tbuckley/cabot-search huggingface dataset:
Integrative analysis of DNA copy number in metastatic NSCLC and drug sensitivity to afatinib.
Authors: Mian Xie, Shen-hai Wei, Mei He
Journal: Journal of Clinical Oncology (2014)

e19094 Background: Afatinib (BIBW-2992) has been approved for patients with untreated metastatic non-small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations. Pharmacogenomic studies have found that genome-wide assays is the unbiased discovery of genomic alterations which is associated with drug response to targeted therapy. The aim of our study is to identify the correlation between DNA copy number profiles and treatment response to Afatinib. Methods: Integrative analysis of DNA copy number alterations (CNA) from 32 metastatic NSCLC patients were performed to identify recurrent regions of genomic change associated with primary response to Afatinib using Affymetrix Mapping 250K Nsp SNP array. Copy number-associated transciptome profiling was identified using Affymetrix Human genome U133 Plus 2.0 array. Comparison of candidate genes correlated with copy number variation and clinical outcome of Afatinib treatment was conducted by quantitative-PCR (qPCR). Results: Predictive model scores generated from cross-validation was correlated with sensitivity to Afatinib. Eight distinct genomic regions were identified in predictive model for Afatinib sensitivity. Regions contained chromosomal gain of EGFR (7p11.2) as well as chromosomal loss of HSD3B2 (1p12) and MTAP (9p21.3). The extreme concordance between DNA copy number and transcript abundance was highly significant for the genes mapping to 7p11.2 in Afatinib sensitive group. Specially, amplification of CCT6A was related to the intrinsic resistance to Afatinib. Conclusions: These data show that integrative analysis of DNA copy number analysis can be used to identify genetic alterations which can be used to discover clinically relevant predictors of drug sensitivity to Afatinib.
Phase II study of cetuximab, pemetrexed, cisplatin and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non-squamous, non-small cell lung cancer (NSCLC): Results of the IFCT-0803 trial.
Authors: Jean Tredaniel, Fabrice Barlesi, Cecile Le Pechoux, Delphine Lerouge, Eric Pichon, Sylvestre Le Moulec, Lionel Moreau, Sylvie Friard, Virginie Westeel, Lidia Petit, Olivier Carre, Francois Guichard, Olivier Raffy, Julie Villa, Alain Prevost, Marie Paule Lebitasy, Franck Morin, Gerard Zalcman, Francoise Mornex
Journal: Journal of Clinical Oncology (2014)

7511^ Background: Cisplatin-based chemotherapy and concurrent radiotherapy, the standard treatments for locally advanced unresectable NSCLC have reach a plateau. New therapeutic combinations of molecular targeted drugs are needed. IFCT-0803 phase II trial aimed to evaluate the benefit of adding cetuximab to a combination of radio and concomitant chemotherapy with cisplatin and pemetrexed in patients with stage III, non-squamous NSCLC. Methods: Based on a 2-stage Simon approach, a total of 106 patients were to accrue. An interim analysis of the first 34 patients authorized the continuation of the study. Eligible patients receive thoracic radiation (66 Gy) along with cisplatin (75 mg/m²) and pemetrexed (500 mg/m²) on D1 administered every 21 days for four cycles; weekly cetuximab (400 mg/m²) for the first week, then 250 mg/m²) is added from the first week of therapy for a total of 12 doses. The primary objective is to assess the disease control rate at the 16th week (16W-DCR), one month after the treatment completion. Results: 99 patients at inclusion were: 60 male, 57 years (median age), PS 0 = 60, ever smoker = 7, stage IIIA = 48 and IIIB = 49, adenocarcinoma = 77. Compliance was good for the first 92 eligible patients : Day 1 chemotherapy was administered to 100% of patients on cycle 1, 98.9% on cycle 2, 93.4% on cycle 3 and 84.8% on cycle 4. Radiotherapy protocol was respected: median was 33 for number of fractions, 66 Gy for total dose, 48 days for treatment duration. The endpoint 16W-DCR was 93.3 % (IC95% : 88.1 - 98.5). 30 patients had a maximal toxicity of grade 3 and 10 of grade 4. Two toxic deaths were observed, one by a traumatic subdural hematoma, as the patient experienced a grade 4 thrombocytemia, another occuring two months post-treatment completion, caused by a grade 4 radiation pneumonia, whereas concurrent cancer progression was documented. Conclusions: IFCT-0803 trial showed both the feasability and high DCR for radiation, cisplatin, pemetrexed and cetuximab combination, with a tolerable toxicity profile. Our data will be updated at the ASCO meeting, the accrual goal (106 pts) being reached on Jan. 2014. Clinical trial information: NCT01102231.
Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children’s Environmental Health Studies: The Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group
Authors: Carrie V. Breton, Carmen J. Marsit, Elaine Faustman, Kari Nadeau, Jaclyn M. Goodrich, Dana C. Dolinoy, Julie Herbstman, Nina Holland, Janine M. LaSalle, Rebecca Schmidt, Paul Yousefi, Frederica Perera, Bonnie R. Joubert, Joseph Wiemels, Michele Taylor, Ivana V. Yang, Rui Chen, Kinjal M. Hew, Deborah M. Hussey Freeland, Rachel Miller, Susan K. Murphy
Journal: Environmental Health Perspectives (2017)

