tbuckley/cabot-search huggingface dataset:
Expression of MET, IGF-1R, IL-6/gp130, and AXL in erlotinib-treated non-small cell lung cancer (NSCLC) patients (p) with EGFR mutations.
Authors: C. Costa, A. Gimenez Capitan, C. Mayo, S. Simonetti, M. Majem, D. Isla, S. Benlloch, M. Taron, J. Sanchez, R. Rosell
Journal: Journal of Clinical Oncology (2010)

7555 Background: We have observed a 70% response rate (RR) in NSCLC p with EGFR mutations treated with erlotinib. Primary resistance to erlotinib could result from the absence of an EGFR-organized network. Crosstalk and transactivation between other receptor tyrosine kinases, such as EGFR, IGF-1R and MET, is recognized as a mechanism of growth in several tumors. Mutant EGFR could activate the IL-6/gp130 pathway. Overexpression of AXL has been observed in NSCLC and in GIST imatinib-resistant tumors. Methods: The expression of MET, IGF-1R, IL-6/gp130 and AXL was examined by QPCR in the original pretreatment tumor biopsies of 98 NSCLC p with EGFR mutations. Expression levels by terciles were correlated with outcome to erlotinib. Results: There was a good correlation between the expression of IL-6/gp130 and AXL (r = 0.33; p = 0.001). No differences were observed in expression of the four genes according to gender, smoking history, type of EGFR mutation, or other clinical characteristics. The highest tercile of AXL expression was associated with a higher incidence of lung metastases (87.5%; p = 0.02). No other association between any of the genes and metastatic sites (including brain and bone) was observed. Overall RR was 70%, progression-free survival (PFS) was 14 months (m), and median survival (MS) was 27 m. No differences in RR, PFS or MS were observed according to the expression of any of the four genes. Conclusions: The coactivation of other receptor tyrosine kinases seems not to affect the initial outcome to erlotinib in NSCLC p with EGFR mutations. The association of high levels of AXL with lung metastases should be further examined, since AXL expression has been correlated with metastasis to the lung in a breast cancer model. The addition of AXL inhibition could be a novel treatment approach for enhancing the effect of erlotinib in p with EGFR mutations. No significant financial relationships to disclose.
TAXYNERGY (NCT01718353): A randomized phase II trial examining an early switch from first-line docetaxel to cabazitaxel, or cabazitaxel to docetaxel, in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Emmanuel S. Antonarakis, Paraskevi Giannakakou, Brian J. Kirby, Leonardo V. Nicacio, Mario A. Eisenberger, David M. Nanus, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2013)

TPS5100 Background: Docetaxel is the standard 1st-line chemotherapy for mCRPC, while cabazitaxel prolongs survival after docetaxel progression. The activity of cabazitaxel in the 1st-line setting is unknown, while the molecular mechanisms of taxane sensitivity/resistance have been understudied. Clinically, a ≥30% PSA decline within 3 months predicts survival in docetaxel- and cabazitaxel-treated men. Molecularly, emerging evidence suggests that sensitivity/resistance to taxanes relates to the ability of microtubules to traffic AR into the nucleus. Circulating tumor cells (CTCs) represent a real-time biomarker to assess drug-target engagement (DTE) which may be predictive of clinical outcome, and novel enrichment techniques present opportunities for molecular testing. Methods: This is a multicenter phase 2 trial for chemo-naïve mCRPC. 100 men will be randomized (2:1) to 1st-line docetaxel or cabazitaxel. Following 4 cycles, if a ≥30% PSA decline is not achieved, men will switch to the alternative taxane; others will remain on the initial taxane until progression (PCWG2) or unacceptable toxicity. CTCs will be obtained at screening, baseline, after 1 and 4 cycles of chemotherapy, at crossover and at progression to interrogate mechanisms of taxane sensitivity/resistance. CTCs will be enriched via a prostate-specific microfluidic device, enumerated, and analyzed via multiplex confocal microscopy for microtubule bundling and AR localization. TaqMan PCR (and RNA sequencing) will be used to detect AR variants, as preliminary data show that variant ARv567 predicts taxane sensitivity while ARv7 predicts resistance. The primary clinical endpoint of the trial is achievement of a ≥50% PSA reduction during the treatment continuum. The primary molecular endpoint is analysis of DTE in CTCs, and correlation with PSA responses. The study will have 80% power to detect a 25% increase in PSA response rate with tight interclass kappa coefficients for primary biomarkers. Secondary endpoints include radiographic and PSA progression-free survival, objective response rates, overall survival, and safety. Clinical trial information: NCT01718353.
Abstract LB-149: LYAR promotes cell proliferation by repressing CHAC1 expression in neuroblastoma
Authors: Yuting Sun, Bernard Atmadibrata, Bing Liu, Tao Liu
Journal: Cancer Research (2016)

