tbuckley/cabot-search huggingface dataset:
Multicenter, single-arm phase II study of nilotinib in Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic-phase (CML-CP) patients with low imatinib trough plasma concentrations.
Authors: S. Lim, R. C. Holdridge, M. Talpaz, C. N. Abboud, S. Yi, E. Noon, S. Ericson, M. Jones
Journal: Journal of Clinical Oncology (2011)

TPS202 Background: Patients with low imatinib trough concentrations are at risk for suboptimal response and treatment failure (Larson. Blood. 2008;111:4022). Nilotinib, with a higher affinity for Abl compared with imatinib, has produced excellent results in newly diagnosed CML-CP patients (Saglio. NEJM. 2010;362:2251) and lacks dependence on the OCT-1 transporter systems. Switching patients with sub-therapeutic imatinib levels to nilotinib may improve outcomes in patients with CML-CP. Methods: Two of 50 planned patients have been enrolled. Adults with Ph+ CML-CP who are within 12 months of diagnosis, have achieved European LeukemiaNet (ELN)-defined response milestones, and who have an imatinib steady-state trough plasma concentration < 850 ng/ml assessed on imatinib at 400 mg/day are eligible. Patients are switched to nilotinib 300 mg twice daily upon obtaining low imatinib trough concentrations and will be treated up to 2 years. The primary endpoint is the number of ELN-defined failure events up to 2 years of nilotinib treatment. Secondary endpoints include the number of ELN-guideline–defined optimal and suboptimal responses up to 2 years; rates of, time to, and duration of complete cytogenetic response, major (≥3-log reduction in BCR-ABL from standardized baseline or 0.1% per International Scale) and complete molecular responses (≥4-log reduction in BCR-ABL); event-free, progression-free, and overall survival; and changes in quality of life (exploratory). All patients receiving at least one dose of nilotinib will be analyzed for efficacy; patients receiving at least one dose of nilotinib with at least one post-baseline safety assessment will be analyzed for safety.
Time-Specific Effects of Spindle Positioning on Embryonic Progenitor Pool Composition and Adult Neural Stem Cell Seeding
Authors: Sven Falk, Stéphane Bugeon, Jovica Ninkovic, Gregor-Alexander Pilz, Maria Pia Postiglione, Harold Cremer, Jürgen A. Knoblich, Magdalena Götz
Journal: Neuron (2017)

The developmental mechanisms regulating the number of adult neural stem cells (aNSCs) are largely unknown. Here we show that the cleavage plane orientation in murine embryonic radial glia cells (RGCs) regulates the number of aNSCs in the lateral ganglionic eminence (LGE). Randomizing spindle orientation in RGCs by overexpression of Insc or a dominant-negative form of Lgn (dnLgn) reduces the frequency of self-renewing asymmetric divisions while favoring symmetric divisions generating two SNPs. Importantly, these changes during embryonic development result in reduced seeding of aNSCs. Interestingly, no effects on aNSC numbers were observed when Insc was overexpressed in postnatal RGCs or aNSCs. These data suggest a new mechanism for controlling aNSC numbers and show that the role of spindle orientation during brain development is highly time and region dependent.
Toward personalized treatment for gastroesophageal adenocarcinoma (GEC): Strategies to address tumor heterogeneity—PANGEA.
Authors: Daniel Virgil Thomas Catenacci, Blase N. Polite, Les Henderson, Peng Xu, Brittany Rambo, Wei-Li Liao, Todd A. Hembrough, Lei Zhao, Shu-Yuan Xiao, John Hart, Theodore Karrison, James J. Dignam, Hedy Lee Kindler
Journal: Journal of Clinical Oncology (2014)