Characterization of the epigenome is a primary interest for children's environmental health researchers studying the environmental influences on human populations, particularly those studying the role of pregnancy and early-life exposures on later-in-life health outcomes.Our objective was to consider the state of the science in environmental epigenetics research and to focus on DNA methylation and the collective observations of many studies being conducted within the Children's Environmental Health and Disease Prevention Research Centers, as they relate to the Developmental Origins of Health and Disease (DOHaD) hypothesis.We address the current laboratory and statistical tools available for epigenetic analyses, discuss methods for validation and interpretation of findings, particularly when magnitudes of effect are small, question the functional relevance of findings, and discuss the future for environmental epigenetics research.A common finding in environmental epigenetic studies is the small-magnitude epigenetic effect sizes that result from such exposures. Although it is reasonable and necessary that we question the relevance of such small effects, we present examples in which small effects persist and have been replicated across populations and across time. We encourage a critical discourse on the interpretation of such small changes and further research on their functional relevance for children's health.The dynamic nature of the epigenome will require an emphasis on future longitudinal studies in which the epigenome is profiled over time, over changing environmental exposures, and over generations to better understand the multiple ways in which the epigenome may respond to environmental stimuli.
Phase II trial of trastuzumab and paclitaxel or docetaxel administered every 3 weeks to patients receiving a first treatment for HER2+ metastatic breast cancer
Authors: J. A. Stewart, L. Fehrenbacher, R. A. Blanchard, G. I. Rodriguez, C. L. Vogel, P. Anavekar
Journal: Journal of Clinical Oncology (2004)

806 Background: Trastuzumab (Herceptin, H) is a humanized monoclonal antibody which showed a significant survival benefit in a randomized trial comparing chemotherapy + H vs. chemotherapy alone in first-line therapy of HER2+ MBC. This phase II multicenter trial assesses safety with particular attention to cardiac toxicity and efficacy in women receiving q3 week H with q3 week taxane as first-line treatment of HER2+ MBC. Methods: Patients had not previously received cytotoxic or H therapy for HER2+ MBC (IHC 3+ or FISH+), had normal left ventricular ejection fraction (LVEF), and had measurable disease. All patients received H (8 mg/kg load -> 6 mg/kg q3 weeks) with either paclitaxel or docetaxel at standard q 3 week doses (choice of taxane per treating physician). H/taxane was to be given for a minimum of 6 cycles followed by H alone until disease progression or limiting toxicity. LVEF was monitored by serial echocardiograms. Results: 36 patients have been enrolled: median age 55yr, ER+/PR+ (31%), ER+/PR- (19%), ER+/PR unknown (3%), ER-/PR+ (8%), ER-/PR- (39%). The objective response rates (ORR = CR + PR) and clinical benefit rates (CBR = CR + PR + SD >6 months) for 32 evaluable patients are shown below. Both H/taxane combinations were well tolerated. Grade 4 toxicities: neutropenic fever (1), resolved. Grade 3 toxicities: hypertension (3), thrombosis (3), nausea/vomiting (2), leukopenia (2), infection (2), non-neutropenic sepsis (1). There were no cases of clinical CHF. The median LVEF was 62% at baseline, 60% at week 9 and 60% at week 18. Conclusions: The combination of H plus a taxane given on a q3 week schedule for HER2+ MBC is well-tolerated and active for both ER+ and ER- patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Aventis; Genentech Genentech Genentech Genentech
A Novel Histone Deacetylase Inhibitor MCT-3 Augments Inhibition of Leukemia Cell Growth and Suppresses Induction of MMP-9 Expression by Azacitidine in HL-60 Cells.
Authors: Hongbin Liu, Penelope A. Mayes, Patrick Perlmutter, Joseph J. Mckendrick, Anthony E. Dear
Journal: Blood (2007)
O-Linked Glycosylation with Sialylated T-Antigen: A Novel Carbohydrate Determinant of von Willebrand Factor Antigen Levels.
Authors: Peter J. Lenting, Carina J.M. van Schooten, Ton Lisman, Marijke van den Berg, Jeroen C.J. Eikenboom, Frank W.G. Leebeek, Jenny Goudemand, Edith Fressinaud, Philip G. de Groot, Cécile V. Denis
Journal: Blood (2006)
A phase II trial of erlotinib for <i>EGFR</i> mutant NSCLC to prospectively assess biopsy feasibility and acquired resistance at disease progression.
Authors: Amanda J. Redig, Myriam Taibi, Geoffrey R. Oxnard, David Boucher, Michael S. Rabin, J Paul Marcoux, Leena Gandhi, Mark Huberman, Deepa Rangachari, Joan Vern Lucca, Linda K. Morse, MaChristine Andan, Bruce E. Johnson, Daniel Botelho Costa, Pasi A. Janne, David Michael Jackman
Journal: Journal of Clinical Oncology (2015)

