tbuckley/cabot-search huggingface dataset:
Prevention of 5-FU-induced toxicities using pretherapeutic DPD deficiency screening: Medical and economic assessment of a multiparametric approach.
Authors: Michele Boisdron-Celle, Olivier Capitain, Roger Faroux, Christophe Borg, Jean-Philippe Metges, Marie-Pierre Galais, Mehdi Kaassis, Jaafar Bennouna, Karine Bouhier Leporrier, Eric Francois, Isabelle Baumgaertner, Veronique Guerin-Meyer, Oana Cojocarasu, Celia Roemer-Becuwe, Claire Stampfli, Ludovic Rosenfeld, Thierry Lecomte, Virginie Berger, Alain Morel, Erick Gamelin
Journal: Journal of Clinical Oncology (2013)

351 Background: 5-FU is the backbone of most chemotherapy regimens in GI oncology. Patients with DPD deficiency can experience early onset severe (5%) even fatal (0.3%) toxic side-effects. We decided to confirm the medical and economic interest of pre-therapeutic screening of DPD deficiency using a multiparametric approach in a multicenter prospective cohort study (Eudract n°2008-000026-39). Methods: Two parallel cohorts of patients treated with 5-FU-based chemotherapy for colorectal carcinoma were compared: Group A: initial DPD activity evaluation; Group B: no evaluation. Enrollment in either group was based on 5-FU administration guidelines at each institution. DPD deficiency screening combined genotyping and phenotyping (ODPM Tox) as well as other patient characteristics (1,2,3). The 2 groups were compared in terms of early 5-FU-induced toxicity grade, toxicity cost and DPD screening cost. The enrollment was to be immediately closed if 5-FU-induced toxic death occurred. Results: 1,130 patients were included from to 16/06/2008 to 07/31/2012. Group A: no severe toxicity despite 1 patient with complete deficiency (5-FU replaced by another TS inhibitor), 17 patients with partial deficiency safely received PK-monitored 5-FU (ODPM Protocol). Group B: 1 death: 65 y.o. patient, adjuvant FOLFOX 4, 5-FU-induced SAE at day 6: grade 4 febrile neutropenia, septicemia, diarrhoea, mucositis and secondary dehydration, renal failure, then death. 5-FU imputable Grade 5 SAE declared by investigator. Complete DPD deficiency retrospectively confirmed. The enrollment was prematurely closed after unanimous experts’ decision for ethical reasons. Data treatment is ongoing. Conclusions: One complete deficiency occurred in both groups: Group A patient had safe treatment whereas Group B patient died due to 5-FU grade 5 toxicity. DPD deficiency screening by a multiparametric approach (ODPM Tox) should be performed before 5-FU treatments. Clinical trial information: 2008-000026-39. [Table: see text]
Development of a new outcome-prediction model for patients with urothelial carcinoma of the bladder prior to cystectomy.
Authors: Mario W. Kramer, Christoph A. J. von Klot, Annika Heinisch, Gerd Wegener, Mahmoud Abbas, Inga Peters, Hossein Tezval, Thomas R. W. Herrmann, Markus A. Kuczyk, Axel S. Merseburger
Journal: Journal of Clinical Oncology (2014)

