tbuckley/cabot-search huggingface dataset:
Antitumor effects of dabrafenib, trametinib, and panitumumab as single agents and in combination in <i>BRAF</i>-mutant colorectal carcinoma (CRC) models.
Authors: LI Liu, Hong Shi, Maureen R Bleam, Vivian Zhang, Jun Zou, Junping Jing, Kurtis E. Bachman, Monica Motwani, Keith W. Orford, Axel Hoos
Journal: Journal of Clinical Oncology (2014)

3513 Background: In contrast to BRAF-mutant melanoma, the inhibition of BRAF or BRAF/MEK has been relatively ineffective in the treatment of BRAF-mutant CRC, possibly due to EGFR-dependent resistance mechanisms. This study aimed to determine the anti-tumor activities for BRAF/MEK inhibition with or without EGFR inhibition in BRAFV600E CRC models and to identify biomarkers of response/resistance. Methods: We assessed cell growth inhibition, apoptosis and cell signaling changes by inhibitors of BRAF (dabrafenib, D), MEK (trametinib, T), and EGFR (panitumumab, P, cetuximab, and erlotinib) dosed as monotherapies and in combination in five BRAFV600E human CRC lines (Colo205, HT29, RKO, SW1417 and LS411N). Further, these inhibitors were evaluated for their anti-tumor effects either alone or in combination in two BRAFV600E CRC patient derived tumor xenografts (PDXs) established in female nude mice. One patient-derived xenograft (PDX) harbored the PIK3CAH1047R mutation (Co-018) and the other (Co-012) was wildtype for PIK3CA. Results: In three out of five lines, all three EGFR inhibitors enhanced cell growth inhibition by D and the combination of D/T. Adding P to D or to the combination of D/T led to sustained suppression of pERK. The triple combination of P/D/T most effectively inhibited both pERK and pS6, and increased PARP cleavage in HT29 cells. P significantly improved the efficacy of either D or D/T in the Co-012 and Co-018 models. The triple combination of P/D/T was highly efficacious in both PDXs, and more effectively delayed tumor growth than the combination of P/D or D/T in Co-018 model, while D and P alone showed little or no activity. Pharmacodynamic changes and baseline characterization including expression levels of EGFR and EGFR ligands are under evaluation, and will be tested in clinical samples. Conclusions: While inhibition of MAPK or EGFR signaling has limited activity in BRAF-mutant CRC, the combined inhibition of MAPK signaling and EGFR has significant anti-tumor activity, with the triple combination being the most efficacious in preclinical models of BRAFV600E CRC. The results support ongoing clinical trials of D/T/P combinations in subjects with V600E BRAF-mutation positive CRC.
Validation of two cancer care plan communication tools.
Authors: Hannah Staunton, Supriya Yagnik, Nicola Williamson, Holly Spencer, Sharan Kaur, Bryan Bennett, Sarah Donelson, Dayo Jagun, Hans-Peter Goertz, Alisha Stein
Journal: Journal of Clinical Oncology (2017)

145 Background: Patient-provider communication is recognized as allowing patients to become more active within the treatment process and treatment related decisions. This paradigm shift of involving patients as active stakeholders in their care promotes a patient-centered approach to healthcare, and may positively impact outcomes. Two tools for use in clinical practice were developed to aid patient-provider communication in oncology: Assessing Treatment Goals and Patient Education. This study aimed to evaluate the face and content validity of these tools. Methods: A non-interventional, cross-sectional, qualitative cognitive interview study was conducted in the US with patients with non-hodgkin’s lymphoma (n = 6), lung cancer (n = 7) and colon cancer (n = 7) and matched caregivers (n = 10). Interviews with oncologists (n = 5) and oncology nurses (n = 5) were also conducted. During the interviews, participants completed both tools as a ‘think-aloud’ process and were asked about the relevance and understanding of the instructions, questions, and response options, from the patient and healthcare provider perspective. Results: Ademographically and clinically diverse participant sample was recruited. Feedback from participants confirmed that the Assessing Treatment Goals tool questions were understood and considered relevant. Minor modifications were proposed including the addition of a question regarding the involvement of family and friends in healthcare decision-making. Similarly, the Patient Education tool topics were well understood and relevant. Minor modifications to simplify topic wording were proposed. Furthermore, the empirical data led to adding two topics: ‘body image’ and ‘beyond cancer care’. No topics were suggested for deletion from this tool. Patients and healthcare providers considered both tools to be valuable for communication. Conclusions: Feedback from participants supported the face and content validity of both tools with minor modifications. The next phase of research is to pilot the tools in clinical practice and assess for usability and feasibility. It is hoped that when used in clinical practice these tools will facilitate greater patient-provider communication and increased satisfaction with care.
Family history for BRCA1 and BRCA2 mutations in patients with pancreatic cancer: An observational, population-based study.
Authors: Daniela Boggiani, Mariangela Bella, Paola Zanelli, Maria Michiara, Giulia Mazzaschi, Antonino Musolino, Nadia Naldi, Beatrice Bortesi, Laura Cortesi, Carmine Pinto
Journal: Journal of Clinical Oncology (2015)

