tbuckley/cabot-search huggingface dataset:
Evaluation of patupilone as monotherapy in patients with advanced hepatocellular carcinoma (HCC)
Authors: A. P. Venook, R. Poon, Y. K. Kang, T. S. Mok, Y. Chao, S. de Bedout, A. Harbott, J. Li, A. R. Johri
Journal: Journal of Clinical Oncology (2007)

15055 Background: Currently, there is no strong evidence that systemic therapies provide a survival benefit for patients (pts) with hCC. However, preclinical data have shown that the novel epothilone patupilone has potent anti-proliferative activity against 8 HCC cell lines with intrinsic multidrug resistance. This exploratory study tested whether patupilone monotherapy has antitumor activity in HCC patients with intact liver function. Methods: This open-label, single-arm, multicenter, 2-stage phase II study was to enroll 24 pts in the first stage and 41 pts in the second stage, if = 3 complete or partial responses were observed in the first stage. Patients with unresectable and/or metastatic HCC (histologically confirmed) with = 1 measurable lesion were eligible if they had well-preserved hepatic function (Child-Pugh Class A) and life expectancy = 3 months. Patupilone was administered as a single IV infusion at 10 mg/m 2 over 20 minutes every 3 weeks. Primary endpoint was objective response. Results: Twenty-five patients were enrolled, 24 were evaluable, and 1 violated protocol. The most common adverse events (AEs) suspected to be study-drug related were NCI CTC grade 1/2 diarrhea, fatigue, and vomiting. Grade 4 serious AEs included hyponatremia (2 pts [8%]), cardiac arrest (1 pt [4%]), diarrhea (1 pt [4%]), and gastrointestinal hemorrhage (1 pt [4%]). Grade 3 serious AEs included diarrhea (3 pts [12%]), hyponatremia (2 pts [8%]), deep vein thrombosis (1 pt [4%]), abdominal pain (1 pt [4%]), and hyperkalemia (1 pt [4%]). Most pts had dose adjustments or delays; 3 discontinued treatment. During the first stage, 1 pt had a confirmed partial response through 4 cycles, and 11 pts (44%) had stable disease for = 2 cycles with a median of 4 cycles (range, 2 to 8 cycles). Median progression-free survival was 3 months (range, 1 to 6 months), and 10 pts (40%) progressed within the first 2 cycles. The study did not progress to stage 2. Conclusions: Patupilone demonstrated an acceptable safety profile. Serious AEs were observed in a minority of patients, and most did not require treatment discontinuation. Patupilone demonstrated only modest antitumor activity in pts with HCC in this study. No significant financial relationships to disclose.
Selective activity of dasatinib for the most common KIT mutation in melanoma (L576P)
Authors: S. E. Woodman, J. C. Trent, K. Stemke-Hale, A. Lazar, S. Pricl, G. M. Pavan, N. Papadopoulos, P. Hwu, G. B. Mills, M. A. Davies
Journal: Journal of Clinical Oncology (2009)

9019 Background: Point mutations in the KIT receptor tyrosine kinase gene have recently been identified in melanomas from mucosal, acral lentiginous (AL), and chronically sun-damaged (CSD) sites. An improved understanding of the molecular characteristics of melanoma-prevalent KIT mutations may lead to more effective therapeutic approaches. Methods: Human melanoma cell lines were screened by mass-spectroscopy based genotyping for KIT mutations, and a cell line with an endogenous L576P KIT mutation was identified. The cell line was treated in vitro with a panel of small molecule KIT inhibitors and the effects on cell viability were quantified. Molecular modeling of the interaction of the inhibitors with the KIT L576P mutant protein was determined to estimate binding affinity. PET/CT studies were performed on patients with mucosal melanoma harboring the L576P mutation pre- and post-dasatinib treatment. Results: We have identified the first human melanoma cell line with an endogenous L576P mutation, the most common KIT mutation in melanoma. In vitro testing demonstrated that this cell line is resistant to imatinib, nilotinib and sorafenib (0 - 1 uM), KIT inhibitors shown to be effective in non-melanoma cells with other KIT mutations. However, the mutant cell line was inhibited by dasatinib at concentrations as low as 10 nM, and was significantly more sensitive than melanoma cell lines with wild-type KIT (p = 0.02). No difference in sensitivity to Src inhibitors was observed, supporting that this sensitivity was due to KIT inhibition. Molecular modeling demonstrated that the L576P mutation induces structural changes in KIT that reduce the affinity for imatinib but not for dasatinib. Two metastatic melanoma patients with the L576P KIT mutation were treated with dasatinib, including one patient previously treated with imatinib. Both patients had marked reduction and elimination of tumor FDG- avidity by PET imaging after dasatinib treatment. Conclusions: This data supports that dasatinib has a selective inhibitory effect against the most common KITmutation in melanoma and has implications for the development of AL, CSD, and mucosal melanoma treatment. [Table: see text]
Paclitaxel and epirubicin versus 5-fluorouracil, epirubicin and cyclophosphamide in preoperative chemotherapy of stage III A and III B of chemotherapy-naïve breast cancer: Comparative analysis of response rate
Authors: A. Badulescu, F. Badulescu, M. Schenker, P. Badea
Journal: Journal of Clinical Oncology (2005)