360 Background: Prognostic models for patients undergoing cystectomy are spares and mostly rely on histopathological parameters. The present study investigated clinical prognostic indicators that are available prior to cystectomy for developing a risk stratification model. Methods: Charts were reviewed from 279 bladder cancer patients that were treated with radical cystectomy and bilateral lymphadenectomy. Of those 194 were eligible for study entry due to availability of necessary data. None of the patients had neoadjuvant therapy. Various preoperative parameters were analyzed and optimum cut-off points were identified using ROC curves. A risk stratification model was developed based on multivariate analysis. Analyzed factors included serum-creatinine, hemoglobin, white blood cells, C - reactive protein (CRP), age, gender, and body mass index. Results: In multivariate analysis, preoperative serum-creatinine (&gt;93 umol/l), white blood cells (&gt;10.2 tsd/ul), CRP (&gt;3 mg/l) and BMI (&lt;18,5 kg/m 2 or ≥30 kg/m 2 ) were independent predictor of poor cancer-specific survival (CSS). A new scoring model was developed, consisting of those four parameters. The stratification model showed significant differences based on Kaplan-Meier analysis for the whole cohort as well as for subgroup analysis (pT2-4, Nx, M0) (p&lt;0.001). CSS after 36 (60) months for low, intermediate and high risk group was 82.6% (76.2%), 37.7% (30.9%) and 22.2% (16.7%), respectively (p&lt;0.0001). Conclusions: Our scoring model based on preoperative clinical parameters can discriminate bladder cancer patients prior to cystectomy in respect of CSS. This might help physicians to recommend treatment options such as neoadjuvant therapy. The scoring model needs external validation considering prospective study design and discriminating patients who received neoadjuvant chemotherapy.
The Prognostic Role of Cell of Origin Profile and Myc Expression Assessed By Immunohistochemistry in Young High-Risk Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Results of First-Line Randomized BIO-DLCL04 Trial of Fondazione Italiana Linfomi (FIL)
Authors: Annalisa Chiappella, Claudio Agostinelli, Maurizio Martelli, Simona Righi, Andrea Evangelista, Emanuele Angelucci, Monica Balzarotti, Angelo Michele Carella, Manuel Gotti, Domenico Novero, Giuseppe Rossi, Caterina Stelitano, Marco Ladetto, Gianluca Gaidano, Stefano A Pileri, Umberto Vitolo
Journal: Blood (2015)
Bevacizumab plus capecitabine as maintenance treatment after initial treatment with bevacizumab plus XELOX in previously untreated metastatic colorectal cancer: Updated findings from a randomized, multicenter phase III trial.
Authors: S. Yalcin, R. Uslu, F. Dane, U. Yilmaz, N. Zengin, E. Buyukunal, S. Buyukberber, C. Camci, O. Sencan, S. Kilickap
Journal: Journal of Clinical Oncology (2011)

3579 Background: Colorectal cancer is one of the most frequent malignancies, second to breast cancer in women and third to lung cancer and prostate cancer in men. The aim of this study in first-line metastatic colorectal cancer (mCRC) was to achieve a better progression-free survival (PFS) and less risk of toxicity by administrating bevacizumab (BEV) + capecitabine + oxaliplatin (XELOX) for 6 cycles, stop oxaliplatin and go with maintenance therapy (BEV + capecitabine) until progression. Methods: BEV (7.5 mg/kg) + XELOX (capecitabine 1000 mg/m2 bid d1–14 + oxaliplatin 130 mg/m2 d1 q3w) were administered until progression (Arm A) or 6 cycles of BEV + XELOX followed by BEV + capecitabine were administered until progression (Arm B). PFS was the primary endpoint; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. A sample size of 118 patients (pts) was calculated to achieve 80% power to detect an increase of 1.5 months in median PFS between Arm A (9.5 months) and Arm B (11.0 months) with a standard deviation of 3.9 months and significance level of 0.05 using a 10% drop-out rate. Results: A total of 122 pts were randomized. No significant differences were found in demographic characteristics between the two arms. Median treatment period was 6.1 (range 0.7–13.4) and 6.8 (range 0.7–12.4) months in Arms A and B, respectively. Interim analysis showed no statistically significant differences in median PFS and ORR between arms (Table). Tolerability was also acceptable in both arms with grade 3/4 diarrhoea in 7.7% vs. 8.2%, weakness in 15.2% vs. 8.4%, hand-foot syndrome in 6.3% vs. 9.4%, and neuropathy in 2.8% vs. 4.6% of pts in Arms A and B, respectively. Conclusions: BEV + capecitabine as maintenance therapy following induction BEV + XELOX is noninferior to continuous BEV + XELOX until progression. These interim findings suggest that maintenance therapy with BEV + capecitabine is an appropriate option following induction BEV + XELOX in pts with mCRC. Updated data will be presented. Efficacy Arm A (n=61) Arm B (n=61) P value Median PFS, months 8.3 9.9 0.064 ORR, % 57.4 69.2 0.207
Effect of oxymatrine on the side population and expression of β-catenin in MCF-7 breast cancer cells.
Authors: Y. Zhang, H. Lin, W. Hou
Journal: Journal of Clinical Oncology (2011)

