tbuckley/cabot-search huggingface dataset:
Needed Innovation in Digital Health and Smartphone Applications for Mental Health
Authors: John Torous, Laura Weiss Roberts
Journal: JAMA Psychiatry (2017)

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Correlation between gefitinib efficacy and HER family expression in recurrent non-small-cell lung cancer (NSCLC)
Authors: M. Nishio, F. Taguchi, F. Ohyanagi, Y. Sato, S. Okumura, Y. Ishikawa, K. Nakagawa, T. Horai
Journal: Journal of Clinical Oncology (2004)

3091 Background: The EGFR signal transduction network plays an important role in malignant profiles of cancer. Gefitinib is an orally active, selective EGFR-Tyrosine Kinase Inhibitors that demonstrates antitumor activity against NSCLC. The degree of EGFR expression is reported not to affect response. It is possible that differential expression of HER family members may predict tumor response to gefitinib. The aim of the study was to evaluate the correlation between HER family expression and gefitinib efficacy in terms of response rate, time to progression (TTP), and overall survival (OS) time. Patients and Methods: 15 Patients with recurrent NSCLC after surgical resection were treated with 250 mg gefitinib until disease progression. HER family (Her1, 2, 3, 4) expression status was determined immunohistochemically, using tumor tissues of the resected surgical materials. Results: Among the 15 patients, we observed 3 PRs, 4 SDs, 5 PDs and 3 NEs. Strong expressions of HER1 and HER3 were predominantly observed in PR patients, while strong expressions of Her2 and Her4 were ubiquitously observed. The triple strong expression of Her1/Her2/Her3 or Her1/Her2/Her4 was seen in all PR patients, whereas no triple strong expression of HER family was seen in SD and PD patients. TTP of triple expressing group (n=3) was 277 days and two patients are still alive at 400 days, although TTP and OS of non-triple expressing group (n=12) were 33 and 116 days, respectively. Conclusions: The coexpression patterns might be a useful marker for predition of response to gefitinib. To confirm this result, we are currently examining HER family expression status in additional cases, only biopsy specimens of whom are available. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca K.K.
Skin toxicity associated with outcome to erlotinib in non-small cell lung cancer (NSCLC) patients (p) with EGFR mutations in the EURTAC study.
Authors: Cristina Buges, Alex Martinez Marti, Rafael Rosell, Alain Vergnenegre, Filippo De Marinis, Bartomeu Massuti, Javier De Castro, Radj Gervais, Enric Carcereny Costa, Teresa Moran, Mariacarmela Santarpia, Enriqueta Felip, Margarita Majem, Rut Porta, Ramon Palmero, Ana Drozdowskyj, Cordula Heidecke, Amaya Gasco, Miquel Taron, Luis G. Paz-Ares
Journal: Journal of Clinical Oncology (2012)

7542 Background: Rash is reported in 75% of p treated with erlotinib and has been associated with improved overall and progression-free survival (PFS) in unselected p although not specifically in p with EGFR mutations. Methods: The EURTAC trial (clinicaltrials.gov NCT00446225) randomized 174 p with EGFR exon 19 deletions or L858R mutations to receive erlotinib or chemotherapy. Overall PFS was 9.7 months (m) vs 5.2 m, respectively (P&lt;0.0001). Rash was defined according to NCI CTC v3.0 and dichotomized by grades 0-1 vs 2+. Grade 2 is macular or popular eruption or erythema with pruritus or other associated symptoms, localized desquamation or other lesions covering &lt;50% of body surface area. We examined outcome in the erlotinib arm according to rash grade. Results: 16 p in the erlotinib arm had no rash (grade 0), 30 had grade 1, and 40 had grade 2+. 80% of cases of rash grade 2+ occurred in p with exon 19 deletions, while only 20% were in p with L858R mutations (P=0.039). There were no differences in rash grade according to sex, age or smoking status. PFS was 11.2 m in p with rash grade 2+ and 8.4 m in p with grade 0-1 (HR, 0.52; P=0.018). There was no correlation between rash grade 0-1 vs 2+ and response or overall survival (OS). Interestingly, when p were divided into those with no rash (16 p) and those with grade 2+ (40 p), PFS was 11.2 m for p with grade 2+ vs 2.7 m for p with no rash (P=0.031), and OS was 24.9 m for p with grade 2+ vs 16.1 m for p with no rash (P=0.033). Conclusions: Although the biological reasons for the association of skin rash with better outcome to erlotinib have not been elucidated, this sub-analysis of the EURTAC trial has enabled us to confirm for the first time that skin rash – especially grade 2+ - can predict better outcome to erlotinib in p with EGFR mutations. In addition, the correlation between rash and type of EGFR mutation warrants further investigation.
Cytosine Β-D Arabino-Furanoside (Ara-C) and CPT-11 inhibit cell proliferation in human colorectal cancer with microsatellite instability
Authors: A. G. Gaba, Z. Yuan, Y. H. Ling, A. Bennett, T. K. Weber
Journal: Journal of Clinical Oncology (2004)

