CI 6–24%) and 2/33 current smokers (6%, 95% CI 1–20%). The incidence of EGFR mutations and number of pack years smoked is in the table below. The areas under the ROC curves for pack years of smoking and years smoke-free are 0.84 and 0.77, respectively. Conclusions: EGFR mutations correlate with smoking history. The likelihood of EGFR mutations decreases as the number of pack years smoked increases. The optimal smoking history parameters identified are <10 pack years and >25 smoke-free years. These data can assist clinicians in assessing the probability of mutations in EGFR, and sensitivity to gefitinib or erlotinib, in patients with lung adenocarcinoma. A smoking history may provide useful information when direct sequencing is not feasible. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Genentech AstraZeneca AstraZeneca
Predictors of treatment interruption/dose reduction of neoadjuvant chemotherapy for rectal cancer: A multicenter study.
Authors: Soundouss Raissouni, Dawn Elizabeth Armstrong, Julie A. Price Hiller, Jamison Mercer, Erin Diana Powell, Anthony MacLean, Maria Jiang, Corinne M. Doll, Rachel Anne Goodwin, Eugene Batuyong, Kevin Zhou, Jose Gerard Monzon, Patricia Tang, Daniel Yick Chin Heng, Winson Y. Cheung, Michael M. Vickers
Journal: Journal of Clinical Oncology (2014)

580 Background: Neoadjuvant chemoradiation (CRT) is the standard of care for patients with locally advanced rectal cancer. Many patients require dose reduction or chemotherapy interruption due to significant toxicities. To assess the predictors of neoadjuvant chemotherapy treatment (tx) adjustments, we performed a retrospective study in four Canadian provinces. Methods: Cancer Registries identified consecutive patients with clinical stage I-III rectal cancer from the Tom Baker Cancer Center, Cross Cancer Institute, BC Cancer Agency, Ottawa Hospital Cancer Centre and the Dr. H. Bliss Murphy Cancer Centre who received CRT and had curative intent surgery (Sx) from 2005 to 2012. Patient, tumor and tx characteristics were correlated with treatment completion. Results: Of the 891 patients included, 886 patients had tx dose adjustments data available. 738 (83.2%) completed the planned neoadjuvant chemotherapy, while 148 (16.7%) failed to complete planned chemotherapy. Patients who required tx interruption/cessation or dose reduction were more likely to be female, elderly, had higher ECOG PS and were treated with fluorouracil (FU) chemotherapy in univariate analysis (see Table). On multivariable analysis, female gender (OR 1.807, 95% CI 1.02-3.2, p=0.042) and tx with FU (vs capecitabine) (OR 2.7, 95% CI 1.52-4.77, p=0.0007) were associated with dose reduction and tx interruption/cessation. Conclusions: Gender and type of chemotherapy are predictors of neoadjuvant chemotherapy interruption or dose reduction in rectal cancer. Careful monitoring of these patients is warranted during neoadjuvant CRT. [Table: see text]
The effect of care at NCI comprehensive cancer centers on disparities in outcome in adolescents and young adults (AYAs) with cancer.
Authors: Julie Anna Wolfson, Can-Lan Sun, Heeyoung Kim, Tongjun Kang, Smita Bhatia
Journal: Journal of Clinical Oncology (2012)

217 Background: AYAs (15-39y at diagnosis) with cancer have not seen the survival improvement evidenced by younger and older age groups with similar diagnoses, leaving an AYA Gap. While treatment on pediatric protocols is associated with superior survival in 15-21y, impact of site of care on survival for vulnerable AYA subpopulations (race/ethnicity) between 22-39y at diagnosis remains unstudied. Methods: Utilizing a cohort of 10,602 AYAs newly diagnosed between 22-39y with lymphoma, leukemia, brain tumors, melanoma, thyroid and GU cancers, and reported to the Los Angeles County cancer registry between 1998 and 2008, we aimed to determine the impact of receiving care at NCI Comprehensive Cancer Centers (NCICCC) on overall survival for AYAs, and disparities in survival by race/ethnicity. We further aimed to understand the role of SES and insurance status in accessing care at NCICCC. Multivariable analyses included race/ethnicity, age at diagnosis, SES, insurance status, primary cancer diagnosis and diagnosis year in the model. Results: A total of 904 (9%) patients received treatment at the 3 NCICCC (City of Hope, Jonsson Cancer Center, and Norris Cancer Center) in LA County. Ten-year overall survival (10y OS) was significantly worse for patients treated at non-NCICCC (81%) when compared with those treated at NCICCC (83%, p=0.02). Also, 10y OS was worse for African Americans (AA) (68%) vs. non-Hispanic whites (86%, p&lt;0.0001). Multivariable analysis adjusting for SES, insurance status, diagnosis and diagnosis year revealed that AA (HR=1.5, p=0.0001) were at an increased risk of death. Among patients treated at NCICCC, the difference in risk of death due to race (HR=0.9, p=0.84) was abrogated. However, among patients treated at non-NCICCC, these differences in outcome persisted (HR=1.48, p&lt;0.0001). Independent of SES, insurance and tumor factors, AA (OR=0.44, p&lt;0.001) were less likely to use NCICCC. Conclusions: Population-based data reveal that receipt of care at an NCICCC abrogates the inferior outcome observed among AA with cancer. AA are less likely to use NCICCC for treatment. Barriers to accessing care at NCICCC are currently being explored.
Multiplexed protein and gene profiling of circulating tumor cells (CTCs) in metastatic castration-resistant prostate cancer (mCRPC) using automated immunofluorescence and fluorescence in situ hybridization.
Authors: Dea Nagy, Eric Tucker, Samatha Rajkovich, Steven French, Karl Garsha, Steve Yun, Katherine Smith, Karim Sallam, Elias Liabotis, Michael Otter, Dena Marrinucci, Ryan Dittamore
Journal: Journal of Clinical Oncology (2013)