e13505 Background: The cancer stem cells (CSCs) play a critical role in both cancer initiation and relapse as they are resistant to most of cytotoxic agents and able to proliferate indefinitely. The recent identification of CSCs in multiple human cancers provides a new inroad to understanding tumorigenesis at the cellular level. Oxymatrine is an alkaloid compound found in plants that display anti-microbial and anti-inflammatory activities. And also has been demonstrated to have the anti-tumor effects. Since to date, very few treatments have targeted cancer stem-like cells, so the detection of CSCs in breast cancer leads us to investigate whether oxymatrine might affect the CSCs specifically. Methods: Cytotoxicity and cancer stem-like cells (side population, SP) identification and sorting were performed. Inhibitory effect was evaluated on the sorted SP and non-SP cells. At the same time, β-catenin, phosphorylated β-catenin, c-myc and cyclinD1 were also detected by fluorescence microscope, FACS, Western blot and fluorescence quantitative PCR among oxymatrine treated MCF-7 and the control one. Cisplatin was the positive control drug of these experiments. Results: SP cells were identified with percentage (3-5%) in MCF-7 cells. Oxymatrine caused a dose-dependent reduction in the proliferation of MCF-7 cells and a decrease in SP cells relative to untreated controls. As compared to non-SP cells, inhibitory effect in the SP cells was higher. Wnt/β-catenin signaling pathway was also examined by analyzing the expression of totalβ-catenin and phosphorylatedβ-catenin in cytoplasm, oxymatrine treatment was associated with an inhibition of Wnt/β-catenin signaling pathway relative to untreated controls. Conclusions: These results indicate that the growth inhibitory effects of oxymatrine treatment on MCF-7 cells may be partly via effects on SP and Wnt/β-catenin signaling pathway. Further work is warranted to explore whether oxymatrine may be a useful novel therapeutic drug for targeting breast CSCs.
A comparison of chemotherapy use in stage IV pancreatic cancer.
Authors: Naomi Whittaker, Kristin Hueftle, Mary Warlaumont, Lauren Brin, David C. Olson, Apar Kishor Ganti, Xiang Fang, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2012)

257 Background: Palliative chemotherapy is the standard of care for stage IV pancreatic cancer patients (SFPC). Methods: This study compares the amount of chemotherapy given for SFPC across insurance types using the National Cancer Database (NCDB), which contains 70% of U.S. cancer cases. Results: The NCDB reported 115,512 patients diagnosed with SFPC from 2000 to 2009. Overall, 38.3% of SFPC patients received chemotherapy. The VAH (28.3%) and Medicare (29.7%) provided significantly less chemotherapy to SFPC patients as compared to Managed Care (48.2%), Private Insurance (46.7%), Tricare/Military (42.8%), Medicaid (37.8%), Medicare Plus Supplement (35.5%), and Uninsured (34.4%). From 2000 to 2009, the rate of chemotherapy for SFPC increased for both VAH (22.9% to 34.3%) and non-VAH (31.1% to 44.1%). At time of diagnosis, the percent of patients less than 60 at the VAH was 32%, non-VAH was 25.5% and Medicare was 7%. From age 20 to 59, the rate of chemo was stable at approximately 49%, but each successive decade demonstrated a marked reduction in use of chemotherapy (from 44% for 60 to 69 years of age to 21% for 80 to 89 and 5% for &gt;90). The VAH PC population diagnosed with PC included 71.1% whites (W), 21.1% blacks (B), 4.8% Hispanics (H), 0.8% Asian-Pacific Islander (API), and 0.6% Native American (NA). Among all insurance types, only Medicaid (25%* B, 14%* H, 6%* API) and Uninsured (20% B, 15%* H, 4%* API) had a greater percentage of minorities. Compared to the average of all patients treated for SFPC (38.3%), blacks (34.7%*) and Hispanics (35.7%*) received less chemotherapy and whites received more (39.1%*). Conclusions: This is the largest study to analyze the use of chemotherapy in stage IV pancreatic cancer. Patients treated within the VAH were less likely to receive chemotherapy compared to all other patients except those with Medicare, who tend to be older at time of diagnosis. As age increases above 59, chemotherapy treatment for SFPC decreases. VAH patients receive less chemotherapy than Medicaid and Uninsured patients, though Medicaid and Uninsured have a greater percentage of minorities, who tend to get less chemotherapy for SFPC.
High-dose melphalan on day 2 versus 1 before autologous stem cell transplantation for multiple myeloma.
Authors: K. Rakszawski, J. J. Drabick, N. G. Dolloff, J. M. Sivik, J. Malysz, D. Claxton, W. C. Ehmann, W. B. Rybka, G. Talamo
Journal: Journal of Clinical Oncology (2011)