Abstract Introduction: Neuroblastoma is a cancer of the sympathetic nervous system occurring mostly in infants and young children. Despite considerable progress in the treatment of neuroblastoma, 5-year survival rates have remained less than 50% for the majority of children with high-risk disease. Amplification of the MYCN oncogene and consequent overexpression of the N-Myc oncoprotein is a major prognostic indicator in neuroblastoma, which is strongly associated with aggressive tumour behaviour and poor patient outcome. N-Myc oncoprotein induces neuroblastoma by modulating gene and protein expression and consequently causing cell proliferation. LYAR (Ly-1 antibody reactive clone), a novel nucleolar protein with zinc finger DNA-binding motifs, is mostly involved in cell growth regulation in many cancers. Results: Here we showed that N-Myc up-regulated LYAR expression in neuroblastoma cells. Conversely, LYAR up-regulated N-Myc expression. Affymetrix gene array studies revealed that the gene most significantly repressed by LYAR siRNAs was ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1). Consistent with this finding, RT-PCR and immunoblot confirmed that LYAR siRNAs increased CHAC1 gene and protein expression. Alamar blue assays and cell cycle analyses demonstrated that LYAR induced MYCN-amplified neuroblastoma cell proliferation in a CHAC1-depedent manner. Additionally, high levels of LYAR gene expression in human neuroblastoma tissues were associated with MYCN gene expression and predicted poor patient survival independent of patient age and disease stage. Conclusions: Our data demonstrate LYAR as a potential target in neuroblastoma oncogenesis, and provide critical evidence to support the application of LYAR inhibitors for the therapy of neuroblastoma patients. Citation Format: Yuting Sun, Bernard Atmadibrata, Bing Liu, Tao Liu. LYAR promotes cell proliferation by repressing CHAC1 expression in neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-149.
Prospective study of UGT1A1*27 polymorphism for irinotecan therapy: result of lung oncology group in Kyushu (LOGiK1004B)
Authors: Minoru Fukuda, Takayuki Suetsugu, Midori Shimada, Takeshi Kitazaki, Junji Kishimoto, Koichi Takayama, Kenji Sugio, Hiroshi Semba, Yoichi Nakanishi, Yukito Ichinose
Journal: Annals of Oncology (2015)
Abstract SY16-03: Targeting Bcl-2 as a therapeutic strategy and predictive biomarker in CLL
Authors: Matthew S. Davids
Journal: Cancer Research (2016)

Abstract The selective BCL-2 antagonist venetoclax has recently demonstrated striking efficacy in patients with CLL, even those with high risk, refractory disease. This presentation will review the preclinical data that supported exploring BCL-2 inhibition in CLL and the clinical trial results of venetoclax monotherapy in this disease. Tumor lysis syndrome and how this risk can be mitigated will also be discussed. Mitochondrial priming reflects the proximity of a cell to the threshold of apoptosis and can be measured using a functional technique known as BH3 profiling. Data will also be presented which suggest that BH3 profiling may serve as a predictive biomarker of response to venetoclax in CLL, and that the change in priming in response to ex vivo drug treatments may help identify optimal combination partners for venetoclax to inform the design of clinical trials for CLL patients. Citation Format: Matthew S. Davids. Targeting Bcl-2 as a therapeutic strategy and predictive biomarker in CLL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY16-03.
A Randomized Trial Evaluating Short-term Effectiveness of Overminus Lenses in Children 3 to 6 Years of Age with Intermittent Exotropia
Authors: Angela M. Chen, Jonathan M. Holmes, Danielle L. Chandler, Reena A. Patel, Michael E. Gray, S. Ayse Erzurum, David K. Wallace, Raymond T. Kraker, Allison A. Jensen
Journal: Ophthalmology (2016)
Abstract 2535: Synergistic anti-tumor activity of the Notch gamma secretase inhibitor BMS-906024 and paclitaxel in the treatment of lung adenocarcinoma
Authors: Katherine M. Morgan, Francis Lee, Erin Michaud, Joseph R. Bertino, Bruce S. Fischer, Sharon R. Pine
Journal: Cancer Research (2015)