2061 Background: Recent studies suggest 5-Fluorouracil-based adjuvant chemotherapy does not improve survival in colorectal cancer (CRC) patients with microsatellite instability (MSI) (NEJM, 349 July: 247–257, 2003). We have reported decreased expression of p12DOC-1 is associated with increased proliferation and apoptosis arrest in human CRC with MSI (Oncogene, 22: 6304–10, 2003). The purpose of this study was to measure differential expression of p12DOC-1 using a Cancer Cell Line Profiling (CCLP) Array (Clontech) and to assess the efficacy of CPT-11 and oxaliplatin, in human MSI CRC cell lines. Methods: A CCLP array containing 702 complex cDNA samples from 26 different human cancer cell lines was treated with a range of chemotherapeutic agents. The array was hybridized with a p32-dCTP labeled p12DOC-1 probe. Array results were confirmed using real-time RT-PCR. In addition, the toxicity of CPT-11 and oxaliplatin (neither agent tested on array) against CRC cell lines, RKO (MSI) and SW480 (microsatellite stable), was measured pre and post transfection with pcDNA3-p12DOC-1. Cell survival was assessed by MTT assay and expressed as IC50 values (50% inhibitory concentration). Results: Ara-C increased p12DOC-1 expression in 2 of 3 MSI CRC cell lines by CCLP array and was confirmed by real-time RT-PCR. Significantly decreased S phase and increased apoptosis was also observed. RT-PCR confirmed an 8-fold increase in p12DOC-1 expression in MSI CRC cell lines after transfection with pcDNA3-p12DOC-1. IC50 values for CPT-11 were significantly higher in all cell lines with increased p12DOC-1 expression (mean IC50= 37 μM), compared to the RKO wild type control (minimal DOC-1 expression) (IC50 =1 μM) (p< 0.05). No differential IC50 values were observed for oxaliplatin. Conclusions: Ara-C induces p12DOC-1 expression, inhibits cell proliferation and increases apoptosis in MSI CRC. In addition, MSI CRC is extremely sensitive to CPT-11. These results suggest that differential gene expression analysis may assist selection of optimal chemotherapeutic agents specifically for the treatment of 5FU resistant MSI CRC. No significant financial relationships to disclose.
EGFR mutation analysis from REASON: A registry for the epidemiologic and scientific evaluation of EGFR mutation status in newly diagnosed NSCLC patients stage IIIB/IV.
Authors: Wolfgang Schuette, Wilfried Ernst Erich Eberhardt, J.-Mathias Graf von der Schulenburg, Manfred Dietel, Peter Schirmacher, Silke Zaun, Michael Thomas
Journal: Journal of Clinical Oncology (2012)

e18016^ Background: Somatic mutations in the EGFR gene predict for sensitivity to EGFR TKI in patients with adv. NSCLC, yet limited data exists on EGFR mutation rates of all 4 exons in all NSCLC histologies. Methods: The REASON study (NCT00997230) aims to generate data on EGFR mutation (M) status, association of EGFR-M status with clinico-pathological parameters, treatment decisions and clinical outcomes for EGFR M+ patients from a large sample of stage IIIB/IV NSCLC patients in Germany. 4279 subjects for whom EGFR M testing was planned were enrolled at 151 sites (85% hospital based) in Germany. Standard test method was Sanger sequencing. While analysis of exons 19 and 21 was obligatory, exons 18 and 20 were not routinely done at all labs. Primary objectives are epidemiological data on EGFR M status and correlation with clinico-pathological features. Secondary aims are clinical outcome of all EGFR M+ patients (PFS, OS, DCR), clinical management and pharmaco-economic data associated with diagnosis and treatment of EGFR M+ patients. Results: A 2 nd interim analysis provided baseline data on 3973 patients. 63% were male; 82% ever-smokers, 18% never-smokers. Adenocarcinoma is most frequent (69%), followed by squamous epithelial carcinoma (19%). 379 patients had EGFR mutations (9.9%) with 9.5% predicting TKI sensitivity and 0.4% resistance. Most common were exon 19 deletions (50%; with 35% DelE746-A750) followed by exon 21 mutations (36.8%; with 72% L858R). Multivariate analysis revealed association of gender, smoking status and histological subtype with EGFR M status (Table). 50% of M+ patients received 1st line TKI vs. 48% doublet CTX. Conclusions: REASON provides the largest data base yet on EGFR M status in Caucasian patients with newly diagnosed stage IIIB/IV NSCLC. Smoking followed by adeno-carcinoma was the strongest predictive factor for EGFR M. Only 50% of EGFR M+ patients received 1 st line TKI. [Table: see text]
Combination chemotherapy with docetaxel and CBDCA in previously untreated advanced non-small-cell lung cancer
Authors: T. Aoki, A. Ebihara, K. Suemasu
Journal: Journal of Clinical Oncology (2004)

