tbuckley/cabot-search huggingface dataset:
Evaluation of VEGF targeted therapy efficacy in mRCC after sorafenib failure or intolerance
Authors: J. Hajdenberg, S. Oberoi, N. Cohen, O. Kayaleh, D. Harding, J. Tseng
Journal: Journal of Clinical Oncology (2007)

15517 Background: Sorafenib, a multi kinase targeted agent with raf and VEGF receptor (VEGF-R) inhibitory properties, has been recently approved for the treatment of metastatic renal cell carcinoma (mRCC). Two other VEGF pathway targeted agents, sunitinib and bevacizumab, have documented efficacy in mRCC. It is not known whether these agents will exhibit biological or clinical activity after prior VEGF directed treatment. Methods: Eligibility applied to patients with mRCC treated with sorafenib within an expanded access program (EAP) at our institution that were later switched to either bevacizumab or sunitinib due to tumor progression or sorafenib intolerance. All patients had measurable disease. Patients were evaluated for response rates (RECIST), treatment duration and progression free survival (PFS). Results: 35 patients that participated in the EAP were identified. 10 patients fulfilled the entry criteria and all of them had clear cell histology. Median age was 66; sex distribution was 70% male-30% female. 6 (60%) received sunitinib and 4 (40%) received bevacizumab. Median treatment duration was 5.5 months (range: 1–15). Of the patients evaluable for response: 5 have SD (50%), 1(10%) had a PR and 1(10%) progressed. 3 are too early to be evaluated. Median PFS was 7 months. Conclusions: Despite the limitations of a small patient sample, the VEGF targeted therapies sunitinib and bevacizumab exhibited a median PFS and reponse rate similar to those reported by other authors as a first line anti-VEGF therapy. Second line anti-angiogenic activity appears to retain efficacy in clear cell mRCC priorly treated with the multi- kinase targeted agent sorafenib. This may provide hypothetical justification for sustained anti-angiogenic therapy after progression. Prospective evaluation of serial and combination approaches is ongoing. No significant financial relationships to disclose.
Abstract A1-69: Predicting drug response by profiling the epigenome: Super-enhancers as biomarkers
Authors: David A. Orlando, Michael R. McKeown, Mei Wei Chen, Cindy Collins, Matthew G. Guenther, Christian C. Fritz
Journal: Cancer Research (2015)

Abstract Identifying biomarkers that predict clinical responses to anticancer therapies is an important challenge in oncology. A desirable biomarker is a cell-identifying feature that can distinguish between drug responsive and unresponsive cell types. Most of the best studied biomarkers are gene mutations or copy-number changes, where the genomic alteration is the key defining feature. However, not all differences in clinical responses can be attributed to genetic differences. Therefore, it is critical that we identify other cellular features that can predict response. A recently described epigenomic feature, termed super-enhancer (SE), defines key cell identity and disease genes and SEs are effectors of initiating and maintaining cell type-specific gene expression programs. In this work we generate super-enhancer maps across multiple cancer cell lines and connect those maps to response to different drug treatments. We show that super-enhancers can be used as biomarkers to predict response to drugs across multiple cell-line models of cancer. This work suggests that interrogating epigenomic features, and in particular super-enhancers, can be a powerful biomarker discovery platform and can enable rational patient selection and therapeutic strategies. Citation Format: David A. Orlando, Michael R. McKeown, Mei Wei Chen, Cindy Collins, Matthew G. Guenther, Christian C. Fritz. Predicting drug response by profiling the epigenome: Super-enhancers as biomarkers. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-69.
Abstract P235: A Virtual Baseline Examination: Effect of Baseline Timeframe on Risk Factor Assessment
Authors: Jason L Vassy, Yuk-Lam Ho, Kelly Cho, J. M Gaziano, Jacqueline Honerlaw, Sanjay Raju, Peter W Wilson, David R Gagnon
Journal: Circulation (2015)

Introduction: Prospective cohort studies in classical cardiovascular disease (CVD) epidemiology begin with a baseline exam at which risk factors are measured, after which participants are followed over time. Longitudinal patient data from electronic health records (EHR) hold potential for CVD epidemiology but may necessitate flexibility in defining the timeframe of baseline risk factor assessment.

Objective: In creating the first CVD cohort study using patient data from a large health system, we tested the hypotheses that widening the timeframe used to measure baseline CVD risk factors increases the yield of eligible patient data without introducing selection bias.