6545
Influence of Karyotype On Overall Survival in Patients with Higher-Risk Myelodysplastic Syndrome Treated with Azacitidine or a Conventional Care Regimen.
Authors: Ghulam J Mufti, Steven D. Gore, Valeria Santini, Pierre Fenaux, Lewis R. Silverman, Anne Hagemeijer, Barry Skikne, Eva Hellstrom-Lindberg, John F. Seymour, CL Beach, Jay Backstrom, Indrasiri Fernando
Journal: Blood (2009)
A randomized, open-label phase II study of nanoliposomal irinotecan (nal-IRI)-containing regimens versus nab-paclitaxel plus gemcitabine in patients with previously untreated metastatic pancreatic adenocarcinoma (mPAC).
Authors: Andrew Dean, Li-Tzong Chen, Ramesh K. Ramanathan, Sarah Blanchette, Bruce Belanger, Deyaa Adib, Eliel Bayever
Journal: Journal of Clinical Oncology (2016)

TPS482 Background: Two combination chemotherapy regimens have emerged as standard of care options for first-line treatment of mPAC: 5-fluorouracil (5-FU)/leucovorin (LV) + irinotecan + oxaliplatin (FOLFIRINOX), and nab-paclitaxel + gemcitabine. Nal-IRI (MM-398) is a nanoliposomal formulation of irinotecan. In a randomized phase 3 study (NAPOLI-1), of patients with mPAC who had been previously treated with gemcitabine-based therapy, nal-IRI + 5-FU/LV demonstrated its safety and significant clinical activity, increasing overall survival (OS) and progression-free survival (PFS) relative to 5-FU/LV. The goal of this current study is to determine the preliminary safety and efficacy of nal-IRI+ + 5-FU/LV with or without oxaliplatin as compared to nab-paclitaxel + gemcitabine in previously untreated patients with mPAC. Methods: This open-label, phase 2 comparative study will be conducted in two parts. Part 1 is a safety run-in of a nal-IRI+5-FU/LV + oxaliplatin regimen. The safety run-in will enroll small cohorts of patients following a traditional 3 + 3 dose escalation design to confirm the target dose of oxaliplatin (n = ~6-18). The primary objective of Part 1 is the safety and tolerability of nal-IRI + 5FU/LV + oxaliplatin. Part 2 is a randomized, efficacy study of a nal-IRI + 5-FU/LV + oxaliplatin regimen (Arm 1), the nal-IRI + 5-FU/LV combination that previously demonstrated efficacy in the NAPOLI-1 trial (Arm 2), versus a nab-paclitaxel + gemcitabine control arm (Arm 3) (n = ~156-168). The primary objective of Part 2 is to assess the efficacy of nal-IRI-containing regimens in first-line mPAC patients compared to nab-paclitaxel + gemcitabine using the progression-free survival (PFS) rate at 24 weeks as the primary endpoint. Secondary of part 1 is a PK study and Part 2 secondary endpoints will include OS, PFS, objective response rate (per RECIST, v1.1), decrease in CA19-9 levels and quality of life assessments. Clinical trial information: NCT02551991.
Impact of meningeal dissemination (MD) on outcome in primary CNS lymphoma in the G-PCNSL-SG1 trial
Authors: A. Korfel, L. Fischer, P. Martus, R. Moehle, H. A. Klasen, M. Rauch, A. Roeth, B. Hertenstein, T. Fischer, H. Mergenthaler, T. Hundsberger, M. Leithäuser, T. Birnbaum, A. Florschütz, K. Jahnke, U. Herrlinger, M. Weller, E. Thiel
Journal: Journal of Clinical Oncology (2011)

2026 Background: The prognostic impact of MD in PCNSL is still debated. Within the framework of a multicenter randomized trial (G-PCNSL-SG1) we evaluated patients for outcome according to the presence of MD. Methods: Immunocompetent adult patients were initially treated with up to six cycles of high-dose methotrexate (HD-MTX; 4g/m2) based chemotherapy without intrathecal therapy. Those randomized to radiotherapy subsequently received whole-brain radiotherapy (WBRT) with 45 Gy, in 1.5 Gy fractions; those randomized to chemotherapy did not receive further therapy in case of complete remission or high-dose cytarabine when complete response was not achieved. MD was defined by the presence of lymphoma cells in the CSF detected by at least one of the following methods: cytomorphology, detection of clonal B cells by IgH-PCR or contrast enhancement of the leptomeninges on MRI. Results: All 526 patients fulfilling the eligibility criteria were entered into the analysis. MD at presentation was detected in 104 (19.8 %) patients: 95 by cytomorphology, 16 by PCR and 17 by MRI. Pretherapeutic characteristics including age, Karnofsky performance score, sex, serum lactate dehydrogenase, lymphoma localization, mode of biopsy, histology, CSF protein elevation (>45mg/dl) and ocular involvement did not significantly differ in patients with MD and other patients (all p>0.05). Only CSF pleocytosis (>5/µl) was significantly more frequent in patients with MD (37 vs. 14%, p<0.001). The type of chemotherapy (HD-MTX: 83 vs. 75%, HD-MTX and ifosfamide: 17 vs. 25%) applied and the frequency of WBRT (39 vs. 34%) were not significantly different in the group with and without MD. Median overall survival (OAS) in the MD group was 21.5 (95% CI 17.1-25.8) months as compared to 22.4 (17.3-27.5) months in other patients (p=0.8); median progression free survival (PFS) was 6.1 (1.6-10.5) and 7.0 (5.2-8.8) months, respectively (p=0.9). Median OAS and PFS were not significantly different in patients with elevated CSF protein or CSF pleocytosis compared to patients with normal CSF values. Conclusions: MD, elevated CSF protein and CSF pleocytosis had no impact on outcome in this trial.
Novel probe-based quantative image of mitochondria in live colon cancer tissues by multiphoton microscopy.
Authors: Eun Sun Kim, Hoon Jai Chun, Yoon Tae Jeen, Bora Keum, Hyuk Soon Choi, Seung Han Kim, Jae Min Lee, In Kyung Yoo
Journal: Journal of Clinical Oncology (2016)

