tbuckley/cabot-search huggingface dataset:
Gemtuzumab ozogamycin (GO) and toxic mortality (TM) in children and adolescents with acute myeloid leukemia (AML) enrolled on Children’s Oncology Group (COG) trial AAML0531.
Authors: Jaszianne A. Tolbert, Lillian Sung, Richard Aplenc, Todd Allen Alonzo, Yi-Cheng Jim Wang, Robert B Gerbing, Soheil Meshinchi, Alan S. Gamis
Journal: Journal of Clinical Oncology (2015)

10008 Background: Survival benefit in children with AML using GO was seen in COG AAML0531, though with greater TM. This retrospective analysis examines the overall causes of mortality focusing on the impact of GO and other potential risk factors of TM. Methods: Patients with de novoAML were randomized to chemotherapy with (GO) or without GO (noGO). Low risk and intermediate risk patients without a matched sib donor received 5 chemotherapy courses while all others received 3 chemotherapy courses and stem cell transplant (SCT). GO included a 3mg/m2/dose on day 6 of Induction I and, if not receiving SCT, on day 7 of Intensification II. Induction death (ID) was defined as any death during the two induction courses. Treatment-related mortality (TRM) was defined as death in the intensification cycles while in complete remission. ID and TRM risk factoring in patient, disease and treatment factors were analyzed. SCT recipients were censored after Intensification I. Results: 1,022 patients (511 per arm) age 0-29 yrs enrolled; 49 experienced first event death during therapy. 22 (2%) died in induction and 29(3%) died while in remission. ID was identical between arms (n = 11), with most deaths in Induction I. TRM occurred more frequently among GO recipients (NoGO 9[2%] v GO 18[4%]; p = 0.096). The majority of TRM occurred in Intensification II and III (NoGO 9[100%] v GO 16[89%]). Infection-related complications were the main cause of all TM (NoGO 13[65%] v GO 19[65%]). ID was proportionately greater in infants < 1yo (p = .01) yet no infant experienced TRM. Multivariate analysis excluding infants showed that WBC > / = 100,000 (OR 3.67, p = 0.013) and non-white race (OR 3.45, p = 0.018) were risk factors for ID. The only significant negative impact upon TRM was obesity (OR 3.33, p = 0.01). Conclusions: GO did not increase ID, but did non-significantly increase TRM during intensification in those not going to SCT. Excluding infants, high WBC and non-white race were significant risk factors for ID whereas obesity was the primary risk factor for TRM. As infection was the primary cause of all TM, continued focus on preventing and treating infection in these identified risk groups is imperative. Clinical trial information: NCT00372593.
Association of genetic variants in obesity-related genes with tumor recurrence in stage II/III colon cancer.
Authors: Robert D. Ladner, Armin Gerger, Wu Zhang, Melissa Janae Labonte, Dongyun Yang, Felicitas Lenz, Cosima Lenz, Pierre Oliver Bohanes, Yan Ning, Thomas Winder, Peter M.D. Wilson, Leonor Benhaim, Rita El-Khoueiry, Anthony B. El-Khoueiry, Syma Iqbal, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2012)

3584 Background: High body mass index (BMI) is an established risk factor for colorectal cancer incidence and death. Recent studies found obesity before the diagnosis of colon cancer was associated with worse survival compared with normal weight. Single nucleotide polymorphisms (SNPs) of obesity-related gene have been related with different cancer risk including colorectal cancer. Here we tested the hypothesis whether SNPs in obesity-related genes (PPAR, LEP, NFKB, CD36, DRG1, NGAL, REGIA and DSCR1) may predict tumor recurrence in adjuvant colon cancer. Methods: Either blood or FFPE tissue specimens were obtained from 234 patients (107 females and 127 males; median age 59 years (range 22–78 years)) with stage II (105 patients) or III (129 patients) colon cancer at the University of Southern California/Norris Comprehensive Cancer Center. The