66 Background: GEC is the second highest cause of cancer mortality worldwide. The promise of ‘personalized’ cancer care with therapies toward specific molecular aberrations has potential to improve outcomes. However, there is recognized molecular heterogeneity within GEC (inter-patient heterogeneity), and within an individual (intra-patient heterogeneity) through space (primary tumor to metastatsis) and time (resistance to treatment) - a hurdle to advancing GEC treatment. Current trial design paradigms are challenged by heterogeneity, as they are unable to test targeted therapeutics against low frequency genomic aberrations with adequate power. Accrual difficulties to GEC trials are exacerbated by low frequencies of molecular ‘oncogenic drivers.’ Oncogenic drivers of GEC including MET and others have even less frequent genomic activation than HER2. To address this challenge, there is need for novel clinical trial designs/strategies implementing novel technologies to account for inter-patient molecular diversity and scarce tissue for analysis. Importantly, there is also need for predefined treatment priority algorithms given multiple aberrations observed within any one individual. Finally, access to multiple therapeutic agents are required to be available for treatment. Intra-patient heterogeneity may be addressed by post-treatment biopsy. Methods: We present a novel trial design 'Personalized Anti-Neoplastics for Gastro-Esophageal Adenocarcinoma' for metastatic GEC, integrating medium throughput proteomic/genomic assays with a practical biomarker assessment/treatment algorithm. Analysis of 50 GEC patients was performed to determine feasibility/timing of testing and treatment assignment into 5 major molecular categories. Results: 50 GEC tumors had biomarker assessment and mock treatment assignment within 60 days, revealing HER2 (26%), MET (30%), FGFR2 (8%), EGFR (20%), KRAS/PI3K (26%). Conclusions: Comprehensive molecular profiling of FFPE tissue was feasible and timely. Tumors were classified into major molecular subgoups. PANGEA is a compromise between the number of potential treatment categories and feasibility of conducting such a trial.
Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho
Authors: Reeti Behera, Amanpreet Kaur, Marie R. Webster, Suyeon Kim, Abibatou Ndoye, Curtis H. Kugel, Gretchen M. Alicea, Joshua Wang, Kanad Ghosh, Phil Cheng, Sofia Lisanti, Katie Marchbank, Vanessa Dang, Mitchell Levesque, Reinhard Dummer, Xiaowei Xu, Meenhard Herlyn, Andrew E. Aplin, Alexander Roesch, Cecilia Caino, Dario C. Altieri, Ashani T. Weeraratna
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Aging is a poor prognostic factor for melanoma. We have shown that melanoma cells in an aged microenvironment are more resistant to targeted therapy than identical cells in a young microenvironment. This is dependent on age-related secreted factors. Klotho is an age-related protein whose serum levels decrease dramatically by age 40. Most studies on klotho in cancer have focused on the expression of klotho in the tumor cell. We have shown that exogenous klotho inhibits internalization and signaling of Wnt5A, which drives melanoma metastasis and resistance to targeted therapy. We investigate here whether increasing klotho in the aged microenvironment could be an effective strategy for the treatment of melanoma. Experimental Design: PPARγ increases klotho levels and is increased by glitazones. Using rosiglitazone, we queried the effects of rosiglitazone on Klotho/Wnt5A cross-talk, in vitro and in vivo, and the implications of that for targeted therapy in young versus aged animals. Results: We show that rosiglitazone increases klotho and decreases Wnt5A in tumor cells, reducing the burden of both BRAF inhibitor–sensitive and BRAF inhibitor–resistant tumors in aged, but not young mice. However, when used in combination with PLX4720, tumor burden was reduced in both young and aged mice, even in resistant tumors. Conclusions: Using glitazones as adjuvant therapy for melanoma may provide a new treatment strategy for older melanoma patients who have developed resistance to vemurafenib. As klotho has been shown to play a role in other cancers too, our results may have wide relevance for multiple tumor types. Clin Cancer Res; 23(12); 3181–90. ©2017 AACR.
Phase I study of safety, pharmacokinetics, and efficacy of TSU-68 plus S-1 combination in patients with advanced hepatocellular carcinoma.
Authors: Masafumi Ikeda, Shuichiro Shiina, Kohei Nakachi, Shuichi Mitsunaga, Satoshi Shimizu, Yasushi Kojima, Hideki Ueno, Chigusa Morizane, Shunsuke Kondo, Yasunari Sakamoto, Ryosuke Tateishi, Yoshinari Asaoka, Kazuhiko Koike, Hitoshi Arioka, Takuji Okusaka
Journal: Journal of Clinical Oncology (2013)