8076 Background: Erlotinib is a first-line therapy for patients (pts) with advanced EGFR mutant non-small cell lung carcinoma (NSCLC). However, tumors develop acquired resistance; choice of further therapy, including third-generation EGFR inhibitors in development, often depends on the mechanism driving resistance. We performed a prospective trial to assess biopsy feasibility and resistance mechanisms in EGFR mutant pts with acquired erlotinib resistance. Methods: Advanced, EGFR TKI naïve EGFR mutant NSCLC pts were enrolled in a phase II trial of erlotinib. At study entry, eligible pts consented to undergo re-biopsy at progression. The primary endpoint was feasibility of re-biopsy and evaluation of acquired resistance. Re-biopsies underwent pathology review and genomic analysis. Secondary objectives included evaluating biopsy features and reason(s) why re-biopsy could not be performed. Results: Between 02/10 and 1/15, 60 EGFR mutant pts (44 women, 34 never-smokers) were enrolled (L858R (17); exon 19 deletion (38); other (5)). 16 pts remain on study. Median age (range): 62.5 years (34-90). Median PFS: 11.0 months. 44 pts discontinued therapy (39 for progression, 5 for adverse events); 31 (70%) underwent re-biopsy. 8 pts did not undergo re-biopsy because of pt refusal (3); clinical contraindication (3); sudden death (1); or discovery of germline T790M (1). 31 re-biopsies identified: T790M mutation (17, 55%); SCLC transformation (3, 10%); no T790M or SCLC (6, 19%); inadequate tissue (3, 10%). Re-biopsy targeted enlarging lesions (26) and stable lesions (5), with T790M identified in 5/5 stable lesions and 12/26 enlarging lesions. Genotyping was done on effusions (3/4), lymph node (8/8), lung lesion (15/17), peritoneal deposit (1/1), and bone (1/1). Conclusions: Repeat biopsy at disease progression on first-line EGFR-directed therapy is feasible in 70% of pts and yields clinically meaningful results for subsequent therapy. It may be possible to identify resistance mechanisms from biopsy of focally stable yet easily accessible sites of disease. However, non-invasive means of detecting acquired resistance will be important, as re-biopsy is not always possible. Clinical trial information: NCT00997334.
<i>HER2</i> testing in breast cancer by quantitative PCR: technical and clinical considerations.
Authors: Rong Yu, Wen-Chung Chen, Kung Y. Chiu, Sunny Lu, Yuan-Chil Liu, Hsiao-Yun Ko, Han-Chieh Wu, Wen-Chaun Hsieh, Zi-jia Lee, Peter Zhang, Lili Shi, Ming Liu, Kung-Chao Chang, Ih-Jen Su, Peggy Su, Yu-Ming Yeh
Journal: Journal of Clinical Oncology (2015)