Methods: The New England network (VISN 1) of the Veterans Health Administration cares for >1 million patients. To define a veteran cohort, we used EHR data to identify 240,479 eligible VISN 1 patients, defined as having valid demographic data and ≥1 set of blood lipid results between 2000-2007. We anchored the index date to the date of the first eligible lipid results. We then expanded the definition of the baseline timeframe by 1-week intervals before or after this date, assessing the proportion of eligible patients with blood pressure (BP) measurements with each successive widening of the baseline timeframe. We compared 3 groups of patients: 1) those with BP from the exact index date, 2) those with BP up to the 85th percentile to either side of the index date, and 3) those with no BP +/-180 days of the index date. We identified baseline CVD and diabetes from ICD-9 codes.

Results: Group 1 contained 146,636 (61.0%) of the eligible patients. This proportion reached 85% by +21 or -56 days from the index date. The 3 groups did not differ in age, BP, or LDL levels, but Group 3 (1.2% of total) had less available race data, lower prevalence of baseline comorbidities, and fewer outpatient visits.

Conclusions: Creating a prospective CVD cohort from EHR data is feasible but may require special handling of patients with infrequent visits to minimize selection bias.

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Molecular predictor of irinotecan (CPT-11) efficacy
Authors: K. E. Rhodes, D. Vallböhmer, W. Zhang, D. Y. Yang, J. Yun, O. Press, M. Gordon, S. Iqbal, H.-J. Lenz
Journal: Journal of Clinical Oncology (2005)

3560 Background: Irinotecan(CPT-11), a topoisomerase I inhibitor, is approved in the use of both first and second line chemotherapy in metastatic colorectal cancer (CRC) patients. Currently, no reliable prognostic factors have been identified to predict the clinical outcome of CPT-11 treatment. Previously, we found that EGFR, IL-8 and GSTP1 polymorphisms are associated with survival in CRC patients treated with first-line CPT-11 (Mallik et al ASCO 2004). In this study we expanded our search on polymorphisms of genes that are involved in general drug metabolism, specifically the Irinotecan pathway: members of the ATP-binding cassette transporter subfamily (ABCB1 C1236T, C3435T and G2677A, ABCG2 T623C), carboxyl esterase 1 (CES1 A1525C), E-Cadherin (E-Cad C-160A) and vascular endothelial growth factor (VEGF C936T). Methods: Genomic DNA from blood samples of fifty-four CRC patients treated with CPT-11 was extracted. Gene polymorphisms were analyzed by PCR-RFLP. Results: Fifty-four patients were enrolled in the study (31 male, 23 female) with a median age of 56 (range: 34–77). The median time to follow up was 23.2 (range11.2- 52.9) months and the median survival time was 28.9 (95% CI: 22.7–31.4) months. Median time to progression is 10.9 (95% CI: 7.6–12.1) months. Polymorphisms in ABCG2, CES1, E-Cad and VEGF showed no significance in disease progression. A correlation trend (p=.06) between C1236T gene polymorphism and time to progression was observed. Furthermore, combined analysis of the ABCB1 C1236T polymorphism showed that patients carrying at least one C allele had a statistically significant longer time to progression than those homozygous for the variant genotype (T/T) (p=0.01, logrank test). This data is controversial to previously published data (Mathijssen et al.) which shows that the T/T allele is associated with increased drug exposure. The ABCB1 G2677A and C3435T polymorphisms also showed trends for time to tumor progression (p=0.07 and p=0.15, log rank test), respectively. Conclusion: This is the first study to link the ABCB1 C1236T gene polymorphism with clinical outcome of CRC patients treated with first line CPT-11. Further investigation is warranted to confirm this preliminary finding. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron, Genentech, Response Genetics Lilly Oncology, Pfizer, Roche, Sanofi NCI, NIH
Demographic features and prognostic profiles of breast cancer patients presenting with nipple discharge in Chinese population
Authors: W. Yin, G. Di, G. Liu, J. Wu, J. Lu, K. Shen, Q. Han, Z. Shen, Z. Shao
Journal: Journal of Clinical Oncology (2009)