median follow-up was 4.4 years. SNPs in obesity-related genes were determined by PCR-RFLP or PCR-based direct sequence. The primary endpoint of the study was time to tumor recurrence (TTR). Results: in univariable analysis, PPAR rs1801282 and DSCR1 rs6517239 were independently associated with time to tumor recurrence (TTR). Patients with PPAR CC genotype had longer median TTR 9.4 months (95% C.I: 5.6, 12.4+) compared to those with CG genotype, had median TTR 3.4 months (95% C.I: 1.7, 16.8+)(p=0.04, log-rank test). Patients with DSCR1 AA genotype had shorter median TTR 6.6 months (95% C.I: 4.0, 16.8+) compared to those with AG and GG genotypes, which had longer median TTR 9.4 months (95% C.I: 5.7, 10.7+)(p=0.027, log-rank test). The multivariate analysis adjusting for stage and type of adjuvant therapy showed a trend in the association between PPAR rs1801282 and DSCR1 rs6517239 and time to recurrence (Wald test p=0.08 and 0.058, respectively). Conclusions: Our preliminary results demonstrated polymorphisms in obesity-related gene might be potential molecular markers to predict TTR in adjuvant colon cancer. Further large and biomarker embedded trial needed to confirm our findings.
ABT-414 in patients with advanced solid tumors likely to overexpress the epidermal growth factor receptor (EGFR).
Authors: Glenwood D. Goss, Everett E. Vokes, Michael S. Gordon, Leena Gandhi, Kyriakos P. Papadopoulos, Drew Warren Rasco, Michelle Pedersen, Judee S. Fischer, Katharine Chu, William Ames, Hao Xiong, Ho-Jin Lee, Jiewei Zeng, Lisa Roberts-Rapp, Peter Ansell, Ed Reilly, Kyle D. Holen, Anthony W. Tolcher
Journal: Journal of Clinical Oncology (2015)

2510 Background: Aberrant EGFR expression and signaling has been identified as a hallmark of cancer growth and survival. ABT-414 is an antibody-drug conjugate composed of the antibody ABT-806, targeting active EGFR/mutant EGFRvIII, linked to the anti-microtubule agent monomethylauristatin F. ABT-414 has shown potent antitumor activity in several EGFR-overexpressing tumor xenografts. This phase 1/2 trial evaluates the safety, pharmacokinetics (PK), and efficacy of ABT-414 in patients (pts) with solid tumors (NCT01741727). Herein, we report the ABT-414 maximum tolerated dose (MTD) and preliminary efficacy in an expanded cohort of pts with EGFR-amplified tumors. Methods: In the dose-escalation cohorts, pts ( ≥ 18 years) with advanced EGFR+ solid tumors received escalating doses of ABT-414 intravenously in 2 schedules, either on day 1 or on days 1 and 8 Q3W. Primary objectives included safety, determination of the MTD, the recommended phase 2 dose (RP2D), and the PK profile. In the EGFR-amplified cohort, pts received ABT-414 at the MTD to further assess ABT-414 safety and preliminary efficacy related to EGFR expression. Results: By 15 Dec 2014, 53 pts received ABT-414 (dose-escalation cohorts, n = 48; EGFR-amplified cohort, n = 5). Most common treatment-emergent adverse events (TEAEs) were blurred vision (49%, commonly due to transient microcystic keratopathy), fatigue (42%), nausea (42%), and dry eyes (36%). Most common grade 3/4 TEAEs were keratitis (8%), blurred vision (6%), dyspnea (6%), and hyponatremia (6%). Eye pain was the only DLT (n = 1 at 2 mg/kg Q3W). Due to several grade 3 ophthalmologic TEAEs in a single pt treated at 4.0 mg/kg, this dose was considered to exceed the MTD and the RP2D was set at 3 mg/kg Q3W. ABT-414 was the predominant circulating antibody with low levels of unconjugated ABT-806. PK exposure of ABT-414 appeared to be dose proportional. In the EGFR-amplified cohort, 1 partial response was observed (triple-negative breast cancer). Stable disease occurred in 11 of 53 pts (21%). Conclusions: The RP2D of ABT-414 (Q3W) is 3 mg/kg. The preliminary efficacy observed in pts with EGFR-amplified tumors suggests antitumor activity and warrants further investigation in this select population. Clinical trial information: NCT01741727.
