tbuckley/cabot-search huggingface dataset:
The cost of adverse events in metastatic breast cancer in taxane- and capecitabine-based regimens.
Authors: Anthony Masaquel, Ryan N. Hansen, Scott David Ramsey, Deepa Lalla, Melissa Brammer, Sara A. Hurvitz, Sean D. Sullivan
Journal: Journal of Clinical Oncology (2013)

261 Background: Over 155,000 women are living with metastatic breast cancer (mBC) in the US. Chemotherapies can prolong survival for women with mBC, but adverse events (AEs) stemming from their use are common and costly to manage. We compared the healthcare costs for taxane- (TAX) and capecitabine-based (CAP) treatments for mBCpatients as either first- or second-line (FL or SL) therapy in the US. Methods: Using the Marketscan Commercial Database, a nationally representative database of over 52 million people, we selected mBC patients diagnosed from 2008-2011. Patients were categorized into FL and SL chemotherapy including either a TAX (paclitaxel or docetaxel) or CAP using an algorithm based on pharmacy and medical claims data. Chemotherapy-related AEs were identified by ICD-9 codes. Costs were tabulated from a payer perspective. Average monthly costs were stratified by treatment and the presence/absence of AEs. Results: Among 15,535 mBCpatients we identified 15,472 FL and 6,809 SL cases treated with TAX or CAP. The mean age of patients was 51 years (SD 8). At least one AE was experienced during FL treatment by 74% (SD 44%) and 68% (SD 46%) of TAX and CAP users and during SL treatment 60% (SD 49%) and 59% (SD 49%), respectively. Average monthly total costs during the FL period were $2,385 higher (p &lt;0.0001) and $1,679 higher (p=0.28) for TAX- and CAP-treated patients who experienced at least one AE. In SL, costs for patients with at least one AE had were $2,995 (p&lt;0.0001) higher for TAX-treated patients and $4,870 (p=0.0026) higher for CAP-treated patients. Conclusions: Among community-treated patients, AEs are common in women with mBC receiving TAX- and CAP-based chemotherapy regimens. These AEs are associated with higher costs in FL and SL. When possible, prevention or earlier management of AEs may represent an opportunity to reduce costs and improve outcomes for women with mBC. [Table: see text]
High-dose bevacizumab in the treatment of patients with advanced clear cell renal carcinoma (RCC): A Sarah Cannon Research Institute phase II trial.
Authors: A. A. Meluch, D. Shipley, D. M. Waterhouse, J. A. Reeves, E. Arrowsmith, D. R. Spigel, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2011)

e15101 Background: Bevacizumab is an active agent in the treatment of RCC. However, dose ranging studies to identify the most efficacious dose have not been performed. Early trials suggested a dose-response relationship (10mg/kg more active than 3mg/kg), and high levels of VEGF are frequently present in RCC. For these reasons, we investigated the efficacy and toxicity of higher bevacizumab doses in advanced RCC. Methods: Two doses of bevacizumab were evaluated in sequential patient cohorts: 15mg/kg q2wks (dose level 1), and 15mg/kg weekly (dose level 2). Eligible patients had metastatic or locally unresectable clear cell RCC; <2 prior regimens; ECOG PS 0 or 1; prior nephrectomy (unless contraindicated); measurable disease (RECIST). Patients were evaluated for response every 8 weeks; treatment continued until disease progression or unacceptable toxicity occurred. Results: 97 patients have been treated: Dose Level 1, 61 patients; Dose Level 2, 24 (of 60 planned) patients. The majority of patients had ECOG PS 0 and low-intermediate Motzer risk scores; 52 patients (54%) were receiving first-line treatment. Efficacy is summarized as follows: Frequent grade 3/4 toxicity included: hypertension (23% dose level 1; 25% dose level 2) and proteinuria (14% dose level 1; 21% dose level 2). 1 patient (with previous mediastinal radiotherapy) developed a tracheoesophageal fistula. No unexpected adverse events occurred. Conclusions: The higher doses of bevacizumab evaluated in this study produced toxicity profiles similar to standard doses. Accrual continues to dose level 2, and updated results will be presented; however, initial efficacy results do not suggest a dose-response relationship. CR+PR+SD Median PFS, mo. Dose Level #Pts Median F/U, mo. All First-Line All First-Line 1 61 22.3 52% 68% 6.3 9 2 24 5.6 50% 57% 5.4 5.5
A phase I safety study of NPC-1C: A novel, therapeutic antibody to treat pancreas and colorectal cancers.