e15236 Background: Although germline BRCA2 mutations, and to a lesser extent BRCA1 mutations, are associated with an increased risk of pancreatic cancer (PC), the influence of BRCA mutations on family history (FH) and clinical characteristics of PC patients is less elucidated. Methods: A clinical database review from two Genetic Oncology Services of the Emilia Romagna Region (nothern Italy) identified 25, non-Ashkenazi, Italian families in which at least one patient with PC had at least one first-degree relative with BRCA-associated breast and/or ovarian cancer. Results: A total of 31 PC patients (male/female ratio: 1.21) were evaluated. Median age at diagnosis was 66 years (range 33-91); 19 (61%) patients were diagnosed with metastatic disease. Ten (32%) patients having at least one first-degree relative with PC were considered familial pancreatic cancers (FPC), while 21 (68%) with no FPC clustering were considered sporadic (SPC). Seventeen (45%) patients had one first-degree relative with BRCA mutation. Malignancies observed in BRCA-associated relatives were: breast cancer (65%), ovarian cancer (16%), breast-ovarian cancer (19%). BRCA1 mutations occurred in 16 (64%) families, while BRCA2 mutations were observed in 9 (36%). No statistically significant association was observed between FPC and BRCA mutation in a first-degree relative (P = 0.81). Similarly, there was no different distribution of BRCA2 mutations between FPC and SPC (P = 1.23). No differences in median overall survival were observed between patients with FPC and patients with SPC, and between patients with BRCA1-linked and patients with BRCA2-linked families (6.8 vs 7.9 months, P = 0.47 and 7.1 vs 7.5 months, P = 0.31, respectively). Conclusions: BRCA1 and BRCA2 mutations are observed with nearly equal distribution in breast and/or ovarian cancer relatives of patients with either FPC or SPC. Future analytic studies are needed to better understand the relationship between FH, BRCA mutations and PC in hereditary cancer syndrome families.
The Right to Health Care
Authors: Howard Bauchner
Journal: JAMA (2017)

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Synergy with combination of AKT inhibitor (MK-2206) and paclitaxel in head and neck squamous cell carcinoma.
Authors: Omar Ahmed, Wen-Liang Kuo, Madhavi Nagilla, Jeannette S. Messer, David L. Boone, Marina Sharifi, Kay Macleod, Ezra E.W. Cohen
Journal: Journal of Clinical Oncology (2013)