7244 Background: This study was conducted to prospectively evaluate the efficacy and toxicity of combination chemotherapy with docetaxel (60 mg/m2) and carboplatin (CBDCA), which was determined by body surface area (300 mg/m2) rather than AUC, in patients with previously untreated advanced (stage IIIB and IV) non-small-cell lung cancer (NSCLC). Methods: Docetaxel 60 mg/m2 was administered intravenously over 3 hours followed by CBDCA 300 mg/m2 over 2 hours on day 1. This treatment cycle was repeated every 3–4 weeks until the patients showed disease progression or refused further treatment. Results: Twenty-one patients were eligible for the treatment. Fourteen patients (66.7%) had adenocarcinoma, three (14.3%) squamous cell carcinoma, and four (19%) large-cell carcinoma or unspecified NSCLC. The median number of cycles was four (range, 2 to 12). The median AUC as calculated by Calvert's formula, using the measured creatinine clearance as GFR, was 4.4 (range, 2.8 to 6.1). Fourteen patients had a major objective response (66.7%; 95% confidence interval, 43.0–85.4%). The median progression free survival was 226 days (range, 59 to 388 days), that for adenocarcinoma patients 257 days (59 to 388 days), and that for non-adenocarcinoma patients 127 days (66 to 198 days). The overall median survival time was 454 days (range, 52 to 823 days), that for adenocarcinoma patients 537 days (67 to 823 days), and that for non-adenocarcinoma patients 193 days (52 to 266 days). The 1-year survival rate was 58.5%. The major toxicity was neutropenia. Grade 3 or 4 neutropenia occurred in 17 patients (81.0%). Conclusions: This regimen shows significant antitumor activity and outcomes. No significant financial relationships to disclose.
Abstract 17514: Differences in Risk of Long Term Atrial Fibrillation and Ischemic Stroke Between Post-operative Atrial Fibrillation After Cardiac and Non-cardiac Surgeries
Authors: Karam Ayoub, Jack Xu, Fuad Habash, Ahmed Almomani, Allison Shaw-Devine, Hakan Paydak, Srikanth Vallurupalli
Journal: Circulation (2016)

Background: New onset post-operative atrial fibrillation (POAF) occurs after both non-cardiac and cardiac surgeries. Comparative differences in long term outcomes between these types of surgeries i...
Optimising alemtuzumab therapy for refractory B cell chronic lymphocytic leukaemia (CLL)
Authors: P. Hillmen, P. Moreton
Journal: Journal of Clinical Oncology (2004)