Authors: Philip M. Arlen, Luis A. Diaz, Nilofer Saba Azad, Leanne Sophia Sleer, Sherri Haley, Michael Morse
Journal: Journal of Clinical Oncology (2012)

2517 Background: NPC-1C (NEO-101; Ensituximab) is a chimeric monoclonal antibody being developed as a novel biological treatment for pancreatic and colorectal cancers. This antibody was selected from a panel of hybridomas generated from mice immunized with semi-purified membrane-associated proteins derived from biologically screened, pooled human allogeneic colon cancer tissues. The NPC-1C target appears to be a variant of MUC5AC that is expressed specifically by human colon and pancreatic tumors with minimal cross-reactivity to normal GI tract tissues. Methods: A phase I open label, multi-center dose escalation clinical trial with NPC-1C has completed accrual of subjects with advanced pancreatic and colorectal cancer refractory to standard therapy. The primary objectives are to determine safety and tolerability of escalating doses of NPC-1C and to assess pharmacokinetics (PK) and select immune responses to the antibody at each dose level. Secondary objectives are to evaluate evidence of clinical benefit and to explore immunologic correlates Results: Three cohorts of subjects have been treated with NPC-1C at escalating dose levels of 1, 1.5, and 2 mg/kg IV every two weeks. All 15 subjects (10 colorectal, 5 pancreatic) have enrolled on study (5/15 non-evaluable). No DLT was noted at the 1mg/kg dose level with 2 of 3 patients showing stable disease at completion of Course 1. At the 2 mg/kg dose level, one patient demonstrated stable disease after course 1. At escalating rates of infusion, 3 subjects experienced mild to moderate hemolysis that resolved without intervention. All 6 patients who have received 1.5 mg/kg at a constant rate of infusion have been evaluated, with no dose limiting toxicity. One of 5 patients re-staged thus far in the 1.5 mg/kg cohort showed stable disease on scans after completing the first course of treatment (4 doses), and continued to receive additional doses. Preliminary data show no drug induced antibody responses in treated subjects. PK, HAMA and cytokine evaluation is ongoing. Conclusions: NPC-1C is tolerated well at the current dose level of 1.5 mg/kg every 2 weeks without producing any DLT We plan to continue accrual in the Phase 2A to evaluate clinical responses and additional safety data.
Impact of the U.S. Preventive Services Task Force update for breast cancer screening on mammography utilization in women age 40 to 49.
Authors: Amy T. Wang, Jiaquan Fan, Holly K. Van Houten, Nilay D. Shah
Journal: Journal of Clinical Oncology (2012)

5 Background: The 11/2009 USPSTF breast cancer screening update recommended against routine screening mammography for women age 40-49, created confusion and prompted organizations to release opposing statements. We aimed to determine if the USPSTF update for breast cancer screening impacted screening mammography utilization in women age 40-49. Methods: We conducted a time-series analysis utilizing administrative claims data from over 100 health plans. Women ages 40-64 with at least one month of enrollment from 01/2006-12/2010 were included. Medicare claims are not included and thus women ≥65 were excluded. The start date of 01/2006 was chosen to account for possible effects of the recent recession. We developed claims-based algorithms to identify the number of monthly screening mammograms. Time series models were fit using SAS PROC AUTOREG; strong seasonal fluctuations were adjusted by including an autoregressive error of order 12. Results: Over 7.9 million women were included. Prior to the intervention, the baseline monthly mammography rate was 40.9/1,000 women for the 40-49 group and 47.4/1,000 women for the 50-64 group. Based on projections from pre-intervention trends, the update was associated with a 5.72% (1.27,10.18) and 4.97% (1.11,8.84) decrease in mammography rate at 3 and 10 months post-intervention, respectively in the 40-49 group. The intervention had no effect on mammography rates in the 50-64 group. This translates to 53,969 fewer mammograms performed in the year following the update for women ages 40-49 in this dataset. Conclusions: We present the first estimates of the impact of the USPSTF breast cancer screening update using a large nationally representative database. The update was associated with a small but significant decrease in mammography rates for women ages 40-49, while no change was seen for women ages 50-64, which is consistent with the context of the guideline change. A modest effect is also in line with public backlash and the release of numerous conflicting guidelines. These findings underscore the need for further research on benefits and risks of screening mammography as it is difficult to act on numerous sources of contradictory information.