262 Background: Sorafenib is the standard chemotherapy for advanced hepatocellular carcinoma (HCC), but its efficacy is limited. TSU-68 is an oral anti-angiogenesis agent that blocks VEGFR-2 and PDGFR. TSU-68 and S-1 have shown favorable efficacy and safety profile for advanced HCC (Kanai et al. 2011; Furuse et al. 2010). This study investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of the TSU-68 plus S-1 combination in patients (pts) with advanced HCC. We also determined the maximum tolerated dose of TSU-68 plus S-1 on the basis of the frequency of associated dose-limiting toxicity (DLT) in this population. Methods: Pts who had not received any prior systemic therapy received 400 mg/day TSU-68 orally and one of the following doses of S-1: 50 mg/m 2 (level 0), 80 mg/m 2 (level 1), or 100 mg/m 2 (level 2). Treatment duration was 4 weeks followed by 2-week rest (A group) or 2 weeks followed by 1-week rest (B group). The starting treatment dose and duration level was 1B, followed by progression to levels 2A and 2B. Treatment safety and tolerability at each level were assessed by enrolling 6 pts according to CTCAE v3.0. Results: Eighteen pts (6 each at levels 1B, 2A, and 2B) were enrolled (age, 58-85 years; male/female, 15/3; HCV/HBV/nBnC, 12/3/4; Child-Pugh class A/B, 18/0). Two pts each at levels 1B (grade 3 gastrointestinal bleeding, grade 2 ascites) and 2A (grade 3 fatigue, grade 3 hand-foot skin reaction) showed DLTs, but no pts at level 2B showed DLTs. The common adverse events were hemoglobin decrease, hypoalbuminemia, and anorexia; these were mild in severity (grade 1-2). PK data from 12 pts at levels 1B and 2A indicated that the area under the curve (AUC) of TSU-68 and 5-FU was unlikely to be affected by TSU-68 plus S-1. Response rate, disease control rate, median time to progression, and median overall survival time were 27.8%, 61.1%, 160 days, and 391 days, respectively. Conclusions: Our findings revealed thatthe TSU-68 plus S-1 combination was well tolerated and had favorable efficacy in patients with advanced HCC, and we recommend treatment with 400 mg/day TSU-68 and 100 mg/m 2 S-1 for 4 weeks followed by 2-week rest in these patients. Clinical trial information: Japic CTI-121970.
Is there a need for new diabetes prevention trials?
Authors: Kristine Færch, Dorte Vistisen
Journal: BMJ (2017)

We read with interest the article by Barry and colleagues on the efficacy and effectiveness of screening tests and interventions in pre-diabetes.1 Fasting glucose, two hour glucose, and HbA1c can now all be used to identify high risk patients.23 As such, none of them can be considered a gold …
Development and validation of a mutivariate model combining cell cycle progression score with CAPRA to predict prostate cancer mortality in a conservatively managed cohort.
Authors: Michael K. Brawer, Matthew R. Cooperberg, Stephen J. Freedland, Gregory P. Swanson, Steven Stone, Julia E. Reid, Alexander Gutin, Peter Carroll, Jack M. Cuzick
Journal: Journal of Clinical Oncology (2013)

67 Background: Prostate cancer outcomes are variable and difficult to predict. Improved tools are needed to appropriately match treatment to a patient’s risk of progression. We developed and validated a multivariate model to predict disease−specific mortality (DSM) by combining clinical parameters (CAPRA score) with a score based on measuring the expression level of cell cycle progression (CCP) genes. Methods: A multivariate prediction model was trained using patients from 4 retrospective cohorts with median clinical follow up of 7.6 years. We used 200 men from the UK diagnosed after TURP, 353 from Scott &amp; White and 388 from UCSF treated with radical prostatectomy, and 118 men from Durham VA treated with EBRT. CCP score was derived from fixed tumor tissue (biopsy or surgical resection). Outcome was either time from treatment to biochemical recurrence (US cohorts) or time from diagnosis to disease specific mortality (UK cohort). The model was validated for predicting time from diagnosis to DSM in 180 men from the UK diagnosed by needle biopsy with clinically localized prostate cancer and managed conservatively (mean/median CAPRA score = 6). Results: A model combining CAPRA with CCP score was fit in the training set by a Cox Proportional Hazards analysis stratified by cohort. The Combined score was defined as 0.39*CAPRA+0.57*CCP score. There were no significant interactions between cohort and CAPRA or CCP score. This suggests that both CCP score and CAPRA confer similar prognostic information regardless of cohort composition, treatment, or specific outcome. In the validation cohort the Combined score was highly prognostic (HR= 2.27, 95%CI: (1.63, 3.16), p = 1.2 x 10−7). By likelihood ratio testing, the Combined score was a better predictor of DSM than CAPRA alone (p = 0.0028). The c−index of the Combined score was 0.75, which was an improvement over CAPRA (c−index 0.71). Conclusions: This multivariate model predicts DSM in a conservatively treated cohort. The model provides prognostic information beyond clinical variables, and can be used to help differentiate aggressive from indolent cancer at diagnosis.
Diagnostic utility of molecular profiling for cancers of uncertain primary.
Authors: M. Laouri, B. Schroeder, E. Chen, M. G. Erlander, C. Schnabel
Journal: Journal of Clinical Oncology (2011)

