tbuckley/cabot-search huggingface dataset:
Abstract 2299: Generation and characterization of inducible KIF5B-RET mouse model of non-small cell lung cancer
Authors: Qingling Huang, Valentina E. Schneeberger, Noreen Luetteke, Chengliu Jin, Domenico Coppola, Jie Wu
Journal: Cancer Research (2015)

Abstract The new precision oncology requires identification of driver oncogenes, validation of oncogene addiction, and development of oncogene-targeted drugs. Lung cancer is molecularly heterogeneous characterized by various genetic alterations, many of them occur at low frequencies. Recurrent RET fusion genes have been found in 1-2% of non-small cell lung cancer (NSCLC). Among them KIF5B-RET fusion is the most prevalent and occurs specifically in NSCLC. To develop an in vivo animal model for evaluation of KIF5B-RET fusion in lung adenocarcinoma, we generated transgenic mice containing a doxycycline (Dox)-inducible tetO-KIF5B-RET transgene. To express KIF5B-RET in lung type II epithelial cells, tetO-KIF5B-RET mice were crossed with CCSP-rtTA mice. CCSP-rtT/tetO-KIF5B-RET bitransgenic mice were induced with Dox and lung tissues were analyzed. KIF5B-RET mRNA and protein were detected in the lungs of Dox-induced CCSP-rtTA/tetO-KIF5B-RET bitransgenic mice. Histological examinations showed lung hyperproliferative lesions and tumors in Dox-induced CCSP-rtTA/tetO-KIF5B-RET bitransgenic mice. Thus, KIF5B-RET fusion is a driver oncogene sufficient to induce lung tumors in transgenic mice. Citation Format: Qingling Huang, Valentina E. Schneeberger, Noreen Luetteke, Chengliu Jin, Domenico Coppola, Jie Wu. Generation and characterization of inducible KIF5B-RET mouse model of non-small cell lung cancer. [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 2299. doi:10.1158/1538-7445.AM2015-2299
Decision Driven Factors for Allopurinol Dosage in Tumor Lysis Syndrome Prophylaxis: The European Experience of the Florence Pivotal Study
Authors: Simone Baldini, Cristina Rossi, Michele Spina, Massimo Federico, Zsolt Nagy, Karin Jordan, Igor Aurer, Josep-Maria Ribera, Gabriela Borsaru, Nataliia Glushko, Sebastian Grosicki, Alexander Pristupa, Alberto Bosi, Eduardo M. Rego, Andrea Nizzardo, Simona Scartoni, Alessandra Scordari, Mariagiuseppa Matera, Carlo Alberto Maggi, Angela Capriati, Cecilia Simonelli
Journal: Blood (2014)
Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Calin Cainap, Shukui Qin, Wen-Tsung Huang, Ik-Joo Chung, Hongming Pan, Ying Cheng, Masatoshi Kudo, Yoon-Koo Kang, Pei-Jer Chen, Han Chong Toh, Vera Gorbunova, Ferry Eskens, Jiang Qian, Mark D. McKee, Justin L. Ricker, Dawn M. Carlson, Saied El Nowiem
Journal: Journal of Clinical Oncology (2013)

249 Background: Linifanib (ABT-869; Lin) is a potent and selective inhibitor of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinase families. In a phase II trial in patients (pts) with advanced HCC, Lin showed clinical activity (objective response rate [ORR] 10.5% in Child-Pugh A [CPA] pts). This open-label, global phase 3 trial evaluated Lin versus sorafenib (Sor) as first-line therapy in pts with advanced CPA HCC (NCT01009593). Methods: Pts were randomized 1:1 to Lin 17.5 mg QD or Sor 400 mg BID and stratified by region (non-Asia/Japan/rest of Asia), ECOG performance status (0/1), vascular invasion or extrahepatic spread (yes/no) and HBV infection (yes/no). The primary efficacy endpoint was overall survival (OS); both non-inferiority (margin 1.0491) and superiority hypotheses were to be tested. Secondary efficacy endpoints included time to progression (TTP) and ORR, using RECIST v1.1. AE severity was graded using NCI-CTCAE v4.0. Results: 1035 pts (median age 60 y, 68% Asian, 65% ECOG 0, 49% HBV, 70% vascular invasion or extrahepatic spread) were randomized at 149 sites in 26 countries. Hazard ratio (HR) for OS was 1.046 (95% CI: 0.896, 1.221). Median OS (95% CI) was 9.1 months (m) (8.1, 10.2) on Lin and 9.8 m (8.3, 11.0) on Sor. For all pre-specifed subgroup analyses, OS HRs ranged from 0.793-1.119, and the 95% CI contained 1.0. TTP HR was 0.759 (95% CI: 0.643, 0.895; p=0.001) favoring Lin. Median TTP (95% CI) was 5.4 m (4.2, 5.6) on Lin and 4.0 m (2.8. 