6522 Background: Approximately half of CLL patients do not respond to alemtuzumab and others progress after responding to alemtuzumab. We report here factors predictive for lack of response and approaches to achieve the best outcome for these patients. Methods: 91 patients with relapsed or refractory CLL received alemtuzumab aiming for minimal residual disease (MRD) negativity. Factors correlated with response were reviewed and strategies for overcoming resistance or relapse are reported. Results: The chance of response was associated with lymph node size (p <0.0001): High dose methyl prednisolone (HDMP; 1g/m2/day x5 every 4 weeks; 4 patients) or CHOP (1) were used to reduce bulky nodes prior to alemtuzumab. 2 of 5 had a resolution of lymph nodes with both achieving MRD negative remissions with alemtuzumab. The other 3 did not respond to HDMP or alemtuzumab. 8 patients refractory to alemtuzumab, due to bulky lymph nodes, received alemtuzumab with concurrent fludarabine and 6 responded (2 MRD negative, 2 CR, 2 PR). In addition, 9 patients relapsing after a median of 23 months (range 8–46) from alemtuzumab were retreated of which 5 responded (1 MRD negative, 2 CR, 2 PR): 2 of the non-responders then received alemtuzumab combined with fludarabine with 1 achieving MRD negativity. One patient was treated on relapse directly with the alemtuzumab/fludarabine combination and achieved a MRD negative CR. Thus 11 refractory patients received combined alemtuzumab and fludarabine with 8 responding (4 MRD negative, 2 CR, 2 PR). Conclusions: Gross lymphadenopathy predicts for poor response to alemtuzumab but therapy with HDMP or CHOP followed by alemtuzumab can be effective in achieving MRD negative CR. The majority of alemtuzumab refractory patients (8/11) respond to the addition of fludarabine. Retreatment with alemtuzumab was effective for 3 of 7 relapsing patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ilex Oncology Ltd. Ilex Oncology Ltd. Ilex Oncology Ltd.
An analysis of malignant bowel obstruction (MBO) outcomes in patients with epithelial ovarian carcinoma (EOC).
Authors: Cristina Martin Lorente, Helen Mackay, Stephane Laframboise, Catherine O'Brien, Marcus O. Butler, Neesha C. Dhani, Michelle K. Wilson, Stephanie Lheureux, Victor Rodriguez-Freixinos, Barry Rosen, Joan Murphy, Sarah E Ferguson, Marcus Bernardini, Jason Dodge, Anthea Lau, Lisa Wang, Amit M. Oza
Journal: Journal of Clinical Oncology (2015)

e16586 Background: Ovarian cancer (OC) is the leading cause of death from gynecological cancer and the fifth cause of cancer mortality in women in Canada. MBO is a common (20-50% incidence) and disturbing complication in women with advanced OC. The management of MBO in recurrent OC represents a major clinical challenge with limited or no level 1 evidence to guide management. Methods: A detailed medical records review of women admitted with MBO and EOC to Princess Margaret Cancer Centre and Toronto General Hospital from January 2009 to December 2013 was performed to assess predictors of outcomes in the overall population and in different subgroups of patients. Results: 91 women were identified during the study period. Median age at time of BO was 60 years (18-82). 8 were low-grade serous, 65 high-grade serous and 18 non-serous or mixed tumors. Median time from diagnosis of EOC to first admission due to MBO was 24 months (0-112). Patients were heavily pretreated, 50% with 3 or more lines of chemotherapy prior to MBO. 24 (26%) underwent surgery (ileostomy, colostomy, bowel resection, stent); 4/24 were deemed inoperable. 19 (21%) received at least one dose of chemotherapy during their admission. Median duration of hospital admission was 10 days (1-60). Successful palliation (adequate oral intake 60 days after resolution of BO) was attained in 33% of the patients. Only surgery and time from diagnosis of OC to MBO were identified as predictors of successful palliation (p 0.009 and 0.047, respectively). Median survival after BO was 169 days. Surgical management was associated with lower 30-day mortality (4% surgical vs. 25% non-surgical patients, p 0.034) and longer survival (184 vs. 77 days, p 0.003), with no significant differences with chemotherapy (11% vs 22%, p 0.343 and 152 vs 102 days, p 0.660, respectively). Median cost per episode was $9713 (1352-51644), with a significant increase in women treated with chemotherapy ($9696 vs $11982, p 0.021). Conclusions: In heavily pretreated EOC patients, effective palliation of MBO could be achieved in only one third of cases. Time from diagnosis of EOC to MBO was found to predict successful palliation, and surgical correction the only approach able to improve survival outcomes.
Fitusiran, an Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia: Updated Results from a Phase 1 and Phase 1/2 Extension Study in Patients without Inhibitors
Authors: Margaret V. Ragni, Pencho Georgiev, Tim Mant, Michael Desmond Creagh, Toshko Lissitchkov, David Bevan, Steve Austin, Charles R Hay, Inga Hegemann, Rashid Kazmi, Pratima Chowdary, Savita Rangarajan, Chang-Heok Soh, Akin Akinc, Angela M. Partisano, Benny Sorenson, K John Pasi
Journal: Blood (2016)
Effects of the histone deacetylase inhibitor (HDACI) LAQ824 on histone acetylation, Hsp70 and c-Raf in peripheral blood lymphocytes from patients with advanced solid tumours enrolled in a phase I clinical trial
Authors: R. S. Kristeleit, D. Tandy, P. Atadja, A. Patnaik, J. Scott, J. S. De Bono, I. Judson, S. B. Kaye, P. Workman, W. Aherne
Journal: Journal of Clinical Oncology (2004)