Abstract Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancer cases, primarily through loss of the endogenous Notch inhibitor, Numb, or via gain-of-function mutations in the Notch1 receptor. Notch activity is associated with poor overall survival among non-small cell lung cancer patients whose tumors are wildtype for TP53. We set out to evaluate the combination of Notch-targeted therapy with front-line chemotherapy as an effective treatment for non-small cell lung cancer. Our study focused on lung adenocarcinoma, the most common histological subtype in lung cancer. To target Notch, we utilized the gamma secretase inhibitor (GSI) BMS-906024 which inhibits Notch activation. BMS-906024 is currently in Phase 1 clinical trials for patients with T-cell acute lymphoblastic leukemia and metastatic solid tumors, including lung cancer. Human cell lines representing the major genetic subtypes of lung cancer, most of which were derived from adenocarcinomas, underwent MTS drug synergy assays consisting of treatment with BMS-906024, cisplatin or paclitaxel, or the combination of GSI and chemotherapy. The dosing and timing for BMS-906024 administration were optimized by examination of maximal Notch1 inhibition. Analysis of the drug effects with CalcuSyn yielded Combination Index (CI) values, in which a CI of 0.5 or less was considered as strong synergism for the drug combination. We found that there were significantly lower CI values for the GSI BMS-906024 combined with paclitaxel than with cisplatin (average CI = 0.54 vs 0.85, respectively; P = 0.001). We then grouped the cell lines by major genetic subtype (wildtype versus mutant or null for EGFR, Kras or TP53). The synergy between BMS-906024 and paclitaxel was significantly greater in Kras-wildtype than Kras-mutant cells (average CI = 0.39 vs 0.68, respectively; P = 0.009), while there was no correlation with EGFR or TP53 status. These results are a step toward identification of potential biomarkers that could be used to predict patient response to Notch-targeted therapy, which could have a positive impact on the care of lung adenocarcinoma patients and be informative for treatment decisions. Citation Format: Katherine M. Morgan, Francis Lee, Erin Michaud, Joseph R. Bertino, Bruce S. Fischer, Sharon R. Pine. Synergistic anti-tumor activity of the Notch gamma secretase inhibitor BMS-906024 and paclitaxel in the treatment of lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2535. doi:10.1158/1538-7445.AM2015-2535
Abstract 142: Mutation and immune profiles in early-stage lung squamous cell carcinoma
Authors: Murim Choi, Humam Kadara, Jiexin Zhang, Edwin Parra Cuentas, Jaime Rodriguez Canales, Stephen G. Gaffney, Zi-Ming Zhao, Carmen Behrens, Junya Fujimoto, Chi-Wan Chow, Neda Kalhor, Cesar Moran, David Rimm, Stephen Swisher, Don L. Gibbons, John V. Heymach, Edward Kaftan, Jeffrey Townsend, Thomas J. Lynch, Joseph Schlessinger, J. Jack Lee, Richard Lifton, Roy S. Herbst, Ignacio I. Wistuba
Journal: Cancer Research (2016)