4.2) on Sor. ORR was 13.0% on Lin and 6.9% on Sor. Grade 3/4 AEs, serious AEs and AEs leading to discontinuations, dose interruptions and reductions were more frequent on Lin versus Sor (all p&lt;0.001). Conclusions: Lin and Sor resulted in similar OS in advanced HCC. Predefined superiority and non-inferiority OS boundaries were not met for Lin. Secondary endpoints (TTP and ORR) favored Lin while safety results favored Sor. Clinical trial information: NCT01009593.
Natriuretic Peptide and High-Sensitivity Troponin for Cardiovascular Risk Prediction in Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Mauro Gori, Deepak K. Gupta, Brian Claggett, Elizabeth Selvin, Aaron R. Folsom, Kunihiro Matsushita, Natalie A. Bello, Susan Cheng, Amil Shah, Hicham Skali, Orly Vardeny, Hanyu Ni, Christie M. Ballantyne, Brad C. Astor, Barbara E. Klein, David Aguilar, Scott D. Solomon
Journal: Diabetes Care (2016)

OBJECTIVE Cardiovascular disease (CVD) is the major cause of morbidity and mortality in diabetes; yet, heterogeneity in CVD risk has been suggested in diabetes, providing a compelling rationale for improving diabetes risk stratification. We hypothesized that N-terminal prohormone brain natriuretic peptide (NTproBNP) and high-sensitivity troponin T may enhance CVD risk stratification beyond commonly used markers of risk and that CVD risk is heterogeneous in diabetes. RESEARCH DESIGN AND METHODS Among 8,402 participants without prevalent CVD at visit 4 (1996–1998) of the Atherosclerosis Risk in Communities (ARIC) study there were 1,510 subjects with diabetes (mean age 63 years, 52% women, 31% African American, and 60% hypertensive). RESULTS Over a median follow-up of 13.1 years, there were 540 incident fatal/nonfatal CVD events (coronary heart disease, heart failure, and stroke). Both troponin T ≥14 ng/L (hazard ratio [HR] 1.96 [95% CI 1.57–2.46]) and NTproBNP &amp;gt;125 pg/mL (1.61 [1.29–1.99]) were independent predictors of incident CVD events at multivariable Cox proportional hazard models. Addition of circulating cardiac biomarkers to traditional risk factors, abnormal electrocardiogram (ECG), and conventional markers of diabetes complications including retinopathy, nephropathy, and peripheral arterial disease significantly improved CVD risk prediction (net reclassification index 0.16 [95% CI 0.07–0.22]). Compared with individuals without diabetes, subjects with diabetes had 1.6-fold higher adjusted risk of incident CVD. However, participants with diabetes with normal cardiac biomarkers and no conventional complications/abnormal ECG (n = 725 [48%]) were at low risk (HR 1.12 [95% CI 0.95–1.31]), while those with abnormal cardiac biomarkers, alone (n = 186 [12%]) or in combination with conventional complications/abnormal ECG (n = 243 [16%]), were at greater risk (1.99 [1.59–2.50] and 2.80 [2.34–3.35], respectively). CONCLUSIONS Abnormal levels of NTproBNP and troponin T may help to distinguish individuals with high diabetes risk from those with low diabetes risk, providing incremental risk prediction beyond commonly used markers of risk.