158 Background: Clinically, CTCs are used primarily in longitudinal monitoring of metastatic disease progression. However, the analysis of specific CTC biomarkers has the potential to optimize patient management by identifying those likely to respond to specific targeted agents. Often, mCRPC is driven by dysregulation of the androgen receptor (AR) and phosphatidylinositol 3-kinase/protein kinase B (PI 3 K/AKT) oncogenic pathways such that blockade of one pathway stimulates the other. These functional deficits in the AR and PI3K/AKT pathways are associated with fusion of the TMPRSS2 and ERG genes and with loss of PTEN protein, respectively. Therefore, we sought to characterize CTCs for the simultaneous presence of both these biomarkers using immunofluorescence (IF) and fluorescence in situ hybridization (FISH). Methods: Nucleated peripheral blood cells from mCRPC patients were attached to slides and examined using CTC technology (Epic Sciences). Cytokeratin-positive/CD45-negative cells with an intact nucleus and a malignancy-consistent morphology were identified as CTCs, and their exact positions on the slides were recorded. The slides were then subjected to multiplex Quantum Dot IF and FISH procedures with anti-AR, -ERG, and -PTEN antibodies and 5’ERG, 3’ERG, PTEN, and Cen10 probes, respectively, on an automated slide-staining platform (Ventana Medical Systems, Inc.). The IF and FISH signals were visualized by spectral imaging (Ventana). Results: The automated IF/FISH staining procedure facilitated multiplex characterization of individual CTCs from patient samples for the protein biomarker targets AR, ERG, and PTEN and the genomic biomarker targets 5’ERG, 3’ERG, PTEN, and Cen10. Conclusions: This method for high-sensitivity, multiplex molecular characterization of critical CTC biomarkers in mCRPC patients might aid oncologists in identifying and stratifying those patients likely to respond to combination therapy with targeted PI 3 K/AKT inhibitors and anti-androgens/Cyp17 inhibitors. Patient trials examining the clinical utility of this assay in mCRPC are currently underway.
Laparoscopic D2 subtotal gastrectomy versus conventional open surgery for advanced gastric cancer: The safety analysis from a multicenter prospective randomized controlled trial in China (CLASS-01 trial).
Authors: Yanfeng Hu, Changming Huang, Yihong Sun, Xiangqian Su, Ziyu Li, Yingwei Xue, Jiankun Hu, Xianli He, Kaixiong Tao, Gang Zhao, Jian Suo, Hong-Bo Wei, Weiguo Hu, Mingang Ying, Xiaohui Du, Guoxin Li
Journal: Journal of Clinical Oncology (2015)

122 Background: The efficacy of laparoscopic D2 gastrectomy for the treatment of advanced gastric cancer (AGC) with curative intent is still controversial. Thus, the Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) group conducted a multicenter prospective randomized controlled trial, aiming to evaluate the surgical safety and long-term outcomes of laparoscopic D2 gastrectomy compared with conventional open surgery for AGC. (NCT01609309) Methods: The patients with tumor located at distal stomach at clinical T2-4a, N0-3, M0 stage were eligible for enrollment, treated by either laparoscopic D2 distal subtotal gastrectomy (LG) or open D2 gastrectomy (OG) after randomization. Seventeen institutions currently participated in the study. The morbidity and mortality within postoperative 30 days were compared between the two groups. Results: A total of 607 consecutive eligible patients were randomly assigned to either LG group (n=308) or OG group (n=299) between September 2012 and January 2014. The compliance rates of D2 lymphadenectomy in the LG group and OG group were similar (97.4% vs. 98.3%; P=0.591). Open conversion rate was 4.5%. There was no significant differences between the LG group and OG group in the incidence of intraoperative complication (5.8% vs. 4.3%; P=0.402), postoperative morbidity (18.8% vs. 14.7%; P=0.175), and mortality (0.6% vs. 0; P=0.499). The severity grade pattern was also similar according to the Clavien-Dindo classification (P=0.372). Conclusions: Laparoscopic D2 distal subtotal gastrectomy for AGC could be safely performed by experienced surgeons. Thus, our multicenter prospective study on long-term outcomes can be ongoing. Clinical trial information: NCT01609309.