Influence of comorbidity on guideline concordant care for breast cancer: Findings from the Center for Disease Control and Prevention National Program of Cancer Registry (NPCR) patterns of care study.
Authors: Gretchen Genevieve Kimmick, Steven Fleming, Susan A Sabatino, Xiao-cheng Wu, Wenke Hwang, J. Frank Wilson, Mary Jo B. Lund, Rosemary Cress, Roger T. Anderson
Journal: Journal of Clinical Oncology (2012)

6052 Background: Comorbidity burden predicts cancer treatment and may influence outcome. We explore the relationship of specific comorbid illnesses with receipt of guideline concordant care for early stage breast cancer. Methods: The NPCR’s Patterns of Care study reabstracted the medical records of breast cancer cases diagnosed in 2004 from 7 cancer registries. We included women with nonmetastatic in situ and invasive breast cancer, known hormone receptor status, node status, and tumor size. Guideline-concordant management, including surgery, radiation, chemotherapy and endocrine components, was based on NCCN guidelines using tumor size, nodal and hormone receptor status. Comorbidity was measured according to the Adult Comorbidity Evaluation Index (ACE). Multivariate logistic regression models were used to determine factors associated with guideline-concordant care, and included overall ACE scores and 26 separate ACE comorbidity categories, as well as age, race, hormone receptor status, and HER2 status. Results: The study sample included 6904 women (mean age 58.7 and range 20-99 years, 76% white, 45% with ACE comorbidity score of 0, 70% ER and/or PR+, 13% HER2+). Overall, 64% received guideline-concordant care. Receipt of guideline-concordant care varied by overall comorbidity burden (71% for none; 65% for minor; 63% for moderate; 50% for severe; p&lt;0.05). The presence of hypertension (OR 1.26, 95% CI 1.08-1.48) predicted receipt of guideline concordant care, whereas, peripheral artery disease (OR 0.44, 95% CI 0.21-0.93), diabetes (OR 0.78, 95% CI 0.63-0.97) and dementia (OR 0.31, 95% CI 0.13-0.74) predicted lack of guideline concordant care. Older age, black race, and hormone receptor positivity were associated with less, and HER2 positivity with receipt of more guideline-concordant care. Conclusions: Overall those with more comorbidity burden received less guideline-concordant care. However, the effects vary by specific conditions. The odds of receiving guideline-concordant care was greater in those with hypertension and less in those with peripheral arterial disease, diabetes, and dementia.
FOLFIRI plus sunitinib versus FOLFIRI alone in advanced chemorefractory esophagogastric cancer patients: A randomized placebo-controlled multicentric AIO phase II trial.
Authors: Markus Hermann Moehler, Peter C. Thuss-Patience, Hans-Joachim Schmoll, Susanna Hegewisch-Becker, Hansjochen Wilke, Salah-Eddin Al-Batran, Florian Weissinger, Frank Kullmann, Ludwig Fischer Von Weikersthal, Jens T. Siveke, Stephan Kanzler, Carl Christoph Schimanski, Melanie Otte, Lukas Schollenberger, Jochem Koenig, Peter Robert Galle
Journal: Journal of Clinical Oncology (2013)

4086 Background: Sunitinib is an receptor tyrosine kinase (RTK) inhibitor of VEGFR1-3, PDGFR-α-β, and other RTK. After we established Sunitinib (Sun) alone associated with limited response rate (RR) and good tolerability in refractory advanced esophagogastric cancer patients (Moehler et al. EUR J Cancer. 2011, 47: 1511), this double-blinded placebo-controlled phase II evaluated safety and efficacy of SUN as add-on in second-line or third-line FOLFIRI (ClinicalTrials.gov NCT01020630). Methods: Patients with failure of any prior docetaxel and/or platinum-based chemotherapy were randomized to receive 6-week cycles including FOLFIRI two weekly and SUN (25 mg) versus (vs) placebo (PLA) daily for 4 consecutive weeks followed by a 2-week rest. Primary endpoint was progression-free survival (PFS). Results: 91 randomized patients (ITT) had similar characteristics in both groups (SUN/PLA 45/46). Both groups had 2.7 treatment cycles. Objective RR was 20/29%, and tumor control rate was 58/56 % for SUN/PLA, respectively. Median PFS was similar for SUN vs. PLA with 3.6 vs. 3.3 months, respectively (HR 1.11; 95%CI 0.70-1.74, P = 0.66). Median overall survival (OS) was longer for SUN vs. PLA with 10.5 vs. 9.0 months, in ITT (HR 0.816; 95%CI 0.50 - 1.34, P = 0.42, one-sided 0.21) and in the per protocol population (HR 0.71; 95%CI 0.41 - 1.24, P = 0.23) respectively. No unexpected higher toxicities, SAE or SUSAR occurred with SUN. For SUN/PLA, all grade AEs (%) possibly related to study drug were nausea 49/47%, fatigue 36/29%, vomiting 27/29%, diarrhoea 36/38%, neutropenia 62/22%, stomatitis 27/20%, and palmar-plantar erythrodysaesthesia 13/3%, and Grade 3+ AEs (%) were neutropenia 56/20%, diarrhoea 2/13%, nausea 7/7%, fatigue 0/9% and pain 0/9%, respectively. Performed quality of life outcomes were mostly in favor of Sunitinib. Conclusions: In our phase II trial, Sunitinib added to FOLFIRI increased hematotoxicity and did not improve response rates or PFS in chemotherapy-resistant GC patients. Since the regimen was safe and patients had a trend to better OS, biomarker analyses will be performed to identify subgroups that benefit from add-on Sunitinib. Clinical trial information: NCT01020630.
Phase II trial of vorinostat (VOR) combined with temozolomide (TMZ) and radiation therapy (RT) for newly diagnosed glioblastoma (GBM) (Alliance N0874/ABTC-0902).
Authors: Evanthia Galanis, S. Keith Anderson, C. Ryan Miller, Jann Nagina Sarkaria, Kurt A. Jaeckle, Jan C. Buckner, Keith L. Ligon, Karla V. Ballman, Dennis Frederic Moore, Manmeet Singh Ahluwalia, Eudocia Quant Lee, Elizabeth Robins Gerstner, Glenn Jay Lesser, Michael Prados, Stuart A. Grossman, Caterina Giannini, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2014)

2030 Background: VOR is a histone deacetylase inhibitor that represents a rational targeted agent in GBM treatment. Given its single agent activity in recurrent disease (Galanis et al 2009) and radiosensitizing properties, this phase II trial was designed to test the addition of VOR to standard chemoradiation in newly diagnosed GBM patients (pts). Methods: Pts received vorinostat at 300 mg/day, days 1-5 weekly during RT in combination with temozolomide (75 mg/m2/day). Following a 4-6 week rest period, pts received up to 12 cycles of standard adjuvant TMZ in combination with VOR at a dose of 400 mg/day on days 1-7 and 15-21 of each cycle (Lee et al, 2012). Results: A total of 107 patients were accrued to this single arm trial. This preliminary report is based on mature outcome data in 73 patients. Final data analysis will be presented at the meeting. With a median follow up of 11.3 months (range 0.8-21.6 months), OS 15, (survival status at 15 mo, primary trial endpoint) was 39.1% with a median OS of 14.3 months and PFS of 8.1 months. MGMT methylation status is available in 52 pts; OS 15 and PFS were 44.4% vs 11.1% and 8.1 vs 6.4 mo in methylated and unmethylated pts respectively. Most common grade 3/4 toxicities were lymphopenia (32%), thrombocytopenia (28%), neutropenia (22%), fatigue (12.1%), anemia (8.4%) and anorexia (6.5%). There were no treatment related deaths. Conclusions: The HDAC inhibitor VOR in combination with TMZ and RT has tolerable toxicity in newly diagnosed GBM patients. Initial analysis based on mature outcome data in 70% of the evaluable patients does not indicate an improvement in outcome; final data will be presented at the meeting. Ongoing RNA sequencing analysis of baseline tumor tissue in 80 pts will assess if a 43 gene VOR responsive signature, identified in preclinical models, can define subgroups of patients deriving benefit from treatment. Clinical trial information: NCT00731731.