Abstract PURPOSE: Lung squamous cell carcinoma (LUSC) accounts for 20-30% of non-small cell lung cancers (NSCLCs). There are limited treatment strategies for LUSC in part due to our inadequate understanding of the molecular underpinnings of the disease. We sought to perform whole-exome sequencing (WES), comprehensive immune profiling and clinicopathological analysis of early-stage LUSCs to increase our understanding of the pathobiology of this malignancy. METHODS: Matched pairs of surgically resected stage I-III LUSCs and normal lung tissues (n = 108) were analyzed by WES. Immunohistochemistry and image analysis-based profiling of 10 immune markers was done on a subset of LUSCs (n = 91). Associations among mutations, immune markers and clinicopathological variables were statistically examined using ANOVA and Fisher tests. Cox proportional hazards regression models were used for statistical analysis of clinical outcome. RESULTS: This early-stage LUSC cohort displayed an average of 209 exonic mutations per tumor. Fourteen genes exhibited significant enrichment for mutation: TP53, MLL2, PIK3CA, NFE2L2, CDH8, KEAP1, PTEN, ADCY8, PTPRT, CALCR, GRM8, FBXW7, RB1 and CDKN2A. Among mutated genes associated with poor recurrence-free survival, MLL2 mutations predicted poor prognosis in both TP53 mutant and wild type LUSCs. We also found that in treated patients, FBXW7 and KEAP1 mutations were associated with poor response to adjuvant therapy, particularly in TP53-mutant tumors. Analysis of mutations with immune markers revealed that ADCY8 and PIK3CA mutations were associated with markedly decreased tumoral PD-L1 expression, LUSCs with PIK3CA mutations exhibited elevated CD45ro levels and CDKN2A-mutant tumors displayed an up-regulated immune response. CONCLUSION: Our findings pinpoint mutated genes that may impact clinical outcome as well as personalized strategies for targeted immunotherapies in early-stage LUSC. Citation Format: Murim Choi, Humam Kadara, Jiexin Zhang, Edwin Parra Cuentas, Jaime Rodriguez Canales, Stephen G. Gaffney, Zi-Ming Zhao, Carmen Behrens, Junya Fujimoto, Chi-Wan Chow, Neda Kalhor, Cesar Moran, David Rimm, Stephen Swisher, Don L. Gibbons, John V. Heymach, Edward Kaftan, Jeffrey Townsend, Thomas J. Lynch, Joseph Schlessinger, J. Jack Lee, Richard Lifton, Roy S. Herbst, Ignacio I. Wistuba. Mutation and immune profiles in early-stage lung squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 142.
Behavioral, Social, and Emotional Symptom Comorbidities and Profiles in Adolescent Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
Authors: Tara M. Brinkman, Chenghong Li, Kathryn Vannatta, Jordan G. Marchak, Jin-Shei Lai, Pinki K. Prasad, Cara Kimberg, Stefanie Vuotto, Chongzhi Di, Deokumar Srivastava, Leslie L. Robison, Gregory T. Armstrong, Kevin R. Krull
Journal: Journal of Clinical Oncology (2016)

Purpose In the general population, psychological symptoms frequently co-occur; however, profiles of symptom comorbidities have not been examined among adolescent survivors of childhood cancer. Patients and Methods Parents of 3,893 5-year survivors of childhood cancer who were treated between 1970 and 1999 and who were assessed in adolescence (age 12 to 17 years) completed the Behavior Problems Index. Age- and sex-standardized z scores were calculated for symptom domains by using the Childhood Cancer Survivor Study sibling cohort. Latent profile analysis identified profiles of comorbid symptoms, and multivariable multinomial logistic regression modeling examined associations between cancer treatment exposures and physical late effects and identified symptom profiles. Odds ratios (ORs) and 95% CIs for latent class membership were estimated and analyses were stratified by cranial radiation therapy (CRT; CRT or no CRT). Results Four symptoms profiles were identified: no significant symptoms (CRT, 63%; no CRT, 70%); elevated anxiety and/or depression, social withdrawal, and attention problems (internalizing; CRT, 31%; no CRT, 16%); elevated headstrong behavior and attention problems (externalizing; CRT, no observed; no CRT, 9%); and elevated internalizing and externalizing symptoms (global symptoms; CRT, 6%; no CRT, 5%). Treatment with ≥ 30 Gy CRT conferred greater risk of internalizing (OR, 1.7; 95% CI, 1.0 to 2.8) and global symptoms (OR, 3.2; 95% CI, 1.2 to 8.4). Among the no CRT group, corticosteroid treatment was associated with externalizing symptoms (OR, 1.9; 95% CI, 1.2 to 2.8) and ≥ 4.3 g/m 2 intravenous methotrexate exposure was associated with global symptoms (OR, 1.5; 95% CI, 0.9 to 2.4). Treatment late effects, including obesity, cancer-related pain, and sensory impairments, were significantly associated with increased risk of comorbid symptoms. Conclusion Behavioral, emotional, and social symptoms frequently co-occur in adolescent survivors of childhood cancer and are associated with treatment exposures and physical late effects. Assessment and consideration of symptom profiles are essential for directing appropriate mental health treatment for adolescent survivors.
Overexpression of β-Catenin and Cyclin D1 is Associated with Poor Overall Survival in Patients with Stage IA–IIA Squamous Cell Lung Cancer Irrespective of Adjuvant Chemotherapy
Authors: Yujin Kim, DongHao Jin, Bo Bin Lee, Eun Yoon Cho, Joungho Han, Young Mog Shim, Hong Kwan Kim, Duk-Hwan Kim
Journal: Journal of Thoracic Oncology (2016)
Abstract 234A: Aberrant sodium current contributes to constitutive mTOR activity in malignant melanoma cells
Authors: Benjamin Gallant, Nicole Lizza, Ryan Garrity, Audrey Madigan, Zachary Jost, Alfredo Gonzalez, Jeanine Justiniano, An Xie, Yinsheng Wan
Journal: Cancer Research (2016)