e22204 Background: Breast cancer patients with nipple discharge (ND) may constitute a distinct clinical entity compared to those without ND, which has not been well elucidated in previous reports. We sought to analyze the demographic features and prognostic profiles of breast cancer patients presenting with nipple discharge in Chinese population. Methods: A total of 3234 patients, categorized as ND (2.47%) and non-nipple discharge (NND; 97.53%) according to different initial signs, were retrospectively analyzed. Survival curves were performed with Kaplan-Meier method and annual recurrence hazard was estimated by hazard function. Results: ND group tended to have smaller tumors and less axillary lymph node (ALN) involvement than NND group (P &lt; 0.05). In the univariate analysis, we found significantly different recurrence-free survivals (RFS) between subgroups (P = 0.0182), with the rate of 77.78% for ND group and 72.46% for the other at the 11th year respectively. In Cox proportional hazards regression analysis, we found that tumor size (P &lt; 0.001), ALN status (P &lt; 0.001) were independent prognostic factors for RFS. To further evaluate whether prognostic effect of ND status remained unabated over time, the test for lack of proportionality was performed. However, it was statistically significant (global test, P = 0.039), which hinted at a demand for the employment of Cox non-proportional hazards regression in this analysis. In time dependent Cox model, ND status (P = 0.0495) as well as ERBB2 status (P = 0.017), tumor size (P &lt; 0.001), ALN status (P &lt; 0.001) were independent prognostic factors when ND and ERBB2 status were taken as time-varying covariates. Annual hazard rates for recurrence remained lower on ND group until approximately 4.5 years after surgery, while the situation was just the opposite thereafter. Conclusions: Our findings suggested that demographic features and prognostic profiles were quite different between breast cancers presenting with and without ND in Chinese population, which may indirectly uncover distinct biological behaviors and potentially enlighten novel therapeutic approaches for patients with different initial signs. No significant financial relationships to disclose.
Exome Sequencing Analysis in Severe, Early-Onset Chronic Obstructive Pulmonary Disease
Authors: Dandi Qiao, Christoph Lange, Terri H. Beaty, James D. Crapo, Kathleen C. Barnes, Michael Bamshad, Craig P. Hersh, Jarrett Morrow, Victor M. Pinto-Plata, Nathaniel Marchetti, Raphael Bueno, Bartolome R. Celli, Gerald J. Criner, Edwin K. Silverman, Michael H. Cho
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Genomic regions identified by genome-wide association studies explain only a small fraction of heritability for chronic obstructive pulmonary disease (COPD). Alpha-1 antitrypsin deficiency shows that rare coding variants of large effect also influence COPD susceptibility. We hypothesized that exome sequencing in families identified through a proband with severe, early-onset COPD would identify additional rare genetic determinants of large effect.To identify rare genetic determinants of severe COPD.We applied filtering approaches to identify potential causal variants for COPD in whole exomes from 347 subjects in 49 extended pedigrees from the Boston Early-Onset COPD Study. We assessed the power of this approach under different levels of genetic heterogeneity using simulations. We tested genes identified in these families using gene-based association tests in exomes of 204 cases with severe COPD and 195 resistant smokers from the COPDGene study. In addition, we examined previously described loci associated with COPD using these datasets.We identified 69 genes with predicted deleterious nonsynonymous, stop, or splice variants that segregated with severe COPD in at least two pedigrees. Four genes (DNAH8, ALCAM, RARS, and GBF1) also demonstrated an increase in rare nonsynonymous, stop, and/or splice mutations in cases compared with resistant smokers from the COPDGene study; however, these results were not statistically significant. We demonstrate the limitations of the power of this approach under genetic heterogeneity through simulation.Rare deleterious coding variants may increase risk for COPD, but multiple genes likely contribute to COPD susceptibility.
Pathologically Confirmed Chronic Traumatic Encephalopathy in a 25-Year-Old Former College Football Player
Authors: Jesse Mez, Todd M. Solomon, Daniel H. Daneshvar, Thor D. Stein, Ann C. McKee
Journal: JAMA Neurology (2016)

This case report describes a 25-year-old former college football player who had more than 10 concussions while playing football and postmortem pathologically confirmed chronic traumatic encephalopathy.
Interleukin 21 efficacy in a mouse model of metastatic renal cell carcinoma
Authors: S. Hughes, L. Chin, K. Waggie, P. V. Sivakumar, C. Everson, C. Clegg
Journal: Journal of Clinical Oncology (2004)