e21103 Background: With availability of targeted therapies, identifying theprimary tumor site is increasingly important. This study characterizes the diagnostic utility of the 92-gene molecular cancer classifier, CancerTYPE ID (CTID), in conjunction with histopathologic analysis. Methods: De-identified cases (N=815) submitted for CTID testing were retrospectively analyzed. Sample characteristics including morphology, tumor grade, IHCs, suspected primary site, and time to completion (TTC) were abstracted from pathology reports. Pathologic diagnoses were categorized as unknown, single suspected primary, differential (2 or more suspected), or no primary site reported. CTID data included top prediction, probabilities, and TTC. Results: Analysis of 754 (93%) evaluable cases (mean age: 62 yr; 49% male; biopsy site: 22% liver, 17% LN, 13% lung) showed that conventional work-up included a mean of 7 IHCs (median: 7; range: 0-35) and a mean TTC of 7.7 d (median: 4; range: 0-127). CK7 (91%), CK20 (86%), TTF1 (76%) were the most common IHCs: 64% underwent all 3. Cases with >7 IHCs had longer TTC than those with ≤7 IHCs (9.3 vs 6.4d, p=.0017). Pathology reports indicated that upon submission for CTID 20% of cases had a single suspected primary, 53% a differential diagnosis, 8% were unknown, and 20% had no specified primary site. Cases with >7 IHCs vs ≤7 IHCs were not associated with an increase in single suspected primaries or a reduction in unknown diagnoses. Sample characteristics indicated clinical utility for CTID in cases of metastatic disease, poorly-differentiated tumors, and differential diagnoses. CTID predicted a primary site in 91% of cases (median probability: 78%, range: 23-96%; mean TTC: 5.1d). CTID provided a prediction in 93% (n=59) of cases with a pathologic diagnosis of unknown. In differential cases (n=399), CTID resolved the diagnosis in 55% and provided a new primary in 36%. Conclusions: This large retrospective analysis demonstrated that current diagnostic processes are nonstandardized in approach, interpretation and TTC, and can yieldequivocal results. CTID is an objective, standardized test that may facilitate diagnosis by providing adjunctive molecular data in tumors with indeterminate or unknown origin.
Risk factors and clinical outcomes of gastric cancer identified by screening endoscopy: A case-control study.
Authors: Hwoon-Yong Jung, Eun-Jeong Gong, Ji Yong Ahn, Hyun Lim, Kwi-Sook Choi, Jeong Hoon Lee, Do Hoon Kim, Kee Don Choi, Ho June Song, Gin Hyug Lee, Jin-Ho Kim, Son Yeong Choi, Jaewon Choe, Min-Ju Kim
Journal: Journal of Clinical Oncology (2014)

8 Background: A customized screening program for gastric cancer would optimize the benefits of screening endoscopy. This study investigated the risk factors for gastric cancer detected during screening, and factors affecting clinical outcomes. Methods: From April 2000 to December 2010, subjects who underwent screening endoscopy at Asan Medical Center were included. To investigate risk factors, age and sex-matched control group were selected.The clinical outcomes of gastric cancer identified during screening (screening group) were compared with age, sex and date of diagnosis-matched subjects who were diagnosed with gastric cancer in the outpatient clinic (outpatient group). Results: Of 109,530 subjects, 327 were diagnosed with gastric cancer. The median age of the screening group was 63.6 years (interquartile range: 56-71 years), and the male to female ratio was 2.4:1. When comparing with the control group, H. pylori seropositivity (odds ratio [OR] 2.933, p&lt;0.001), carcinoembryonic antigen (OR 8.633, p=0.004), family history of gastric cancer (OR 2.254, p=0.007), and drinking (OR 3.312, p&lt;0.001) were independent positive risk factors, and the use of aspirin a negative risk factor for gastric cancer (OR 0.445, p=0.012) in multivariate analysis. Low density lipoprotein cholesterol (hazard ratio [HR] 0.987, p=0.005), cancer antigen 19-9 (HR 21.713, p&lt;0.001), resectability (HR 59.833, p&lt;0.001), and family history (HR 0.308, p=0.009) were independent risk factors for death. The 5-year survival rate was significantly higher in the screening group than in the outpatient group (p&lt;0.001). Conclusions: Early detection of gastric cancer by screening endoscopy while asymptomatic enhances patient outcomes, especially in high risk groups.
Induction of broad repertoire of melanoma associated antigen-specific CD4+ T cells by dendritic cell vaccine loaded with killed allogeneic melanoma cells in patients with metastatic melanoma
Authors: H. Ueno, L. Bourdery, J. Blanck, J. W. Fay, J. Banchereau, A. K. Palucka
Journal: Journal of Clinical Oncology (2008)