e11619 Background: HER2 gene is amplified and/or overexpressed in approximate 15% to 20% of primary breast cancers. Knowing the HER2 status is therefore essential for making right decision. Quantitative PCR is originally designed for analyzing gene expression, and now is gaining wide use in molecular diagnostics. We made some key changes to the steps and streamlined the whole process to provide a convenient method for determining the HER2expression level in breast cancer patients. Methods: A total of 80 freshly-frozen or FFPE breast tumor samples, with a minimal of 30% tumor cell content, were collected from three different locations. Total RNA was extracted by a dual process and was adjusted to a concentration of 25 ng/ml. The same amount of RNA from each sample was analyzed by RT-PCR. Result was reported automatically as delta Ct (ΔCt) respect to a cutoff reference point (CRP), which was derived from a tumor HER2 mRNA population study and monitored in each assay with a traceable material, synthetic oligo. The ΔCtvalue then was used for determination of HER2 expression level. Results: We simplified quantitative PCR steps and optimized assay process by incorporating a self quality control mechanism. Our studies demonstrated that the improved method had a linear range up to 7-order magnitude with less than 8% intra- and inter-assay variance. We established criteria for using total RNA as assay normalizer; therefore, eliminated the needs for choosing a particular reference gene. We introduced a new scoring system based on a CRP, which produced consistent/comparable scoring results on different PCR machines and in different laboratories. A comparison study with FISH revealed an overall 90% agreement. Our method was also suitable for HER2 testing in blood samples, making it feasible to track patient HER2level after clinical intervention. Conclusions: HER2 testing by quantitative PCR method is accurate, consistent, and cost-effective. The whole process can be accomplished in less than 3 hours. The improved method also circumvents many drawbacks associated with testing by IHC and FISH. It is beyond doubt that adoption of quantitative PCR represents a new trend in HER2 testing and would improve clinical outcomes.
Young patients with bladder cancer: Outcomes from the National Cancer Database.
Authors: Samuel L Washington, Maxwell V. Meng, Sima P. Porten
Journal: Journal of Clinical Oncology (2017)

380 Background: Bladder cancer (BC) affecting young patients is not well characterized but seems to be increasingly diagnosed. We aim to describe pathologic findings and BC outcomes in patients less than 40 years old using the National Cancer Database (NCDB), a US population based cohort capturing approximately 70% of newly diagnosed cancer cases. Methods: We identified 362,091 patients diagnosed with BC from 2004 to 2013. We compared demographic, clinical and pathologic information between those younger and older than 40 years. Univariate analysis was performed using Chi-square test for categorical variables and Independent Samples t-test for continuous variables. Multivariable Cox regression was used for survival analysis with hazard ratios (HR) and 95% confidence intervals (CI). Multivariable model was used to identify independent predictors of mortality (overall survival, OS). Results: 3,799 patients (1.1%) were 40 or younger with mean age of 34.5 years. Fewer young patients were women (25.2% vs 30.3%, p&lt;0.001). More identified as nonwhite (11.6% vs 7.3%, p&lt;0.001), had lower clinical T stage (cTa 51.4% vs 38.3%, cT1 13.3% vs 19.6; p&lt;0.001), and longer median follow-up (46.4 months IQR 23.3-73.9 vs 35.3 months IQR 16.7-61.6). Age less than 40 (HR 0.3, 95% CI 0.2-0.3), chemotherapy (HR 0.9, 95% CI 0.9-0.9) and cystectomy (HR 0.8, 95% CI 0.8-0.9) were associated with decreased mortality when controlling for clinical characteristics (p&lt;0.001). In sub-analysis of young patients with cystectomy, more had pT0 disease (20.3% vs 18.2%, p=0.005) with squamous cell carcinoma (13.6% vs 4%) and small cell (3.2% vs 1.6%) more prevalent (p&lt;0.001). In adjusted models, squamous cell carcinoma (HR 1.1, 95% 1.1-1.2), small cell carcinoma (HR 1.5, 95% CI 1.4-1.7), RT (HR 1.2, 95% CI 1.!-1.3) and black ethnicity (HR 1.1, 95% CI 1.1-1.2) were independent predictors of worse OS. Conclusions: Younger patients with BC were more commonly non-white, men, and had low stage disease. In young patients undergoing cystectomy, squamous cell carcinoma, small cell carcinoma and black ethnicity were associated with worse OS. Further exploration in this younger patient cohort is needed to better characterize the optimal oncologic management for these patients.
Nationwide analysis: Changes in the natural history of low risk localized prostate cancer.
Authors: John Thomas Helgstrand, Nina Klemann, Birgitte Grønkaer Toft, Ben Vainer, Martin Andreas Røder, Peter Iversen, Klaus Brasso
Journal: Journal of Clinical Oncology (2017)