e13532 Background: Though there have been many advances in the treatment of HNSCC, the 5-year survival rate remains at 50%. This is partly due to molecular alterations such as the activation of the PI3k-AKT pathway in HNSCC, which has been associated with treatment failure. We stained human tissue samples and saw increased expression of p-AKT and pS6 in HNSCC compared to normal and dysplasia. This led us to investigate the role of the AKT inhibitor MK-2206 in combination with an already established chemotherapeutic agent, paclitaxel. Methods: Cell viability and Combination index were used to determine synergy in 4 HNSCC cell lines. PI exclusion and Annexin/PI staining were used to determine cell death and apoptosis, respectively. Autophagy was measured through changes in LC3BII protein levels using western blot analysis and a stably transfected GFP-LC3BII cell line was used to detect changes in protein localization under confocal microscopy. Results: All cell lines were sensitive to paclitaxel while only some were sensitive to MK-2206. However, there was effective synergy to the combination treatment in all cell lines. Apoptotic synergy was observed in some cell lines indicating that the combination stimulates cell death in the appropriate context. In one autophagy competent cell line, MK-2206 induced robust autophagy while paclitaxel blocked a latter step in the pathway leading to an accumulation of autophagosomes prior to induction of apoptosis. Conclusions: Paclitaxel and MK-2206 appears to be an effective combination in HNSCC possibly through their effect on autophagy trafficking, leading to an accumulation of autophagosomes and eventual apoptosis. Clinical trials examining this combination are warranted.
Targeting BCL6-Mediated Resistance to BCR-ABL Targeted Tyrosine Kinase Inhibitors (TKIs) in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) through the Addition of Histone Deacetylase (HDAC) Inhibitors
Authors: Gordon Cohen, Colleen E. Annesley, Rachel E. Rau, Shannon Kelley, Daniel Magoon, Patrick Brown
Journal: Blood (2015)
Histamine H 2 Receptor Antagonists, Left Ventricular Morphology, and Heart Failure Risk
Authors: Peter J. Leary, Ryan J. Tedford, David A. Bluemke, Michael R. Bristow, Susan R. Heckbert, Steven M. Kawut, Eric V. Krieger, Joao A. Lima, Carolina S. Masri, David D. Ralph, Steven Shea, Noel S. Weiss, Richard A. Kronmal
Journal: Journal of the American College of Cardiology (2016)
Treatment patterns and comorbidities in a population-based cohort of glioblastoma patients diagnosed 1997-2008.
Authors: Susan A. Oliveria, Laura Chu, Deborah Casso, Karen Wells, Wei Dong, Robert Dubrow, Asha Das, David R Nerenz, Marianne Ulcickas Yood
Journal: Journal of Clinical Oncology (2012)

1591 Background: Glioblastoma multiforme (GBM) is one of the most common, most malignant and rapidly progressive forms of brain cancer. Published reports of GBM in non-trial populations are limited. The purpose of this study was to assemble a population-based cohort of GBM patients with comprehensive clinical and demographic information and to define treatment patterns and outcomes in this population. Methods: GBM patients served by Henry Ford Health System (HFHS), a major GBM referral center, were identified using ICD-O and histology codes from the HFHS tumor registry. Eligible patients were newly diagnosed with GBM between 1997 and 2008. Comprehensive, population-based data were compiled using tumor registry data (including histology and mortality) with linkages to pharmacy data (including infusion), outpatient and inpatient encounter data, and laboratory results. Results: Overall, 812 GBM patients were identified; mean age was 54 years (standard deviation 15.8). The cohort was 63% male and 84% white. Among the most common post-diagnosis comorbidities/complications, 14% of patients had venous thromboembolism (95% confidence interval [CI] 12-17), 16% had seizures (95% CI 14-19), and 6% had central nervous system hemorrhage (95% CI 4-7). Arterial thromboembolism occurred in 3% of patients (95% CI 2-4), while 7% experienced infections such as candidiasis, herpes simplex, and pneumocystis pneumonia (95% CI 5-9) and 2% experienced wound dehiscence (95% CI 1-3). 94% (95% CI 93-96) of the cohort received some form of treatment with 81% undergoing surgery (95% CI 78-84), 75% receiving radiation therapy (95% CI 72-78), and 67% receiving chemotherapy (95% CI 64-70). Median overall survival after diagnosis was 1.4 years (95% CI 1.3-1.5) among all patients, and 1.6 years (95% CI 1.4-2.0) among those diagnosed 2005-2008. Conclusions: This study presents a well-characterized population-based cohort of GBM patients. Understanding treatment patterns and comorbidities outside the clinical trial setting is important in informing and evaluating real-world treatment decisions. Additional results exploring time trends in systemic cancer therapy and Kaplan-Meier survival curves will be presented.
Reliability of administrative data for evaluating the quality of systemic treatment for cancer.
Authors: Melanie Lynn Powis, Nathan Taback, Christina Diong, Katherine Enright, Christopher M. Booth, Maureen E. Trudeau, Monika K. Krzyzanowska
Journal: Journal of Clinical Oncology (2017)