Mechanism of action of p28, a first-in-class, non-HDM2 mediated peptide inhibitor of p53 ubiquitination.
Authors: T. Yamada, K. Christov, T. K. Das Gupta, C. W. Beattie
Journal: Journal of Clinical Oncology (2011)

e13513 Background: Exposure of a wide variety of wild type and mutated p53 cancer cells to a 28 aa peptide (p28) derived from azurin, a redox protein secreted from the opportunistic pathogen Pseudomonas aeruginosa, produces a post translational increase in the level of p53 and inhibits the cell cycle at G2/M. We now report an underlying mechanism for the increase in p53. Methods: p53 wt MCF-7 and MCF-7 derived MDD2 p53dom/neg breast cancer cells were exposed to increasing doses of p28 for 24-72 hrs and Western analysis used to determine the levels of p53, the ubiquitin ligases HDM2, COP1, TOPORS and Pirh2, cyclin-dependent kinase inhibitor p21, G2/M-specific protein FoxM1, and stathmin (STMN1), an important regulatory protein of microtubule dynamics. We also used computer simulation (ClusPro, GROMACS) and domain specific antibodies to p53 to identify a potential site of p28 binding to p53. Results: p28 significantly increased the levels of p53 and p21 in MCF-7 cells, while significantly reducing the level of FoxM1 over a 72 hr exposure. The level of STMN1 was not altered, suggesting the block at G2/M does not involve microtubules. p28 also decreased the level of COP1> 80%, but did not significantly decrease TOPORS, Pirh2 or HDM2 levels in MCF-7 cells. In contrast, the levels of p53, p21, FoxM1, STMN1, COP1, TOPORS and Pirh2 either remained essentially at control levels (p53, p21) or were elevated (FoxM1, STMN1, COP1, TOPORS, Pirh2) at some point during a 72 hr exposure of p53dom/neg MDD2 cells to p28. Modeling and antibody studies suggest p28 binds to motifs that span aa 110-146 in flexible L1 loop and 80 and 276 of the p53 DNA binding domain (DBD), respectively. These data suggest that COP1, but not TOPORS or Pirh2, also binds within this region of p53 and that COP1 is a major regulator of p53 activity in breast cancer. Conclusions: p28 binds to a specific motif within the DBD of p53 that blocks COP1 mediated degradation suggesting it is a prototype non-HDM2 mediated peptide inhibitor of p53 degradation.
Role of TRPM8 in the mechanism of acute hyperexcitability to cold sensation associated with oxaliplatin-induced neurotoxicity.