12 Background: Increased use of prostate-specific antigen (PSA) has introduced an increase in PCa incidence and a lead time and stage migration at diagnosis, altering the natural history of PCa. Contemporary PCa patients are likely younger and have smaller tumor burden at diagnosis. We investigated if changes in the PCa landscape have altered the course of low-risk localized PCa. Methods: In the Danish Prostate Cancer Registry (DaPCaR), patients diagnosed from 1995 to 2011 with localized (T1-2, N0/X, M0) PCa with Gleason score ≤ 6 were identified. Patients were stratified into three periods of diagnosis; 1995-2000 (period 1), 2001-2005 (period 2) and 2006-2011 (period 3). Competing risk analysis treating PCa and other-cause death as competing events was performed. Results: Of the 5,660 patients identified, 35.9% had undergone radical prostatectomy (RP). From period 1 to period 3, the median age at diagnosis decreased from 72.2 to 66.0 years and the median PSA decreased from 16.2 to 8.6 ng/mL. From period 1 to period 3, the 5-year risk of PCa-death decreased from 14.3% (95% CI: 12.1-16.4%) to 1.3% (95% CI: 0.83-1.7%), p &lt; .0.0001 and the risk of other cause death decreased from 18.1% (95% CI: 15.8-20.5%) to 7.2% (95% CI: 6.2-8.2), p = 0.0001. In patients undergoing RP, the 5-year risk of PCa-death decreased from 0.67% (95% CI: 0.67-2.0%) for patients diagnosed in period 1 to 0.45% (95% CI: 0.0055-0.84), for patients diagnosed in period 3, p = 0.92. For patients not undergoing RP, the 5-year risk of PCa death decreased from 16.6% (95% CI: 14.1-19.1) to 2.0% (95% CI: 1.2-2.7%), p &lt; 0.0001. Conclusions: In a nationwide cohort of patients with low risk localized PCa, the 5-year risk of PCa-death significantly decreased when comparing patients diagnosed during 2006-2011 to those diagnosed during 1995-2000. This was mainly driven by patients not undergoing RP. In the most recently diagnosed group, the difference in 5-year PCa-death between patients undergoing RP and not undergoing RP was small (0.45% vs. 2.0%). Our data demonstrate that the impact of PSA induced lead-time and stage migration has diminished the absolute effect of RP on the risk of 5-year PCa-death because contemporary low-risk localized patients have a significantly better prognosis.
Rituximab, gemcitabine, cisplatin, and methylprednisolone (R-GEM-P) in treatment of relapsed diffuse large B-cell lymphoma (DLBCL).
Authors: Sarah Rachel Barton, Eliza Anne Hawkes, David Cunningham, Clare Peckitt, Sue Chua, Andrew Wotherspoon, Ayoma Attygalle, Alan Horwich, Claire E. Dearden, Mike Potter, Ian Chau
Journal: Journal of Clinical Oncology (2013)

e19543 Background: Patients with DLBCL who relapse after 1st line therapy have poor prognosis. Although there is limited evidence for benefit of rechallenging patients with rituximab, this is considered justified by minimal toxicity and potential outcome improvement. GEM-P+/-R is an accepted salvage regimen, with merits of outpatient delivery and mainly non-overlapping toxicity with 1 st line therapy, but there are relatively few reports of its efficacy and tolerability. Methods: We performed a retrospective single centre analysis of all patients meeting the following criteria: age≥18, histologically proven DLBCL, ≥1 FDG-PET, treated between 2001-2011 with GEM-P+/-R (gemcitabine 1000mg/m 2 D1, D8, D15, methylprednisolone 1000mg D1-5, cisplatin 100mg/m 2 D15 every 28 days +/- rituximab 375mg/m 2 D1 &amp; D15) or GEM-CARBO+/-R (cisplatin substituted for carboplatin AUC5). Data were collected on patient and treatment characteristics, response evaluated by modified IWG 2007 criteria (FDG-PET +/- CT), survival, and toxicity (CTCAE v4.0). Results: We identified 74 patients with median age 56 (range 25-79) who received a median of 3 cycles (range 1-6) of either GEM-P (89%) or GEM-CARBO(11%), combined with rituximab in 69%. 41% had transformed indolent lymphoma. Overall response rate (ORR) was 49% (complete response (CR) 16%, partial response (PR) 32%). Among 40/74 patients evaluated with FDG-PET, metabolic ORR was 63% (mCR 23%, mPR 40%). Of 51/74 patients treated in 2 nd line, ORR was 45%. Significantly higher ORR was observed in patients treated with R-chemotherapy (61% vs 22%, p=0.002), despite 88% having received prior rituximab. 17 patients proceeded to autologous transplant. With median follow up of 50.5 months, 3 yr overall survival in all patients from start of GEM-P was 39% and 3 yr progression free survival 19%. Predominant Grade≥3 toxicity was haematological; thrombocytopenia 69%, neutropenia 58%, anaemia 15% and febrile neutropenia 8%. Conclusions: R-GEM-P is an effective salvage regimen in DLBCL, with the convenience of outpatient delivery. Despite previous rituximab exposure, patients in our cohort benefited from the addition of rituximab, supporting current practice.