208 Background: There is ongoing interest in leveraging administrative data to examine quality but methodological concerns persist. We evaluated the reliability of a previously established panel of administrative data derived quality measures for systemic cancer treatment. Methods: The study cohort consisted of women diagnosed with early stage (stage I-III) breast cancer (ESBC) in Ontario, Canada, in 2010. Performance on 11 quality indicators evaluated using deterministically linked healthcare administrative databases has been reported previously. The sensitivity and specificity of these 11 indicators were examined using the chart as the gold standard. Results: The administrative cohort consisted of 6,795 women with ESBC from which a validation cohort of 705 patients was randomly selected from among patients who underwent cancer surgery at one of five hospitals chosen to balance feasibility and institutional characteristics.Sensitivity and specificity varied by indicator (Table). Reliability of some indicators may have been affected by suboptimal chart documentation in instances where care spanned multiple settings or the medical record was fragmented, or where the number of eligible patients for that indicator was low. Conclusions: Administrative data can be used to evaluate quality of systemic cancer therapy but understanding the reliability characteristics of individual indicators is essential to inform their appropriate use and interpretation. [Table: see text]
A phase II trial of high-dose calcitriol and docetaxel in patients with untreated, incurable pancreatic adenocarcinoma
Authors: C. D. Lopez, T. Beer, K. Todd, C. D. Blanke
Journal: Journal of Clinical Oncology (2007)

15099 Background: Taxanes have activity in patients with advanced pancreatic adenocarcinoma. In preclinical studies, calcitriol, the active form of vitamin D, potentiates docetaxel-induced cell death in pancreatic and prostatic cancer cell lines. Clinically, single institution and randomized prostate cancer trials using weekly high-dose calcitriol with docetaxel have demonstrated high PSA response rates (J Clin Oncol 2003, 2007). Herein we report results from a phase II study of the identical regimen in patients with incurable pancreatic adenocarcinoma. Methods: Patients with a histologic diagnosis of locally advanced or metastatic pancreatic adenocarcinoma, Zubrod PS 0–2, and adequate organ function were eligible. Previous non-docetaxel adjuvant chemotherapy and radiation were permissible. Patients received calcitriol 0.5 mcg/kg orally day 1, followed by docetaxel 36 mg/m 2 on day 2. Therapy was given weekly for 3 weeks, followed by a 1 week break, and patients were treated until progression. The primary endpoint was time-to-progression (TTP). Results: 24 patients with metastatic and 1 with locally advanced (25 total) were enrolled, treated and are evaluable for efficacy and toxicity. Median age and PS were 60 (range 30 to 79) and 1, respectively. 68% were males, and all were white. Three patients are alive and 22 have died. The median number of cycles was 1 (range 0 to 12). 3 patients (12%, 95% CI 3 to 31) achieved a partial response, and 7 (28%) stable disease for at least 7 weeks. Median TTP and median overall survival were 2.2 and 5 months respectively. Potentially treatment-related common grade 3/4 toxicities included: thrombosis -12%, abnormal LFTs-16%, nausea-8%, fatigue-16%, infection-12%, neutropenia/leucopenia-16%, effusion-8%, abnormal electrolytes-24%, and infusion reaction-4%. Conclusions: The combination of docetaxel and high-dose calcitriol has activity in pts with advanced pancreatic cancer, but the regimen offers no apparent advantage over historical results achieved with standard gemcitabine. No significant financial relationships to disclose.
Update of a phase I/II trial of carboplatin/gemcitabine plus escalating doses of celecoxib for first-line treatment of stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: J. D. Burton, E. Badine, D. El-Sayah, E. Dib, F. Forte, T. Terjanian, M. Odaimi, M. Vesoniaraki, P. Friscia, J. Lowry
Journal: Journal of Clinical Oncology (2004)