3029 Background: Tumor-specific CD4+ T cells play an important role in antitumor immunity. CD4+ T cells recognizing melanoma associated antigens can be spontaneously generated in patients with metastatic melanoma as demonstrated by the infiltration of such cells at tumor sites; however, they are often dysfunctional. We analyzed tumor-specific CD4+ T cell repertoires in the blood of metastatic melanoma patients, and examined whether dendritic cell (DC) vaccine loaded with killed allogeneic melanoma cells administered to metastatic melanoma patients can induce and/or improve melanoma-specific CD4+ T cell immunity. Methods: PBMCs were obtained from ten metastatic melanoma patients who received at least four monthly DC vaccine injections (GM-IL-4 DC vaccine loaded with killed allogeneic melanoma cells, matured with CD40L and TNFa). Melanoma-specific T cell repertoires at baseline and after vaccinations were assessed with EPIMAX approach using overlapping peptide libraries spanning MART-1, gp100, and TRP-1 antigens. The frequencies of CD4+ T cells responding to the identified peptides were assessed by intracellular cytokine detection assay with flow cytometry. Results: At baseline, four out of ten patients displayed gp100-specific CD4+ T cells which secreted IFNg and/or IL-2, while none displayed MART-1-specific CD4+ T cells. Nine gp100 CD4+ T cell epitopes were identified in total. The T cells lacked proliferative capacity (seven out of nine gp100-specific T cells) in spite of cytokine secretion in response to peptide stimulation. We found PD-1 expression on specific CD4+ T cells which lacked the proliferative capacity. Analysis of post-vaccine showed the presence of proliferative gp100-specific CD4+ T cells in four patients. One of these patients experienced a complete response and another one a long-term survival. The frequencies of specific CD4+ T cells secreting IL-2 and/or IFNg were increased at post-vaccine. Functional MART-1 and TRP-1-specific CD4+ T cells were also induced in both patients. Conclusions: DC vaccine loaded with killed tumor cells can prime broad repertoire of tumor-specific CD4+ T cells as well as revert dysfunction of pre-existing specific T cells. No significant financial relationships to disclose.
Exploring the effect of medication features in renal cell carcinoma: A patient preference study.
Authors: Sandy Srinivas, Carol Mansfield, Rickard Sandin, A. Brett Hauber, Subramanian Hariharan, Ewa Matczak, Amy Pugh, Connie Chen
Journal: Journal of Clinical Oncology (2015)

463 Background: Limited information exists about patient preference (PP) for renal cell carcinoma (RCC) medication profiles, especially related to uncertainty in outcomes, potential correlation between toxicity and efficacy, and dosing schedules. Methods: RCC patients in the United States and Canada completed an online survey with questions that examined PP for medication profiles by varying efficacy (progression free survival [PFS]), tolerability (fatigue, hand-foot syndrome, hypertension, diarrhea) and dosing schedules (with or without 2 week break). A discrete-choice experiment (DCE) survey tested the impact of information on correlation between PFS and toxicity on medication choice, with half of the sample randomly assigned to receive the information. Separate exploratory questions assessed patient tradeoff between higher toxicity during treatment vs. the chance of longer PFS (2+ years) and type of dosing schedules, respectively. Results: The interim survey results included 343 RCC patients (172 metastatic (mRCC), 96 currently on treatment). In the exploratory questions, 50% of mRCC patients and 51% of patients receiving treatment selected the option with higher toxicity and a 5% higher chance of longer PFS. Patients who received information on a potential correlation between tolerability and PFS were more likely to say they would tolerate worse toxicity for a 5% higher chance of longer PFS than those who did not receive the information (49% vs. 31%). A majority of RCC patients preferred a treatment with a 2-week break in the dosing schedule compared to continuous treatment (59% vs. 25%). When told side effects were worse during the treatment period for the medication with the break vs. the continuous treatment (moderate vs. mild), 42% of RCC patient, 50% of mRCC patients, and 55% patients on treatment still preferred a break. Additional DCE analysis is underway and will provide more results on patient preferences for medication profiles, including the importance of information received. Conclusions: Patients have heterogeneous preferences over medicine features and outcomes. Physicians need to provide patients with comprehensive information about medication features and efficacy to provide a personalized and optimal approach to treatment.