Authors: T. Kono, M. Satomi, Y. Ebisawa, N. Chisato, M. Suno, K. Matsubara, T. Okayama, H. Karasaki, H. Furukawa
Journal: Journal of Clinical Oncology (2011)

e13580 Background: Oxaliplatin is commonly associated with peripheral neurotoxicity, particularly cold-induced paresthesia. However, the mechanisms that lead to these enhanced cold sensations in oxaliplatin-treated patients are unknown. Menthol induces cold sensations by interacting with the peripheral cold receptor, transient receptor potential melastatin 8 (TRPM8). Therefore, we hypothesized that TRPM8 may be involved in the mechanisms of acute oxaliplatin-induced peripheral neurotoxicity. Methods: To test this hypothesis, varying concentrations of L-menthol (from 0.0005 % to 0.5 %) were topically applied to the tongues of healthy subjects and colorectal cancer patients before and after they were treated with oxaliplatin and then the cold sensations were examined. All subjects experienced a cold sensation at the menthol application site and the intensity of the cold sensation detection threshold (CDT) was obtained. The CDT was calculated based on the menthol concentration. Results: In healthy subjects, the mean (± SD) CDT was 0.07 (± 0.025) %, and the CDT was not less than 0.005%. In colorectal cancer patients, CDT significantly decreased from 0.069 (± 0.043) % to 0.031 (± 0.023) % (p = 0.0058) after the patients received oxaliplatin infusions, and this enhanced cold sensation also occurred (from 0.186 [± 0.048] % to 0.077 [± 0.026] %; p = 0.0014) in patients who had previously received oxaliplatin (median, 320 mg/m2; range, 170-2,450 mg/m2). Conclusions: These findings indicate that TRPM8 is involved in acute hyperexcitability to cold sensation and contributes to acute oxaliplatin-induced neurotoxicity. Furthermore, these results indicate that TRPM8 is a potential target to understand the oxaliplatin-induced neurotoxicity as well as a good candidate for a prognostic marker of neurotoxicity severity score, although the methodology using menthol has not been firmly established.
The role of amide proton transfer imaging in detecting active malignant glioma.
Authors: J. O. Blakeley, X. Ye, M. Lim, H. Zhu, L. Blair, A. Quinones-Hinojosa, C. Eberhart, P. Barker, J. Laterra, P. C. M. van Zijl, J. Zhou
Journal: Journal of Clinical Oncology (2011)

2024 Background: The inability to distinguish active tumor from treatment-related injury is a major challenge in neuro-oncology. Amide Proton Transfer (APT) is a new magnetic resonance imaging (MRI) technique thought to image protein content at the cellular level. We assessed if APT-weighted MRI can improve the diagnostic value of MRI for malignant gliomas (MG). Methods: Two groups of patients were accrued. Group 1: patients with MG were imaged 1mo after radiation (RT) and temozolomide (TMZ) to assess APT, FLAIR, and T1w Gadolinium (T1wGd) enhancing volumes. Group 2: pre-operative glioma patients were imaged to correlate APT hyperintensity with pathology. Whole brain APT-weighted imaging was performed (FOV = 212x186 mm2; resolution = 2.2x2.2 mm2; 15 slices at 4.4 mm thickness) with FLAIR and T1wGd enhanced MRI. Regions of interest (ROI) were: (a) high APT-weighted signal intensity (≥ 2.5%), (b) T1wGd and (c) FLAIR enhancement. APT-based ROIs were digitally overlaid on T1wGd and FLAIR images and uploaded to the surgical navigation system for tissue sampling. A neuro-pathologist blinded to ROI reviewed all samples. The primary endpoints were volume of abnormal signal on MRI (group 1) and correlation between APT-weighted % hyperintensity and pathology (group 2). Results: Nine patients were studied in group 1. FLAIR volume was largest (median 34 cm3, range 2-117), APT-weighted signal intensity was intermediate (9 cm3, range 0-31), and T1wGd volume was smallest (median: 5 cm3,range 0-31). Ten patients were studied in group 2. Regions of high pre-operative APT-weighted signal intensity (≥2.5%) were associated with pathologically confirmed active MG in 7/7 patients; 3/3 patients with low APT-weighted signal intensity (<2.5%) had pathologically confirmed low grade glioma. Conclusions: APT imaging provides spatially distinct visual data from either FLAIR or T1wGd in patients with glioma. We observed 100% correspondence of high or low APT-weighted signal intensity with pathologically confirmed active MG (≥2.5%) or not (<2.5%) in patients with both newly diagnosed and recurrent/progressive gliomas. Additional longitudinal and pathologic correlation studies are ongoing to confirm the sensitivity and specificity of APT for active MG.