7339 Background: This phase I/II trial is being conducted to test the safety, toxicity, and initial efficacy of this novel regimen of celecoxib plus carboplatin/gemcitabine for advanced NSCLC. Celecoxib is a selective COX-2 inhibitor with strong inhibitory effects on NSCLC cell lines. Since NSCLC often overexpresses COX-2, and celecoxib's toxicity does not overlap with chemotherapy, we postulated this combination would be safe. Methods: Phase I used a modified Fibonacci design. For phase I & II, chemotherapy was fixed (gemcitabine, 1100 mg/m2 [d 1 & 8]; carboplatin, AUC=5 [d 8 only] q 4 weeks). Celecoxib was given d 1–12, and all planned dose levels (120 mg/m2 - 600 mg/m2 [≈500 mg BID]) were evaluated. Patients with SD or better could receive up to 8 cycles of treatment. CT scans were done q 2 cycles. Results: 38 patients have been enrolled, with 36 evaluable for toxicity and 25 for tumor response. 19 have completed ≥4 cycles, with 7 completing the maximum of 8 cycles. Celecoxib was escalated to the final dose level (600 mg/m2≈500 mg BID) without dose-limiting toxicity. 23 patients have been treated at this celecoxib dose. 136 cycles of therapy have been given, with 7 episodes of transient grade 4 hematologic toxicity, but no episodes of febrile neutropenia or treatment-related mortality. 5 patients had one episode each of transient grade 3 hepatic toxicity. There was no grade 3/4 renal, GI or other non-hematologic toxicity. 6 patients (3 at the highest celecoxib dose) had confirmed ORs (1 CR, 5 PR, ORR=24%), 14 patients had SD for ≥4 months (overall SD=56%), and 5 patients had PD by the 4th cycle of treatment (20%). Conclusions: Celecoxib plus platinum-based chemotherapy in the 1st-line for stage IIIB/IV NSCLC is safe, and has an acceptable initial tumor response rate. The 1st-stage of phase II was completed and the 3 ORs in this cohort support ongoing accrual to complete the 2nd-stage of phase II. Supported in part by Eli-Lilly, Inc. No significant financial relationships to disclose.
A phase I study of S-1 and low dose cisplatin for patients with recurrent or advanced gastric cancer
Authors: S. Shimoyama, M. Kaminishi, N. Hiki, N. Shimizu, H. Yamaguchi, K.-I. Mafune
Journal: Journal of Clinical Oncology (2004)

4161 Background: We conducted a phase I trial of S-1, a DPD inhibitory fluoropyrimidine, in combination with low dose cisplatin, on an outpatient setting. Objectives of this trial were to determine the maximum tolerated dose (MTD) and recommended dose (RD) of this combination and to examine preliminary evidence of its therapeutic activity. Methods: Eligible patients had measurable metastatic lesions of histologically confirmed gastric adenocarcinoma, had ECOG PS 0–2, were aged between 20 and 75, exhibited adequate organ functions without serious comorbidity, and were fully informed. S-1 was administered orally twice daily with a fixed dose of 80mg/m2/day for three consecutive weeks (days 1–21) with cisplatin as a dose escalation in increments of 5mg/m2, commencing at a dose of 15mg/m2 (level 1) and reaching a dose level of 25mg/m2 (level 3) on days 1, 8, and 15. Cisplatin was administered with only 500ml hydration for 90 minutes. Treatment cycle consisted of a 3-week administration followed by a 2-week rest. Adverse events were evaluated at the end of the first cycle and dose limiting toxicities (DLTs) were determined as grade 3 or more hematological and/or nonhematological toxicities. Results: Nine patients (male: female 5:4, mean age 68 years old) were enrolled, including recurrent or residual diseases with prior gastrectomy in six and unresectable diseases in three. Three patients were chemotherapeutically naive, and the remainders had received prior FU based regimen. All patients were treated on an outpatient setting. At the end of the first cycle, none experienced DLTs nor required hospitalization. Two patients in level 1 and one patient in level 2 showed partial response. Conclusions: We conclude 25mg/m2 of cisplatin is a recommended dose in combination with S-1 for further studies. The therapy comprises a well-tolerated, active, outpatient regimen for metastatic and/or advanced gastric cancer. No significant financial relationships to disclose.