Indirect traumatic optic neuropathy
Authors: Eric L. Singman, Nitin Daphalapurkar, Helen White, Thao D. Nguyen, Lijo Panghat, Jessica Chang, Timothy McCulley
Journal: Military Medical Research (2016)

Indirect traumatic optic neuropathy (ITON) refers to optic nerve injury resulting from impact remote to the optic nerve. The mechanism of injury is not understood, and there are no confirmed protocols for prevention, mitigation or treatment. Most data concerning this condition comes from case series of civilian patients suffering blunt injury, such as from sports- or motor vehicle-related concussion, rather than military-related ballistic or blast damage. Research in this field will likely require the development of robust databases to identify patients with ITON and follow related outcomes, in addition to both in-vivo animal and virtual human models to study the mechanisms of damage and potential therapies.
Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia.
Authors: A F List, C Spier, J Greer, S Wolff, J Hutter, R Dorr, S Salmon, B Futscher, M Baier, W Dalton
Journal: Journal of Clinical Oncology (1993)

PURPOSE To determine the toxicities and maximum-tolerated dose of cyclosporine (CsA) administered with daunorubicin as a modulator of multidrug resistance (MDR) in acute leukemia, and to evaluate response to treatment and its relationship to mdr1 gene expression. PATIENTS AND METHODS Patients with poor-risk acute myeloid leukemia (AML) received sequential treatment with cytarabine (3 g/m2/d intravenously [i.v.]) days 1 to 5, and daunorubicin (45 mg/m2/d) plus CsA as a 72-hour continuous infusion (CI) days 6 through 8 in a phase I/II trial. A loading dose of CsA administered over 1 to 2 hours preceded the CI. CsA dose escalations ranged from 1.4 to 6 mg/kg (load) and 1.5 to 20 mg/kg/d (CI). Whole-blood concentrations of CsA were monitored by immunoassay; plasma concentration of daunorubicin and daunorubicinol were determined by high-pressure liquid chromatography (HPLC). Specimens were analyzed for P-glycoprotein expression, and results confirmed by a quantitative RNA polymerase chain reaction (PCR) assay for the mdr1 gene transcript. RESULTS Forty-two patients are assessable for toxicity and response. P-glycoprotein was detected in 70% of cases. Dose-dependent CsA toxicities included nausea and vomiting (22%), hypomagnesemia (61%), burning dysesthesias (21%), and prolongation of myelosuppression. Transient hyperbilirubinemia developed in 62% of treatment courses and was CsA-dose-dependent. Reversible azotemia occurred in three patients receiving concurrent treatment with potentially nephrotoxic antibiotics. Steady-state blood concentrations of CsA &gt; or = 1,500 ng/mL were achieved in all patients receiving CI doses &gt; or = 16 mg/kg/d. Mean plasma daunorubicin, but not daunorubicinol, levels were significantly elevated in patients who developed hyperbilirubinemia (P = .017). Twenty-six (62%) patients achieved a complete remission (CR) or restored chronic phase and three patients achieved a partial remission (PR) for an overall response rate of 69% (95% confidence interval, 54% to 84%). The response rate was higher in patients who developed hyperbilirubinemia (P = .001), whereas MDR phenotype did not influence response to treatment. Among five patients with MDR-positive leukemia, cellular mdr1 mRNA decreased (n = 1) or was absent from relapsed specimens (n = 4), while mdr1 RNA remained undetectable at relapse in two patients who were MDR-negative before treatment. CONCLUSION High doses of CsA, which achieve blood concentrations capable of reversing P-glycoprotein-mediated anthracycline resistance in vitro, can be incorporated into induction regimens with acceptable nonhematologic toxicity. Transient hyperbilirubinemia occurs commonly with CsA administration and may alter daunorubicin pharmacokinetics. Recommended doses of CsA for phase II and III trials are a load of 6 mg/kg and CI of 16 mg/kg/d.