Abstract Transformation from disciplined melanocytes to untamed melanoma cells remains an enigma. Our previous studies have demonstrated that melanoma cells are more resistant to oxidative stress and melanoma cells exhibit constitutive mTOR activity. Surprisingly, further studies have failed to present the expression and activity of EGFR using conventional anti-EGFR antibodies. We hypothesized that constitutive mTOR activity in melanoma cells may be due to mutated EGFR variants and membrane channel activities. Using patch clamping technique, we have shown that melanoma cells (WM 266-4) but not human skin melanocytes exhibit Na+ current which is blocked by TTX. Interestingly, mTOR inhibitor, rapamycin, blocks Na+ current. Western blot and confocal microscopy data further revealed that Na+/Ca2+ exchanger blocker KB-R7943 (KBR), and L-type Ca2+ channel blocker Nifedipine (NIF) inhibits mTOR activity in melanoma cells in a dose dependent manner. To further characterize Na+ channels, we used commercially available channel antibodies. Western blot analysis data showed that melanoma cells but not human melanocytes express Na+ v1.5 and Na+ v1.6 and NCX3. Functional studies also indicated that KBR and NIF inhibit melanoma cell proliferation and migration. Taken all together, our data suggest that aberrant Na+ current contributes to constitutive mTOR activity in melanoma cells and channel blockers may be potential for the treatment of melanoma. Citation Format: Benjamin Gallant, Nicole Lizza, Ryan Garrity, Audrey Madigan, Zachary Jost, Alfredo Gonzalez, Jeanine Justiniano, An Xie, Yinsheng Wan. Aberrant sodium current contributes to constitutive mTOR activity in malignant melanoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 234A.
Surgeon specialization and operative mortality in United States: retrospective analysis
Authors: Nikhil R Sahni, Maurice Dalton, David M Cutler, John D Birkmeyer, Amitabh Chandra
Journal: BMJ (2016)

<b>Objective</b> To measure the association between a surgeon’s degree of specialization in a specific procedure and patient mortality. <b>Design</b> Retrospective analysis of Medicare data. <b>Setting</b> US patients aged 66 or older enrolled in traditional fee for service Medicare. <b>Participants</b> 25 152 US surgeons who performed one of eight procedures (carotid endarterectomy, coronary artery bypass grafting, valve replacement, abdominal aortic aneurysm repair, lung resection, cystectomy, pancreatic resection, or esophagectomy) on 695 987 patients in 2008-13. <b>Main outcome measure</b> Relative risk reduction in risk adjusted and volume adjusted 30 day operative mortality between surgeons in the bottom quarter and top quarter of surgeon specialization (defined as the number of times the surgeon performed the specific procedure divided by his/her total operative volume across all procedures). <b>Results</b> For all four cardiovascular procedures and two out of four cancer resections, a surgeon’s degree of specialization was a significant predictor of operative mortality independent of the number of times he or she performed that procedure: carotid endarterectomy (relative risk reduction between bottom and top quarter of surgeons 28%, 95% confidence interval 0% to 48%); coronary artery bypass grafting (15%, 4% to 25%); valve replacement (46%, 37% to 53%); abdominal aortic aneurysm repair (42%, 29% to 53%); lung resection (28%, 5% to 46%); and cystectomy (41%, 8% to 63%). In five procedures (carotid endarterectomy, valve replacement, lung resection, cystectomy, and esophagectomy), the relative risk reduction from surgeon specialization was greater than that from surgeon volume for that specific procedure. Furthermore, surgeon specialization accounted for 9% (coronary artery bypass grafting) to 100% (cystectomy) of the relative risk reduction otherwise attributable to volume in that specific procedure. <b>Conclusion</b> For several common procedures, surgeon specialization was an important predictor of operative mortality independent of volume in that specific procedure. When selecting a surgeon, patients, referring physicians, and administrators assigning operative workload may want to consider a surgeon’s procedure specific volume as well as the degree to which a surgeon specializes in that procedure.