Optimizing the collection and reporting of wait time data.
Authors: Colleen Bedford, Deanna Langer, Melissa Kaan, Jonathan Norton, Brian Ho, Ann Thomas, Julian Dobranowski
Journal: Journal of Clinical Oncology (2016)

121 Background: Wait times for critical interventional radiology (IR) procedures have long been reported as barriers to access for cancer patients. Wait times have been difficult to measure in the province of Ontario as no mechanisms exist to capture IR data. Three individual programs at Cancer Care Ontario (CCO) began collection of CT-guided biopsies wait time data, with nuances dependent on program area of focus. The Cancer Imaging Program collects appointment availability for lung biopsies through a monthly email survey. The Diagnostic Assessment Program collects patient-level lung biopsy data at select facilities in the province. The Access to Care program collects patient-level data from facilities that perform CT biopsies, but the data is not specific to lung biopsies. To streamline data collection processes and provide a comprehensive report for the province, the three programs are collaborating to validate current data sets and optimize data collection. Methods: A four phase approach has been developed to prepare for the ongoing comprehensive report: Planning – identify target audience, timelines, and data; Data Validation – three step evaluation to compare data sets; Test Report – consultation of draft report with clinical experts; and Evaluation – lessons learned from steps one to three to prepare for ongoing report. Results: This initiative allows each program to: Critically assess the components of their respective datasets; Cross-validate data for consistency or alignment; and Frame the clinically relevant data components to support and inform decision making and reporting processes. Through this process, efficiencies are gained by streamlining data collection and ensuring alignment between program areas. The collaborative approach ensures the business needs of each program are protected in the final product. Furthermore, this process will allow decision makers at CCO to analyze various methods of wait time data collection and aid in methodology decisions of future collections. Conclusions: The final product of this initiative will provide physicians and decision makers throughout Ontario with robust data to understand what is happening in their hospitals. The report will also facilitate impact analysis of interventions to reduce wait times.
In Vivo Downregulation of Bcl-2 by G3139 (G) Enhances Rituximab (R) Anti-Tumor Activity: Effect of Sequential Versus Concurrent G3139 Administration on Survival in a Lymphoma-Bearing SCID Mouse Model.
Authors: Jeyanthi Ramanarayanan, Francisco J. Hernandez-Ilizaliturri, Myron S. Czuczman
Journal: Blood (2004)
Effect of catumaxomab treatment in patients with peritoneal carcinomatosis and malignant ascites due to gastrointestinal cancers on survival.