Changing patterns of practice in the management of nasopharynx carcinoma (NPC): Analysis of the National Cancer Database (NCDB)
Authors: H. Hoffman, J. S. Cooper, R. Weber, K. Ang, K. Porter, C. J. Langer
Journal: Journal of Clinical Oncology (2004)

5501 Background: Standard therapy (Tx) for NPC has evolved over the last 8 yrs. At ASCO in 1996, Al-Sarraf presented a randomized phase III trial showing a survival advantage for concurrent Cisplatin-based chemoradiation (CT/RT) followed by additional CT vs RT alone in the Tx of stage III/IV NPC; 3 yr PFS & OS were respectively 66% & 76% for CT/RT vs 26% & 47% for RT alone. Results were published in 1998 (JCO)4; 16(4) 1310–1317). Methods: We queried the NCDB for two separate periods (1989–1997 & 1998–2001) to determine if these results heralded a change in patterns of care for the Tx of non-metastatic stage III/IV NPC & whether these changes were either ethnicity or age-related. Results: From 1989–1997, 6327 NPC pts in the NCDB matched the eligibility criteria of the Al-Sarraf trial, of whom 67.5% were male (M), 76.2% were Caucasian or African-American (W/B), 16.7% were Asian (A), and 7.1% other (O); from 1998–2001, 2315 pts were entered into the NCDB, of whom 68.9% were M, 75.4% were W/B, 16.6% A, & 8% O. The likelihood of receiving CT/RT between 1989 & 1997 was 38.2% compared to 65.1% for pts treated between 1998 & 2001; the percentage of pts in each period receiving CT/RT based on age, stage & ethnicity is summarized below Conclusions: The patterns of care reflect the results of the (+) intergroup trial. For the more recent diagnostic period, the likelihood of receiving CT/RT for each age, stage, and ethnic cohort increased & nearly doubled for those between 50 & 80 yrs; younger pts, & pts of Asian-American ethnicity were more likely to receive CT/RT. Stages IV pts were more likely to receive CT/RT between 1985 and 1997 compared to stage III pts (41.3% vs 27.6%), but there were no stage-specific differences in the 1998–2001 period. Subsequent analyses will correlate long term survival & patterns of recurrence with treatment (CT/RT vs RT) & determine if ethnic or age-specific differences in outcome exist. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb AstraZeneca
Abstract 19297: Cardiac Specific Deletion of Mcl-1 Leads to Impaired Autophagy and Rapid Development of Heart Failure
Authors: Robert L Thomas, Youngil Lee, David Roberts, Rita Hanna, Xiaoxue Zhang, Shigeki Miyamoto, Mark A Sussman, Åsa B Gustafsson
Journal: Circulation (2012)

Mcl-1 is an anti-apoptotic Bcl-2 protein which is expressed at high levels in the heart compared to other anti-apoptotic Bcl-2 proteins. However, very little is known with respect to how Mcl-1 regulates cell survival in cardiomyocytes. To investigate the functional role of Mcl-1 in the heart, we used a loxP/α-MHC-Cre-recombinase system to generate inducible, cardiomyocyte-specific Mcl-1 knockout mice. Mcl-1 deletion led to rapid contractile dysfunction, cardiac hypertrophy, and interstitial fibrosis in the absence of stress. Surprisingly, loss of Mcl-1 did not activate apoptosis. Instead, Mcl-1 deficiency led to necrotic cell death characterized by mitochondrial permeability transition pore (mPTP) opening, mitochondrial swelling, and cellular rupture. To clarify how mPTP opening and necrosis contribute to heart failure in Mcl-1-/- mice, we generated Mcl-1/Cyclophilin D (CypD) double knockouts. CypD is an essential component of the mPTP, and CypD deficiency has been shown to reduce cardiac necrosis. CypD deletion significantly delayed development of heart failure in Mcl-1-/- mice, but did not rescue the phenotype. Although autophagy is an important cellular quality control mechanism, electron microscopy revealed no autophagosome formation in Mcl-1-/- cardiomyocytes. Further analysis revealed that loss of Mcl-1 led to impaired basal autophagic flux. Western blot analysis for autophagy proteins revealed reduced LC3II/I ratios and accumulation of p62 in Mcl-1-/- hearts. Chloroquine injection, which inhibits the fusion between autophagosomes and lysosomes, led to accumulation of LC3II and p62 in WT hearts but not in Mcl-1-/- hearts. To investigate whether autophagy could be induced in Mcl-1-/- hearts, we subjected mice to acute exercise. Autophagy was rapidly enhanced in wild type hearts after 80 minutes of swimming, but no change in autophagy occurred in Mcl-1-/- hearts. Conversely, adenoviral overexpression of Mcl-1 in rat neonatal cardiomyocytes led to increased LC3 processing and autophagy. These data suggest that, in addition to its anti-apoptotic role, Mcl-1 is essential in initiating autophagy in cardiomyocytes. Increased understanding of Mcl-1 mechanisms in the myocardium may provide new therapeutic avenues for heart disease.