581 Background: Multiphoton endomicroscopy is the recentely updated technique for endoscopy and virtual image and optical sectioning. However optimized probe has not been established for multiphoton endomicroscopic image. Therefore we developed novel probe for mitochondria and applied for colon neoplasm tissues. In cancer cell, abnormally increased mitochondrial replication is related mitochondrial dysfunction and Warburg effect. Methods: We used newly developed multiphoton probe for micochondria imaging which are made using benzofuran derivative (BFP, maximal multiphoton fluorescence at 570 nm). Fresh mucosal tissues of colonic adenoma and adenocarcinoma were obtained from endoscopic biopsy. Multiphoton probe BFP for mitochondria was stained for tissues and imaging performed using multiphoton microscopy. Results: BFP shows high enhancement factor upon binding mitochondria, good selectivity, cell permeability, and can readily detect mitochondria in human tissues by multiphoton microscopy. Mitochondria were detected in human colon mucosa tissues. Calculated mitochondria area were increased in adenocarcinoma tissues compared to normal mucosal tissues. Conclusions: Newly developed multiphoton probe for mitochondria are usable to image human live colon tissues.
Characterization of brivanib pharmacokinetics and exposure-response (E-R): Relationship of fatigue in patients with advanced and metastatic solid tumors.
Authors: X. Wang, S. Syed, E. Masson, I. B. Walters, A. Roy
Journal: Journal of Clinical Oncology (2010)

3095 Background: Brivanib alaninate is the L-alanine ester prodrug of brivanib, an oral selective dual inhibitor of vascular endothelial growth and fibroblast growth pathway receptors. It is currently in phase III development for advanced hepatocellular carcinoma (HCC) and colorectal cancer (CRC). This analysis characterized the relationship between brivanib exposure and the incidence of fatigue, the most common adverse event (AE) with oral multikinase inhibitors. Methods: A PPK model was developed with data collected in 167 subjects with advanced and metastatic solid tumors (including HCC) from phase I and II clinical studies. The model was applied to determine the following summary measures of brivanib exposure: steady-state average (Cavg), trough (Cmin), and peak concentration (Cmax). Fatigue incidence within the first month of brivanib treatment was chosen to better reflect the drug induced fatigue and to differentiate with disease associated events. The relationship between brivanib exposure and incidence of early fatigue (worst grade within first month) was characterized by ordered categorical logistic regression. Results: The PPK of brivanib was characterized by a 2-compartment model with first-order absorption and elimination. Clearance was found to increase with body weight (p<0.01), but the effects of age, gender and race on clearance were not statistically significant. E-R analysis showed that Cmin better predicted the risk of fatigue (p<0.01) than Cmax or Cavg. The risk increased with increasing Cmin (1.33-fold for each doubling of Cmin) and increasing age (1.38-fold for each decade of life, p<0.01). The median relative risk of fatigue with 800 mg QD (phase III dose) vs. 400 mg BID (which produces equivalent Cavg), is 0.67 (90% CI: 0.44-1.01). Preliminary analysis showed that similar efficacy was obtained in both regimens. Conclusions: Brivanib PK was adequately described by a linear 2-compartment model, and clearance increases with increasing body weight. Early incidence of fatigue increases with increasing Cmin and age. QD regimen is expected to have less fatigue than the BID regimen by achieving lower Cmin and similar Cavg. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb