bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT033: Phase 1b study of heat shock protein 90 inhibitor onalespib in combination with paclitaxel in patients with advanced, triple-negative breast cancer (NCT02474173)
Authors: Wesolowski Robert , Lustberg Maryam B. , Mrozek Ewa , Layman Rachel , Reinbolt Raquel , Poi Ming , Osman Nadia , Lively Andrea , Stephens Julie , Grever Michael , Ramaswamy Bhuvaneswari 
Published: July 2016

Abstract
Background: Heat shock protein 90 (HSP90) is a molecular chaperone that is required for proper folding and stabilization of proteins. Client proteins of HSP90 include many mediators of signal transduction known to be over-activated in triple negative breast cancer such as AKT, EGFR, members of RAS/MAPK signaling pathways and androgen receptor. Expression of HSP90 has been found to be upregulated in multiple triple negative breast cancer cell lines and associated with poor outcome of breast cancer patients. In addition, over-expression of HSP90 client proteins such as AKT and c-RAF has been implicated in paclitaxel resistance. Onalespib (AT13387) is a synthetic non-ansamycin small molecule that acts as an inhibitor of HSP90 by binding to the amino terminal of the protein and has dissociation constant (Kd) of 0.71 nM.
Materials and Methods: Patients with inoperable or metastatic triple negative or weakly hormone receptor positive breast cancer are treated with onalespib and paclitaxel on days 1, 8, 15 every 28 days. Paclitaxel is given at a standard dose of 80 mg/m2 while the dose of onalespib is gradually increased using standard 3+3 design (see table). In order to assess the effect of each drug on pharmacokinetics of the other drug, onalespib is given on day -7 prior to cycle 1 and skipped on day 1 of cycle 1 during which paclitaxel in administered alone. The primary objective of the study is to determine recommended phase 2 dose and assess the toxicity profile of the combination. The secondary objectives include effect of onalespib on pharmacokinetics of paclitaxel and effect of paclitaxel on pharmacokinetics of onalespib. Overall response rate, response duration and progression-free survival will also be assessed. Dose Escalation ScheduleDose LevelDoseOnalespib (mg/m2 IV on days 1, 8, 15)Paclitaxel (mg/m2 IV on days 1, 8, 15)Level -110080Level 112080Level 215080Level 320080Level 426080
Conclusion: The study opened to accrual on January 15, 2016 and is currently enrolling the first 3 patients to dose level 1.
Citation Format: Robert Wesolowski, Maryam B. Lustberg, Ewa Mrozek, Rachel Layman, Raquel Reinbolt, Ming Poi, Nadia Osman, Andrea Lively, Julie Stephens, Michael Grever, Bhuvaneswari Ramaswamy. Phase 1b study of heat shock protein 90 inhibitor onalespib in combination with paclitaxel in patients with advanced, triple-negative breast cancer (NCT02474173). [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 CT033.
Abstract CT075: Tumor mutation status will predict metabolic response to metformin in lung cancer treated with stereotactic body radiation therapy (SBRT)
Authors: Skinner Heath D. , Guerrero Thomas , Hobbs Brian , Court Laurence , Nitsch Paige L. , Heymach John 
Published: July 2016

Abstract
At present, there are over 100 clinical trials examining the role of metformin in malignancy, either alone or in combination with chemotherapy. However, despite significant preclinical data, trials examining the role of metformin as a radiosensitizer are few. Moreover, the effects of endogenous tumor mutations on response to metformin are unknown, as some data suggests that certain mutations (eg. TP53, STK11) may confer sensitivity to this agent. Finally, the effects of metformin on FDG-uptake in solid tumors is far from clear, as this agent can actually lead to an increased uptake of FDG in normal bowel. Because of these questions, we have designed an imagining-guided trial of 70 patients, randomized 6:1 in favor of metformin treatment in patients with non-small cell lung cancer to be treated with stereotactic body radiotherapy (SBRT). Patients receive either placebo or metformin at a loading dose of 1,000 mg per day for one week followed by 1-2 weeks of metformin at 2,000 mg per day. Prior to study entry, an FDG-PET scan is performed which is then repeated after 2-3 weeks of metformin treatment. Metformin or placebo is maintained throughout SBRT and the standard daily cone-beam CTs are taken. Metformin or placebo stops at the end of SBRT followed by an additional FDG-PET scan 6 months after completion of therapy. All tumors with available tissue will be subjected to targeted sequencing. The primary outcome is FDG-PET response following initial metformin or placebo monotherapy as well as at 6 months. Secondary outcomes include the effect of common mutations (TP53, STK11, Kras) on metformin FDG-PET response. Currently, 14 patients have been registered for this trial. We anticipate that this study will provide a unique insight on how metformin affects FDG-PET response, if this response is affected by tumor mutation status, and provide preliminary data on the clinical efficacy of metformin in the setting of SBRT.
Citation Format: Heath D. Skinner, Thomas Guerrero, Brian Hobbs, Laurence Court, Paige L. Nitsch, John Heymach. Tumor mutation status will predict metabolic response to metformin in lung cancer treated with stereotactic body radiation therapy (SBRT). [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 CT075.
Abstract CT091: A neoadjuvant co-clinical trial in triple-negative breast cancer patients with genomic discovery analysis
Authors: Ademuyiwa Foluso O. , Li Shunqiang , Luo Jingqin , Skinner Tracy , Hoshower Jason , Ma Cynthia X. , Weilbaecher Katherine , Naughton Michael , Hernandez-Aya Leonel , Mardis Elaine R. , Ellis Matthew J. 
Published: July 2016

Abstract
Background: Patients with TNBC who do not achieve a pathologic complete response (pCR) or near pCR have high rates of relapse, due to chemotherapy resistance, within the first few years after their diagnosis. Molecular biomarkers predictive for chemotherapy sensitivity are lacking. This ongoing trial is evaluating carboplatin and docetaxel in the neoadjuvant setting to determine whether these drugs will increase the pCR rate compared to historical controls. Correlative studies include exome and transcriptome sequencing on samples acquired from patients as a means to decipher the genomic architecture and clonal evolution of those who achieved a pCR compared to those who did not. The simultaneous development of patient derived xenografts (PDX) from host tumors is also planned.
Methods: Patients with clinical stage 2 or 3 histologically confirmed TNBC will receive six cycles of neoadjuvant carboplatin AUC 6 and docetaxel 75 mg/m2 every 3 weeks, followed by definitive surgery. Forty-one eligible patients will be treated according to this protocol, permitting us to attain a power of 83% to detect our expected pCR rate of 54% compared to the historical 35% rate, based on a two-sided exact binomial test at the 4.8% significance level. Eligibility: tumor size at least 2 cm, adequate organ and bone marrow function, no bilateral or inflammatory breast cancer, no invasive cancer within 5 years, ECOG performance status of ? 2, no prior sentinel lymph node biopsy. Tissue collection for xenografting and correlative studies will occur at baseline, at cycle 1 day 3, and at surgery. The primary objective is to determine the pCR rate, defined as the absence of invasive cancer in breast or nodes at definitive surgery. Secondary and exploratory objectives include xenografting rates, evaluation of mutational signatures of chemotherapy resistance and response, and comparison of chemotherapy responses between patients and their xenografts. The study was activated on 7/7/2014 and is still recruiting. Twenty (48.8% of planned 41) patients have been enrolled and have had baseline tissue banked. Fourteen patients have completed protocol therapy. Three patients have tissue at all 3 time points (9 samples), and are presently being studied by exome and transcriptome sequencing.
Citation Format: Foluso O. Ademuyiwa, Shunqiang Li, Jingqin Luo, Tracy Skinner, Jason Hoshower, Cynthia X. Ma, Katherine Weilbaecher, Michael Naughton, Leonel Hernandez-Aya, Elaine R. Mardis, Matthew J. Ellis. A neoadjuvant co-clinical trial in triple-negative breast cancer patients with genomic discovery analysis. [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 CT091.
Abstract CT115: Pharmacokinetics of standard versus short high-dose dexamethasone therapy in childhood acute lymphoblastic leukemia: results from the UKALL 2011 trial
Authors: Jackson Rosanna K. , Irving Julie AE , Veal Gareth J. 
Published: July 2016

Abstract
Dexamethasone (Dex) is a key component of ALL therapy, with glucocorticoid sensitivity strongly linked to prognosis. However, it also contributes to life threatening toxicities. The ongoing UKALL 2011 trial is investigating a new schedule of Dex (10mg/m2 × 14 days vs 6mg/m2 × 28 days), in an attempt to bring about a more rapid cytoreduction whilst limiting toxicities associated with long term steroid exposure. There are limited data regarding Dex pharmacokinetics, however large variability has been reported in children with ALL (Yang et al. 2008).
For Dex pharmacokinetic studies, blood samples were collected up to 8h post oral administration on one of the first and last three days of induction chemotherapy. Plasma Dex levels were analysed using a validated LC-MS method, with a range of 5-250ng/ml, and non-compartmental pharmacokinetic analysis was performed.
Pharmacokinetic parameters from day one sampling are shown below. Exposure, as defined by AUC0-12h, and Cmax were significantly higher on the short arm (p = 0.0002 and 0.0007, respectively). However there was substantial overlap between the two arms, with a number of patients on the standard arm exhibiting higher exposures than those on short therapy, despite having a longer duration of treatment. This is reflected in the AUC0-12h ranges observed on the two arms (short: 202-1606; standard: 38-1009 hr*ng/mL). Pharmacokinetic profiles also differed between the two days of treatment, with AUC0-12h being significantly higher at the end of induction chemotherapy (n = 37, study day 1: 655 ± 322; study day 2: 894 ± 496 hr*ng/mL, p = 0.003).
Based on these preliminary data it will be important to consider pharmacokinetic variability when analysing the results generated from the UKALL 2011 trial. Further evaluation of relationships between pharmacokinetic variation, dose scheduling and clinical outcome may enable better stratification of Dex therapy for future patients. Dexamethasone pharmacokinetics in short and standard therapy arms following day one samplingPharmacokinetic parameters (mean ± SD)Half life (hr)Tmax (hr)Cmax(ng/mL)Clearance(L/hr/m2)AUC0-12h(hr*ng/mL)Short (n=43)3.96 ± 3.21.9 ± 1.0128 ± 558.1 ± 5.3692 ± 325Standard (n=33)3.68 ± 2.11.7 ± 1.187 ± 419.2 ± 12.7443 ± 202
Citation Format: Rosanna K. Jackson, Julie AE Irving, Gareth J. Veal. Pharmacokinetics of standard versus short high-dose dexamethasone therapy in childhood acute lymphoblastic leukemia: results from the UKALL 2011 trial. [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 CT115.
Abstract CT120: Radiotherapy in pediatric patients with atypical teratoid rhabdoid tumor of the central nervous system
Authors: Frick Melissa , Minturn Jane , Li Yi-Mei , Hill-Kayser Christine 
Published: July 2016

Abstract
Atypical teratoid/rhabdoid tumor (ATRT) of the CNS is a rare, highly malignant tumor of early childhood. Current protocols favor multimodality treatment, but practice guidelines differ with regard to radiotherapy. The aim of this study was to evaluate outcomes and prognostic factors in pediatric ATRT receiving multimodality treatment including postoperative radiation. Pediatric subjects with CNS ATRT treated at our institution between 2000 and 2014 were evaluated. Kaplan Meier method was used to estimate progression free survival (PFS) and overall survival (OS) over time and log-rank tests were used to examine associations of demographic and treatment factors with PFS and OS. 20 pediatric subjects (median age 23.5 months; range 4-99 months) with CNS ATRT treated at our institution between 2000 and 2014 were retrospectively evaluated. All underwent surgical resection, adjuvant radiotherapy, and aggressive multi-agent chemotherapy. PFS at 1-year was 63.3% (95% CI, 38.1% - 80.6%) and 2-years was 46.1% (95% CI, 22.9% - 66.5%). OS at both 1- and 2-years was 73.0% (95% CI, 46.7% - 87.8%). Infratentorial disease, lack of metastatic disease at diagnosis, and gross total tumor resection were identified as beneficial prognostic factors in PFS and OS. Progressive disease after radiation was identified as a poor prognostic factor in OS. Radiation modality (proton versus x-ray) did not affect disease-related outcomes. Modern treatment for ATRT with aggressive multimodality therapy including radiotherapy results in a significant portion of subjects with long-term disease control. Prognosis appears to be improved in subjects with localized, completely resected disease.
Citation Format: Melissa Frick, Jane Minturn, Yi-Mei Li, Christine Hill-Kayser. Radiotherapy in pediatric patients with atypical teratoid rhabdoid tumor of the central nervous system. [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 CT120.
Abstract CT126: Single arm study of neoadjuvant chemotherapy without taxane for BRCAness cases in triple-negative breast cancer
Authors: Ishikawa Takashi , Teraoka Saeko , Kaise Hiroshi , Yamada Kimito , Hosonaga Mari , Ueda Ai , Kawai Yoko , Okazaki Miki , Oba Mari S. , Sato Eiichi 
Published: July 2016

Abstract
BACKGROUND: BRCA1 impaired cancers are sensitive to DNA damage. This is associated with the defective homologous recombination (HR) pathway in these tumors. In contrast, these tumors are resistant to mitotic poisons, because BRCA1 protein activates the mitotic spindle checkpoint and triggers apoptosis in microtubule damage. Both preclinical evidence and clinical evidence have shown that the single-agent taxane is not active for BRCA1 mutated breast cancers.
It is reported that BRCA1 function may be impaired in approximately 60% of triple negative breast cancer (TNBC) without mutation. This is called ‘BRCAness’. Previous studies have demonstrated that BRCAness identified tumors with HR deficiency. Thus, taxane may not be necessary for all TNBC cases, although combined treatments of anthracycline and taxane are standard at present.
STUDY PROTOCOL: We have launched a single arm study of neoadjuvant chemotherapy (NAC) for TNBC to confirm that taxane is unnecessary in BRCAness cases.
For the study protocol, TNBC cases requiring NAC are enrolled. Four cycles of an anthracycline-based regimen (FEC 100 or dose-dense EC) are started and BRCAness is examined simultaneously in core-needle specimens. BRCAness is determined by Multiple Ligation-dependent Probe Amplification (MLPA) methods (FALCO Biosystems), which consist of 2 steps. These include copy number analysis in 34 loci specific to BRCA1 mutant and scoring with prediction analysis for microarray. If BRCAness is determined by MLPA, surgery is performed without proceeding to taxane. The primary endpoint is a pathological complete response (pCR) in surgical specimens. The expected pCR and threshold pCR are estimated at 55% and 40%, respectively, based on our previous randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel for hormone receptor-negative breast cancer (Ishikawa T. ASCO 2013). With a one-sided significance of 5%, 70 BRCA cases are required.
This study was approved in September 2015 and has been started. Interim analysis is planned when 30 cases are completed.
Citation Format: Takashi Ishikawa, Saeko Teraoka, Hiroshi Kaise, Kimito Yamada, Mari Hosonaga, Ai Ueda, Yoko Kawai, Miki Okazaki, Mari S. Oba, Eiichi Sato. Single arm study of neoadjuvant chemotherapy without taxane for BRCAness cases in triple-negative breast cancer. [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 CT126.
Abstract CT155: The effect of perioperative probiotics treatment for colorectal cancer: short-term outcomes of a randomized controlled trial
Authors: Ma Yanlei , Wei Qing , Yang Yongzhi , Qin Huanlong 
Published: July 2016

Abstract
This study was designed to mainly evaluate the anti-infective effects of perioperative probiotic treatment in patients receiving confined colorectal cancer (CRC) respective surgery. From November 2011 to September 2012, a total of 60 patients diagnosed with CRC were randomly assigned to receive probiotic (n = 30) or placebo (n = 30) treatment. The operative and post-operative clinical results including intestinal cleanliness, days to first - flatus, defecation, fluid diet, solid diet, duration of pyrexia, average heart rate, length of intraperitoneal drainage, length of antibiotic therapy, blood index changes, rate of infectious and non-infectious complications, postoperative hospital stay, and mortality were investigated. The patient demographics were not significantly different (p &gt; 0.05) between the probiotic treated and the placebo groups. The days to first flatus (3.63 versus 3.27, p = 0.0274) and the days to first defecation (4.53 versus 3.87, p = 0.0268) were significantly improved in the probiotic treated patients. The incidence of diarrhea was significantly lower (p = 0.0352) in probiotics group (26.67%, 8/30) compared to the placebo group (53.33%, 16/30). There were no statistical differences (p &gt; 0.05) in other infectious and non-infectious complication rates including wound infection, pneumonia, urinary tract infection, anastomotic leakage, and abdominal distension. In conclusion, for those patients undergoing confined CRC resection, perioperative probiotic administration significantly influenced the recovery of bowel function, and such improvement may be of important clinical significance in reducing the short-term infectious complications such as bacteremia.
Trial Registrations: ChiCTR-TRC-13003332 (http://www.chictr.org/en/)
Citation Format: Yanlei Ma, Qing Wei, Yongzhi Yang, Huanlong Qin. The effect of perioperative probiotics treatment for colorectal cancer: short-term outcomes of a randomized controlled trial. [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 CT155.
Abstract LB-002: Methylation of the EGF receptor regulates signaling and therapeutic response
Authors: Liao Hsin-Wei , Hsu Jung-Mao , Xia Weiya , Hung Mien-Chie 
Published: July 2016

Abstract
Epidermal growth factor receptor (EGFR)-targeted monoclonal antibody, cetuximab, is one of the most effective ways of controlling colorectal cancer progression. However, resistance to cetuximab has been observed in clinical setting. Here, we report a mechanism contributing to cetuximab resistance in which protein arginine methyltransferase 1 (PRMT1) methylates the extracellular domain of EGFR at R198 and R200, leading to an increase in the binding affinity between EGF and methylated EGFR, and subsequently receptor dimerization, downstream signaling activation, and cell proliferation in vitro. R/K mutation of the EGFR methylation sites reduces tumor growth in mouse orthotopic xenograft model. Increased EGFR methylation retains its signaling activation and cell proliferation in the presence of cetuximab. Importantly, EGFR methylation level is correlated with higher recurrence rate after cetuximab treatment and poor overall survival, suggesting that the methylation status of EGFR has the potential to predict resistance to cetuximab treatment in colorectal cancer and head and neck cancer patients.
Citation Format: Hsin-Wei Liao, Jung-Mao Hsu, Weiya Xia, Mien-Chie Hung. Methylation of the EGF receptor regulates signaling and therapeutic response. [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-002.
Abstract LB-005: TRIP13/PCH2 is a novel regulator of EGF-mTOR signaling promoting hepatocellular carcinoma development
Authors: Meissburger Bettina , Chan Jessica , de Guia Roldan , Herzig Stephan , Berriel Diaz Mauricio 
Published: July 2016

Abstract
Hepatocellular carcinoma (HCC) is currently the third most common cause of cancer-related mortality with limited treatment options and bleak prognosis. The main risk factors for HCC have been linked to hepatitis infection, alcoholic liver injury, non-alcoholic fatty liver disease (NAFLD) and metabolic diseases. Current therapeutic options are limited, which could be due to the lack of understanding of the key cellular players and signalling pathways in HCC.
In order to find novel regulators of HCC development, we surveyed expression data of human hepatocellular carcinoma (E-GEOD-25097) and found the AAA-ATPase Thyroid Hormone Receptor Interactor 13 (TRIP13) to be upregulated in tumorous tissue compared to non-tumorous tissue. Consistently, using a mouse model for HCC by injection of Diethylnitrosamine (DEN), we observed induced expression of TRIP13 in liver tumors compared to healthy liver tissue. Additionally, in a model of liver regeneration by partial hepatectomy, induction of TRIP13 coincided with a peak in cell proliferation in the regenerating liver. Strinkingly, Adeno-associated virus (AAV)-mediated hepatocyte-specific knockdown of TRIP13 impeded liver regeneration upon partial hepatectomy, suggesting an important role of TRIP13 in liver cell proliferation. Indeed, knockdown (KD) of TRIP13 severely impaired cell growth and proliferation in different human and murine HCC cell lines in vitro.
To investigate the oncogenic potential of TRIP13 in vivo, we injected lentiviral infected cells subcutaneously into mice and measured tumor growth. Remarkably, knockdown of TRIP13 in Hepa1-6 cells led to the development of smaller tumors compared to control cells, whereas TRIP13-deficient Huh7 cells did not form any tumors.
Interestingly, shRNA knockdown of TRIP13 in HCC cell lines showed decreased phosphorylation of key players in the mTOR signalling pathway and reduction of the downstream Cyclin D1 levels. Concurrently, the mRNA and protein expression of EGF receptor was also downregulated in TRIP13 KD-cells.
Taken together, we identified a novel role of TRIP13 during hepatocyte proliferation both in liver regeneration and HCC. Additionally, our findings also support an oncogenic function of TRIP13 through the regulation of the EGFR-mTOR signalling axis.
Citation Format: Bettina Meissburger, Jessica Chan, Roldan de Guia, Stephan Herzig, Mauricio Berriel Diaz. TRIP13/PCH2 is a novel regulator of EGF-mTOR signaling promoting hepatocellular carcinoma development. [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-005.