Simplification of cetuximab (Cet) administration: double dose every second week as a 60 minute infusion
Authors: P. Pfeiffer, J. K. Bjerregaard, C. Qvortrup, B. V. Jensen, M. Yilmaz, D. Nielsen
Journal: Journal of Clinical Oncology (2007)

4133 Background: CetIri (Cetuximab and irinotecan (Iri)) is effective in pretreated patients with advanced colorectal cancer (ACRC). Presently it is recommended that Cet is administered weekly. Inspired by a pharmacokinetic study (Tabernero et al, ASCO 2006), and due to long waiting time to begin CetIri in our institutions, we have gradually simplified the administration of CetIri. Methods: From January to September 2005, patients received standard CetIri (Cet loading dose 400 mg/m 2 as a 120 minutes infusion and then weekly Cet 250 mg/m 2 in 60 minutes. Iri 180 mg/m 2 every second week started 1 hour after completion of Cet). From October 2005 we gradually enhanced the simplicity of administration. Presently Cet 500 mg/m 2 is administered every 2 weeks. The first course is infused in 120 minutes followed 1 hour later by Iri 180 mg/m 2 as a 30 minutes infusion. Subsequent courses of Cet are infused in 60 minutes, immediately followed by Iri - resulting in a total treatment time of only 90 minutes per 2 weeks. Results: All patients had ACRC resistant to 5-FU, Iri and Ox and CetIri was offered independently of EGFR expression. 65 consecutive patients with ACRC received standard CetIri and 57 patients biweekly CetIri. There was no difference in patient characteristics. Duration of therapy (4.7 vs 4.1 months), response rate (20 vs 23 %), TTP (5.4 vs 4.8 months) and survival (10.4 vs 9.8 months) were similar. Grade 3–4 non-hematological toxicity was rare (skin toxicity: 8 vs 7%, diarrhea: 10 vs 8 %, fatigue: 8 vs 5 %). Conclusion: Salvage therapy with simplified CetIri every second week is a convenient, effective and well-tolerated regimen in ACRC patients resistant to 5-FU, Iri, and Ox. To confirm results an ongoing phase II study will include 100 patients. No significant financial relationships to disclose.
Prognostic importance of performance status (PS) in small cell lung cancer (SCLC): A North Central Cancer Treatment Group (NCCTG) investigation
Authors: N. R. Foster, S. J. Mandrekar, S. E. Schild, G. D. Nelson, K. M. Rowland Jr, R. L. Deming, T. F. Kozelsky, J. R. Jett, R. S. Marks, A. A. Adjei
Journal: Journal of Clinical Oncology (2008)

19041 Background: We previously presented a pooled analysis of 1623 patients (pts) from 15 SCLC trials exploring the prognostic importance of many baseline factors on overall survival (OS), among which PS, age, gender, and stage were found to be significant. This present study assessed the prognostic importance of PS in the presence of other baseline factors within limited-stage (LD-SCLC) and extensive disease (ED-SCLC) separately. Methods: Data on 688 pts with LD-SCLC and 935 pts with ED-SCLC disease were included. Age, gender, PS, body mass index, creatinine levels, hemoglobin levels, white blood cell counts, platelet counts, bilirubin levels, and number of metastatic sites were tested for prognostic significance for OS both univariately and multivariately using a Cox Model. Models were stratified by protocol, and analyses carried out on the complete data available based on the selected covariates within each stage. A split sample approach (70% and 30%) was used for model development and validation within each stage. Results: 92% of the LD-SCLC pts and 76% of the ED-SCLC pts had ECOG PS of 0–1. Poorer PS led to worse OS within ED- SCLC, but not within LD-SCLC (median OS for PS 0, 1, 2 within