3023 Background: Several HDACIs, including LAQ824, are now undergoing clinical evaluation. Preclinical data indicate that as well as promoting histone acetylation, these agents can also affect the activity of the molecular chaperone Hsp90 resulting in increased expression of Hsp70 and degradation of key client proteins such as c-Raf. Hsp90 represents an important target for novel therapeutics (Fuino et al. Mol. Cancer Ther. 2003). The purpose of this study was to determine whether an HDACI-mediated impact on Hsp90 could be detected clinically. The assessment was performed on peripheral blood lymphocytes (PBL) taken from patients participating in a Phase I trial of LAQ824. Methods: A dose-escalating, open-label, Phase I trial was undertaken, with LAQ824 being administered by i.v. infusion on days 1–3 q21 days. PBL were collected at various timepoints on days 1, 3, 4, 5 and 8, lysed and assayed for acetylated histone H3 and H4, Hsp70 and c-Raf expression using Western blotting and, in some cases, ELISA. Histone extracts and whole cell lysates from two human colorectal tumour cell lines (HCT116 and HT29) either untreated or treated with LAQ824 were analysed as controls. Results: A consistent increase in acetylation of histones H3 and H4 in PBL lysates on days of treatment with LAQ824 was observed from doses of 36mg/m2 (50% MTD) and maintained for at least 24 hours. Additionally, in selected samples from patients treated at 36 mg/m2 and above, an effect on Hsp90 activity was demonstrated with increased expression of Hsp70 and decreased c-Raf levels over a similar time course. These results were consistent with those obtained from LAQ824 treated HCT116 and HT29 cells. Conclusions: These observed events in PBL suggest that as well as increasing histone acetylation, HDAC inhibition by LAQ824 does inhibit Hsp90 activity in patients at doses that are generally well-tolerated. Additional evaluation of these pharmacodynamic markers in tumour biopsies is ongoing. The biological importance of these non-histone mediated effects requires further study. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis
Survival rates of male breast cancer compared to female: A Surveillance, Epidemiology, and End Results (SEER) database analysis.
Authors: Rao Mushtaq, Mohammed Shaik, Shams Mistry, Omar Abed Alkharabsheh, Mahmoud Shaqfeh, Seyedamirhossein Afsharimani, Delshad Ahmad, Eyassu Habte-Gabr, Khalil Katato, Deimante Tamkus
Journal: Journal of Clinical Oncology (2013)

6567 Background: Breast cancer (BC) is rare in males (M) compared to females (F). There were 2,190 new cases of MBC out of total 226,870 BC cases diagnosed in 2012. Recently, the incidence of MBC is rising but mortality is decreasing in both MBC and FBC. Therefore we want to evaluate survival difference between MBC and FBC. Methods: Using SEER database we analyzed 4,192 MBC compared to 591,268 FBC diagnosed between 1983-2009. Data including age, sex, tumor size, grade, stage, and ER/PR status was used in analysis. Overall five year survival (OS) and Disease specific survival (DSS) rates were calculated using Kaplan-Meier (KM). We further analyzed the data based on race (Black vs White) and calculated 5yr-OS and 5yr-DSS using KM. Results: The majority of MBC were diagnosed at later stages (49.2% vs 35.3%), with greater number of +veLN (44% vs33.5%), and higher percentage of positive ER/PR(95% vs79%) compared to FBC. When analyzed stage-by-stage, males had significantly lower 5-yrOS in all stages except in the stage with distant metastasis (mets) (Table1a). There was no significant difference in 5-yr DSS survival in both sex. Based on race, black males had worse 5-yrOS and 5yr-DSS, followed by white males, black females, and white females (p= 0.0001)(Table1b). Conclusions: Even though MBC presents with advanced disease at diagnosis, our analysis shows there is no difference in DSS when analyzed stage-by-stage. White females had better prognosis compared to others, and black males had worse prognosis. Prospective studies needed to be done to evaluate the prognosis of male breast cancer. [Table: see text] [Table: see text]