Clinical significance of LKB1 protein and gene expression in breast cancer.
Authors: I Chun Chen, Yuan-Ching Chang, Yen-Shen Lu, Chiun-Sheng Huang, Wen-Hung Kuo, Ming-Yang Wang, Kuan-Ting Kuo, Pei-Fang Wu, Tsu-Hsin Hsueh, Ching-Hung Lin, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2015)

e11538 Background: LKB1 is a tumor suppressor and decrease of LKB1 expression may lead to mTOR activation. Because of limited studies with small sample size, the clinical significance of LKB1 expression in breast cancer remained unclear. Methods: LKB1 protein expressions were analyzed by immunohistochemistry (IHC) in tumors from 569 and 277 patients with stage I-III breast cancer diagnosed at National Taiwan University Hospital (NTUH cohort) and Mackay Memorial Hospital (MMH cohort) in Taiwan, respectively. LKB1gene expressions were obtained from the METABRIC dataset which included 988 and 975 patients with stage I-III breast cancer in discovery and validation cohorts, respectively. The correlation of LKB1 protein and gene expressions with clinicopathological factors and patients’ outcome were analyzed. Results: In the four cohorts, the correlation of estrogen receptor (ER) expressions with LKB1 in two cohorts is statistically significant, but in opposite direction. There was no significant association between LKB1 expressions with other clinicopathological factors. LKB1 protein expression did not predict relapse-free survival or overall survival (OS) in the NUTH and the MMH cohorts. LKB1gene expression did not predict breast cancer-specific survival or OS in the two METABRIC cohorts. In a subgroup analysis from the NTUH and MMH cohorts, high LKB1 protein is predictive of better overall survival in HER2 positive breast cancer patients (p = 0.023). Conclusions: This large scale study identifies a potential but opposite association between LKB1 expression with ER in two cohorts. LKB1 was not prognostic except as a potential overall survival predictor in a subset of HER2 positive patients.
Clinical, pharmacodynamic (PD), and pharmacokinetic (PK) evaluation of cediranib in advanced hepatocellular carcinoma (HCC): A phase II study (CTEP 7147).