Authors: M. A. Ströhlein, M. M. Essing, M. Hennig, D. Seimetz, M. G. Ott, M. M. Heiss
Journal: Journal of Clinical Oncology (2011)

490 Background: In 2009 the trifunctional antibody catumaxomab was approved for the intraperitoneal (i.p.) treatment of malignant ascites (MA) in EpCAM-positive carcinomas in Europe. Overall survival (OS) results for gastric cancer patients from the pivotal trial showed a significant treatment benefit of catumaxomab in this patient group. We present the results for the gastrointestinal (GI) cancer subgroup from the pivotal trial including long-term survivors. Methods: A total of 86 patients with MA due to GI cancer (gastric, pancreatic, colon, esophagus, rectum carcinoma) were treated with paracentesis plus catumaxomab (59 patients) vs. paracentesis alone (control, 27 patients). The primary endpoint was puncture-free survival; main secondary endpoints were time to next puncture, overall survival and safety parameters. The endpoints were compared between the catumaxomab and the control group using the Kaplan-Meier method and log-rank test. Analyses were performed for the Full Analysis Set (FAS) and the Safety Set (patients who received at least 1 catumaxomab infusion; 95%). Results: For puncture-free survival, a median of 35 days for catumaxomab vs. 14 days for control was observed (p&lt;0.0001, HR: 0.340 with 95 % CI from 0.194 to 0.597, FAS). Time to next puncture resulted in a median of 118 days vs. 15 days (p&lt;0.0001, HR: 0.161 with 95 % CI from 0.069 to 0.378, FAS). Although the study was not powered nor designed for OS, the difference between treatment and control arm was significant for the Safety Set (median: 61 vs. 44 days, p&lt;0.05, HR: 0.553). ADRs were generally mild to moderate, limited to the treatment period and reversible. Conclusions: I.p. catumaxomab is an EMA-approved treatment for patients suffering from malignant ascites. The positive efficacy results were demonstrated in an advanced stage patient population together with a predictable and manageable safety profile. Patients suffering from peritoneal carcinomatosis with malignant ascites due to GI cancers experience a significant survival benefit from i.p. treatment with catumaxomab. [Table: see text]
Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling
Authors: Chrystal M. Paulos, Claudia Wrzesinski, Andrew Kaiser, Christian S. Hinrichs, Marcello Chieppa, Lydie Cassard, Douglas C. Palmer, Andrea Boni, Pawel Muranski, Zhiya Yu, Luca Gattinoni, Paul A. Antony, Steven A. Rosenberg, Nicholas P. Restifo
Journal: Journal of Clinical Investigation (2007)
Association of low serum levels of transforming growth factor β1 (TGF-β1) and high levels of vascular endothelial growth factor-A (VEGF-A) following neoadjuvant chemoradiotherapy with poor outcome in esophageal cancer patients receiving combined modality therapy: A preliminary analysis using proximity ligation assay.
Authors: Madeline S Graber, Jason C. Cheng, Feng-Ming Hsu, Albert Koong
Journal: Journal of Clinical Oncology (2013)

80 Background: Currently, serum biomarkers do not influence the treatment of esophageal cancer. The purpose of this project is to investigate, using the proximity ligation assay (PLA), serum biomarkers that predict treatment response and survival outcome for patients with locally advanced esophageal cancer (LAEC) undergoing neoadjuvant concurrent chemoradiotherapy (CCRT) followed by radical esophagectomy. Methods: From 2004 to 2011, 79 patients with LAEC receiving CCRT of taxane-based chemotherapy and 40 Gy followed by curative surgery were enrolled in this study. Serum samples were collected before and within one month after CCRT. Fifteen biomarkers (Axl, BMP2/4, EGFR, FAM84B, Gas6, Her2, IGFBP3, MMP1, MMP13, OPN, PDGFR-α, Periostin, SPARC, TGF-β1, VEGF-A) were analyzed using PLA. Pathological responses were classified into complete response (CR), microscopic residual (MicroR), or macroscopic residual (MacroR). Associations between serum level of each biomarker and pathological response, disease-free survival (DFS), and overall survival (OS) were evaluated by ANOVA and Log-rank tests. Results: Of 79 patients, 30 had CR (38%), 37 had MicroR (47%) and 12 had MacroR (15%). With a median follow-up of 54.5 months, the median OS and DFS were 34 and 43 months, respectively. Among evaluated biomarkers, TGF-β1 was the most significant one associated with pathological response (p=0.009, two-way ANOVA), with higher post-CCRT TGF-β1 levels predicting better response (p=0.035, one-way ANOVA). Patients with higher post-CCRT TGF-β1 levels (≥3 rd quartile) had significantly better DFS (median not reached vs. 27 months, p=0.03). Patients with both lower levels of post-CCRT TGF-β1 and higher levels of VEGF-A had significantly worse DFS (13 months, p=0.001) and OS (18 months, p=0.035). Conclusions: Post-CCRT serum TGF-β1 and VEGF-A levels by PLA may be used to predict pathological response and survival outcome for esophageal cancer patients receiving combined modality therapy.