2598 Background: Interleukin 21 (IL-21), a member of the IL-2 cytokine family, is produced by activated CD4+ T cells. We have previously shown recombinant murine IL-21 (mIL-21) to be both efficacious and well tolerated in the mouse B16F10 melanoma model. Efficacy in this model is likely mediated through IL-21 enhancement of NK and T cell cytotoxicity, and possibly through increased survival of tumor-specific CTLs. The current study examined efficacy of mIL-21 in mice bearing renal cell carcinoma tumors (Renca). Methods: 80 Balb/c mice were injected intravenously with Renca cells (3 x 104 or 1 x 105); treatments began 3 hours later. Dose levels of 0, 0.05, 0.3 and 2 mg/kg mIL-21 (n=10/treatment group) were administered by intraperitoneal injection once daily on study days 1–5 and 15–19. For each set of 40 mice defined by their initial tumor inoculums, all mice were euthanized when signs of limiting tumor burden appeared in one or more mice. Tumor burden was quantitated by lung weight and/or number of surface lung metastases. Results: Mice that received the higher initial tumor burden with no mIL-21 treatment became moribund by day 22. As determined by lung weight, differences in tumor burden between treatment groups were highly significant (p< .0001, ANOVA). Relative to the control group, all mIL-21 dose groups showed significant and dose-dependent reductions in tumor. Similar results were observed in mice that received the lower initial tumor injection. Tumor burden was significantly reduced in the 0.3 and 2 mg/kg dose groups, but not in the lowest dose group due to overall lower tumor burden in these mice. Consistent with observations of reduced lung weight, differences in the number of lung metastases between treatment groups were highly significant (p< .0001, ANOVA). Compared to the control group, the average number of metastases in mice treated with 0.3 and 2 mg/kg mIL-21 was reduced by 30% and 64%, respectively. Conclusions: These data demonstrate significant efficacy of IL-21 in a model of metastatic renal cell carcinoma and support plans for inclusion of patients with this type of tumor in IL-21 clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ZymoGenetics, Inc. ZymoGenetics, Inc.
Medicine and nursing
Authors: A. Mulhall, A. Jones
Journal: BMJ (1995)

Medicine and nursing need both scientific and naturalistic inquiry

EDITOR,--The issue of the BMJ of 29 July, exploring how nursing and medicine may interact more usefully, should prompt the nursing journals to initiate a similar debate in their pages. It was with dismay, though, that we read the two letters1 2 concerning an article by Hay.3 Although Hay's article received comment in the nursing press, the arguments surrounding it provide a timely rejoinder to the articles in …
Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16-year median follow-up duration.
Authors: J L Misset, M di Palma, M Delgado, R Plagne, P Chollet, P Fumoleau, B Le Mevel, D Belpomme, J Guerrin, P Fargeot, R Metz, M Ithzaki, C Hill, G Mathé
Journal: Journal of Clinical Oncology (1996)

PURPOSE To determine the long-term impact on disease-free survival (DFS) and overall survival (OS) of adjuvant anthracycline-based chemotherapy, when prospectively compared by random allocation with standard cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-positive (N+) breast cancer patients. PATIENTS AND METHODS Two hundred forty-nine patients with N+ breast cancer, recruited from eight French cancer centers, were randomized to receive 12 monthly cycles of adjuvant chemotherapy, either CMF (n = 112) or doxorubicin, vincristine, cyclophosphamide, and fluorouracil (AVCF) (n = 136). All had a negative metastatic work-up before inclusion, which was stratified by accrual center, tumor stage (International Union Against Cancer [UICC]), and menopausal status. RESULTS No severe adverse effect related to grade 4 (World Health Organization [WHO]) toxicity was observed. There was no difference in second primary tumor incidence between the two arms. The treatment given was 88% of planned for AVCF and 75% for CMF in both premenopausal and menopausal patients. With a median follow-up time of 16 years (range, 13 to 17), the OS and DFS rates are significantly longer in the AVCF arm (56% v 41% [P = .01] for OS, and 53% v 36% [P = .006] for DFS). These differences are significant, irrespective of tumor stage (T1 to T2 v T3 to T4), and remain positive in patients with or without postoperative locoregional radiotherapy (55% of cohort). When analyzed according to menopausal status, the differences remain significant only for premenopausal patients. CONCLUSION This set of mature controlled data confirms the added value of anthracycline-based combination adjuvant therapy for N+ breast cancer patients when compared with CMF, with both regimens given for 1 year.
Does breast density affect the ability of MRI to detect mammographically occult cancers?
Authors: Beth Cutler Freedman, Jocelyn Luongo, Alyssa Gillego, Tamara Fulop, Susan K. Boolbol
Journal: Journal of Clinical Oncology (2012)