Authors: Andrew X. Zhu, Marek Ancukiewicz, Jeffrey G. Supko, Lawrence Scott Blaszkowsky, Jeffrey A. Meyerhardt, Thomas Adam Abrams, Nadine Jackson McCleary, Pankaj Bhargava, Charles S. Fuchs, David P. Ryan, Rakesh K. Jain, Dan G. Duda
Journal: Journal of Clinical Oncology (2012)

4112 Background: Sorafenib remains the only approved systemic therapy in HCC. We performed a phase II study of cediranib (AZD2171)—a more potent and selective pan-VEGF receptor inhibitor—in advanced HCC patients (pts). Methods: Eligibility criteria included unresectable or metastatic measurable HCC, ECOG PS ≤2, CLIP score ≤3, and adequate organ function. Patients received cediranib at 30 mg po qd continuously (4-wk cycle). The primary endpoint was progression free survival (PFS). We also assessed overall survival (OS) and response rates, steady-state PK of cediranib, and blood circulating biomarkers. Results: Since 6/16/09, we have enrolled the targeted 17 pts required for the first stage of the planned study: ECOG 0/1/2=5/11/1, CLIP 1/2/3=6/4/7, Child A/B=14/3, BCLC C=17. Nine pts had prior sorafenib. The best response was stable disease in five pts (29%). The median PFS was 5.3 months (95% CI: 3.5-9.7). The median OS was 11.7 months (95% CI: 7.5-13.6). Grade 3 toxicities included hypertension (29%), hyponatremia (12%), elevated SGOT (12%) and one pt each (6%) in SGPT, fatigue, hyperbilirubinemia, cardiac ischemia, and proteinuria. Grade 4 pulmonary embolism and brainstem hemorrhage occurred in 1 pt each. Steady-state PK parameters (mean±SD) were, C min , 22±21 ng/mL; C max , 55±33 ng/mL; AUC τ , 887±503 ng*h/mL. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2 and Ang-2 decreased significantly after cediranib treatment (p&lt;0.05). PFS was inversely correlated with baseline levels of bFGF, sVEGFR2 and VEGF, and OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-alpha and CD34+CD133+ hematopoietic progenitor cells (p&lt;0.05). Conclusions: Cediranib at 30 mg daily is associated with high frequency of grade 3 hypertension and shows preliminary evidence of antitumor activity in advanced HCC pts. Exploratory studies confirmed potential PD and response biomarkers of anti-VEGF therapy. Cediranib exhibits similar PK in HCC pts as in those with other tumor types and normal/near normal hepatic function. This study was stopped by AstraZeneca after discontinuation of cediranib development for unrelated factors.
Symposium International sur la Psychothérapie de la Schizophrénie
Authors: G. Benedetti, P.C. Racamier, R. Schindler, W.Th. Winkler, Martti Siirala, A. Fuchs-Kamp, A. Storch, F.W. Beese, F. Meerwein, H. Bach, M. Sechehaye, K. Ernst, N. Elrod, Gerdhild von Staabs, Torsten Herner, Kauko Kaila, Georg Schwöbel, M. Boss
Journal: Psychotherapy and Psychosomatics (1957)
FoxM1 as a potential therapeutic target for triple-negative breast cancer.
Authors: Cha Kyong Yom, Kyung-Min Lee, Wonshik Han, Sung-Won Kim, Hyeong-Gon Moon, Dong-Young Noh
Journal: Journal of Clinical Oncology (2013)

e22063 Background: Elevated expression or activity of the transcription factor forkhead box M1 (FoxM1) is associated with development and progression of breast cancer. In this study, we show that whether inhibition of FoxM1 in triple negative breast cancer (TNBC) cell lines causes the changes of cancer progress and response to the treatment. Methods: We inhibited FoxM1 using thiostrepton (FoxM1 inhibitor) and identified the activity of VEGF, cyclin B, cyclin D1, p27, CD44 and cleaved capase-3 in MDA-MB-231 cells. Invasion assay was evaluated in BT-20 cells and combination with cisplatin and inhibition of FoxM1 were treated in triple negative breast cancer (TNBC) cell lines including MDA-MB-231, MDA-MB-157, and BT-20. Results: When FoxM1 was inhibited using thiostrepton in MDA-MB-231 cells, expressions of VEFG, cyclin B, cyclin D1, p27, and CD44 were decreased. On the other hand, cleaved caspase-3 expression was increased. Intersetingly, response to inhibition of FoxM1 depended on the expression of p53 in each cell lines. Invasiveness of BT-20 cells is markedly reduced by inhibitioh of FoxM1. Co-treatment with thiotrepton and cisplatin synergistically induced apoptosis of breast cancer cells in MDA-MB-231, MDA-MB-157, and BT-20. Conclusions: Inhibition of FoxM1 increases apoptosis and decreases invasiveness and VEGF exprsssion of TNBC cells. And when inhibition of FoxM1 combines with cisplatin treament, synergistic effect was shown. Therefore, FoxM1 is valuable as a potential target for not only anticancer activity but also overcoming cisplatin resistance in TNBC.