ED-SCLC were 11.2, 9.5, and 7.4 months, respectively). Other negative prognostic factors included increased age and male gender within LD-SCLC and ED-SCLC, and increased number of metastatic sites at baseline within ED-SCLC. Conclusions: PS is a strong and independent prognostic factor in ED-SCLC, and therefore it is critical to stratify for PS in this subgroup. More research is needed to assess the importance of PS within LD-SCLC. Title: Prognostic Factors for OS within LD-SCLC and ED- SCLC Factor (LD) HR 95% CI P (ED) HR 95% CI P Age (10 yr increase) 1.19 1.07- 1.32 0.001 1.10 1.01- 1.19 0.03 Gender (Male vs. Female) 1.25 1.05- 1.48 0.01 1.23 1.07- 1.41 0.004 PS 1 vs. PS 0 1.08 0.90- 1.29 0.45 1.24 1.04- 1.48 <0.0001 PS 2 vs. PS 0 1.23 0.87- 1.72 0.45 1.70 1.39- 2.09 <0.0001 No. of metastatic sites (2 + vs. 0, 1) NA NA NA 1.36 1.19- 1.56 <0.0001 LD = Limited Stage SCLC, ED = Extensive Stage SCLC, HR = Hazard Ratio, CI = Confidence Interval, P = p-value No significant financial relationships to disclose.
Phase I trial of weekly short infusion of single agent docetaxel in patients with advanced NSCLC/MBC.
Authors: Hsing-Ju Pan, Meng-Yi Tasi, Guang-Chang Huang, Wen-Tsung Huang, Tsai-Yun Chen, Wu-Chou Su, Chao-Jung Taso
Journal: Annals of Oncology (2000)
First-line phase II trial of sorafenib (BAY 43–9006) in patients with advanced renal cell carcinoma unsuitable for cytokine treatment
Authors: P. Maroto-Rey, J. Bellmunt, J. M. Trigo, V. Guillem, J. A. López-Martín, J. Carles, A. Antón-Torres, L. Urruticoechea
Journal: Journal of Clinical Oncology (2007)

15640 Background: Sorafenib (BAY 43–9006) is a serine/threonine and receptor tyrosine kinase inhibitor that prevents tumor cell proliferation and angiogenesis. The objective of this open-label, phase II trial was to determine median progression-free survival (PFS) following sorafenib therapy in patients with renal cell carcinoma (RCC) unsuitable for cytokine treatment. Methods: Eligible patients had cytologically or histologically confirmed clear cell RCC; Eastern Cooperative Oncology Group (ECOG) Performance Status 0–1; adequate renal, liver and medullar function; no active central nervous system metastases; had received no previous treatment with antiangiogenic agents; and had at least one evaluable lesion. Sorafenib was given as first-line treatment in patients unsuitable for cytokine therapy, defined as being intolerant to or ineligible for immunotherapy. Treatment consisted of oral sorafenib 400mg twice daily continuously until disease progression or unacceptable toxicity. The primary endpoint was PFS; secondary endpoints were response rate according to Response Evaluation Criteria in Solid Tumors, tolerability and overall survival. Results: Twenty-six patients were enrolled between March and July 2006 (median age: 68.5 years [48–82]; male/female: 17/9, ECOG Performance Status 0: 11 patients; prior nephrectomy: 19 patients). The main metastatic locations were lung and bone, 14 patients had = 2 metastatic lesions, and 2 patients had abnormal lactate dehydrogenase levels. As of 31 December 2006, with a median follow-up of 6.4 months, the median PFS had not been reached. In 19 patients evaluable for response, the overall clinical benefit rate was 68.4% (1 complete response; 1 partial response; 11 stable disease). Six patients experienced serious adverse events, only one of which was related to treatment. Conclusions: Sorafenib first-line therapy is a tolerable alternative for patients unsuitable for cytokine treatment. Final PFS data will be available in June 2007. No significant financial relationships to disclose.