54 Background: In breast cancer patients, the use of preoperative MRI is increasing. A change in the operative plan due to MRI findings occurs in 8%-20% of cases. Preoperative MRI is used routinely by many surgeons and radiologists, but debate persists with regard to its indications. We evaluated whether mammographic breast density affected MRI findings. We also examined whether the number of MRI detected synchronous cancers were affected by breast density. Methods: A retrospective chart review was performed of newly diagnosed breast cancer patients who underwent preoperative MRI from 2008-2011. There were three categories of breast density: fat-replaced, scattered fibroglandular densities, and dense. We determined the number of patients in each group who underwent biopsies based on MRI findings, and evaluated the number of occult cancers diagnosed as a result of these biopsies. Results: 301 patients were included. Overall, 64 patients (21%) who underwent an image guided biopsy based on pre-operative breast MRI were diagnosed with an additional focus of cancer. Of the 17 patients with fat-replaced breasts, 4 underwent additional biopsy, and carcinoma was identified in all patients. 149 patients had scattered fibroglandular densities; 53 (36%) underwent additional biopsies. New cancers were diagnosed in 28 patients (19%). Of 135 patients with dense breasts, 61 patients (45%) had additional biopsies, and new cancers were diagnosed in 24 % of these patients. Conclusions: MRI detected additional cancer in 21% of patients in this study. MRI is sensitive and specific in patients with fat-replaced breasts (100%), but due to the small number of patients in this group, additional studies must be done to evaluate the usefulness in this group of patients. We conclude that MRI is useful for detecting additional cancers in patients of all breast densities, and may change the surgical options of the patient when multicentric or contralateral disease is diagnosed.[Table: see text]
Prognostic significance of immunohistochemical expression of <i>p</i>53 gene product in invasive breast cancer
Authors: Y.-R. Do, H.-S. Song, S. H. Kang, K.-Y. Jung, Y.-S. Kim, J.-L. Lee, W.-S. Lee
Journal: Journal of Clinical Oncology (2005)

675 Background: Tumor suppressor gene, p53 appears to be a useful prognostic marker, however, consensus as to the need for routine immunostaining has not occurred. The aim of this study was to investigate the prognostic significance of the expression of p53 gene products by immunohistochemical analysis in invasive breast cancer. Methods: Between January 1993 and December 2001, 439 curatively treated invasive breast cancer patients underwent immunohistochemical staining for p53, and we retrospectively analyzed their correlation with the clinical outcome. Results: Median age was 47 (range: 23–85). Modified radical mastectomy was performed in 369 (84.1%), and breast conserving surgery in 70 (15.9%). Hormonal therapy was performed in 336 (76.5%), and adjuvant chemotherapy was in 364 (83.3%). Stage was as follows: I 23.9%, IIA 38.5%, IIB 32.6%, IIIA 4.8%. Overexpression of p53 was 51.7%. Overexpression of p53 was associated with younger age (p=0.035), more right breast cancer (p=0.031), less neuronal invasion (p=0.041), and less lymph node metastasis (p=0.013). The tumor size, tumor histology, hormonal receptor status, and tumor stage were not related to overexpression of p53. The five- and ten-year overall survival (OS) rates, and relapse free survival (RFS) rate of patients were 91.5%, 89.1% and 80.3%, 78.5%, respectively. Upon multivariate Cox regression analysis, LN metastasis, expression of p53, numbers of tumor, and tumor size were important prognostic factor for OS, and LN metastasis, estrogen receptor status were important for RFS. In subgroup analysis, p53 negative group is better OS than p53 positive group in only patients with LN metastasis. The five- and ten-year OS rates were 91.2%, 91.2% in p53 negative group and 79.4%, 72.1% in p53 positive group, respectively (p=0.017). Upon multavariate Cox rergression analysis, expression of p53 (HR 2.716, 95% CI, 1.160 to 6.358) and tumor size (HR 1.274, 95% CI, 1.070 to 1.518) were important prognostic factor for OS. Conclusions: Immunohistochemical staining of p53 gene product was an independent prognostic factor for predicting overall survival in lymph node positive invasive breast cancer patients. No significant financial relationships to disclose.