772 Background: The most efficient neoadjuvant regimen for locally advanced BC remains to be determinate. Methods: We have conducted a randomized, prospective clinical trial to compare the efficacy of epirubicin 75 mg/mp iv in day 1 followed by paclitaxel 175mg/mp iv over 3 hours in day 1 - every 21 days (PE), versus 5-fluorouracil 500 mg/mp iv followed by epirubicin 100 mg/mp iv and cyclophosphamide 500 mg/mp iv all in day 1 - every 21 days (FEC 100), administrated preoperative in stages III A or III B BC. Eligibility criteria included stage III A or III B of cytological confirmed BC, ECOG 0–2, at least one measurable lesion according to RECIST, no prior chemotherapy for BC and written informed consent. The primary endpoint was to demonstrate that PE regimen is superior to FEC 100 regimen regarding response rate. Secondary endpoints were to compare the median number of cycles in both arms and to compare toxicity. Analysis was conducted until every patient was surgical treated or remove of the study because of progressive disease, intolerable toxicity or withdrawal of consent. Results: 98 patients (pts) were randomized between 01.2002 and 03.2004 (50 pts in FEC 100 arm and 48 pts in PE arm). Response rate was 85,42% for PE regimen (29,17% complete response-CR and 56,25% partial response-PR) and 76% for FEC 100 regimen (20% CR and 56% PR) with OR=0,54, confidence limits 0,17 - 1,68, p-value 0,238 performing percentage comparison test. The median number of cycles was 3,1 for PE regimen and 3,9 for FEC 100 regimen. No significant difference was observed regarding toxicity. Conclusions: The higher response rate with the same toxicity for PE regimen recommends this as a treatment of choice for preoperative chemotherapy of stage III A and III B BC. No significant financial relationships to disclose.
Bortezomib-associated transient and cyclical thrombocytopenia: evidence for lack of marrow cytotoxicity
Authors: S. Lonial, E. K. Waller, P. G. Richardson, S. Jagannath, R. Z. Orlowski, C. R. Giver, D. L. Jaye, B. Barlogie, L. T. Heffner, K. C. Anderson
Journal: Journal of Clinical Oncology (2005)

6610 Introduction: Bortezomib (VELCADE, btz) is a first-in-class proteasome inhibitor with efficacy in multiple myeloma (MM). Btz has been associated with transient, cyclical thrombocytopenia (TP). Preliminary data suggest the mechanism of TP with btz may differ from standard cytotoxic treatment (tx), & clinical data suggest no difficulty in collecting stem cells after btz. Methods: 228 patients (pts) with relapsed &/or refractory MM received IV bolus btz 1.3 mg/m2 on day (d) 1, 4, 8, & 11 of a 21-d cycle in the SUMMIT (N Engl J Med 2003;348:2609) & CREST (Br J Haematol 2004;127:165) trials. Plts were measured on tx d. In a murine study, normal male BALB/c mice received IV btz 2.5 mg/kg or vehicle. Results: Mean plt counts decreased with tx in each cycle & rapidly recovered to baseline by d1 of the subsequent cycle with a mean maximal 60% reduction. Among pts with complete or partial response, the lowest mean plt nadir occurred in cycle 1; among all pts, this nadir occurred later, in cycle 4. For the entire population, plt transfusion requirements decreased from 14–16% in cycles 1–2 to 8% in cycle 4 & 4% in cycle 6. An appropriate increase in serum thrombopoietin was noted with TP as assessed in a pt subset. Response to tx was independent of baseline plt count (table). Mice receiving single dose btz developed TP 2–4d post tx; plt count recovery was rapid (6–14d post tx). Megakaryocyte cellularity & morphology during & following tx showed no significant difference between btz & control. D14 marrow showed increased megakaryocyte numbers with higher ploidy suggesting rebound response to peripheral TP. Conclusions: Bortezomib is associated with transient, reversible TP. Based on murine studies, bortezomib does not affect megakaryocyte content or morphology thus sparing them irreversible cytotoxic injury. Since baseline plt count is not predictive of response to bortezomib & plt nadir occurs early in tx, supporting pts with TP using transfusions may maximize the benefit of tx. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Advisory Board, Celgene, Millennium Celgene, Millennium, Speakers Bureau Millennium
A pharmacogenetic model predicting low paclitaxel clearance based on the DMET platform.
Authors: Annemieke J.M. Nieuweboer, Anne-Joy M. de Graan, Laure Elens, Marcel Smid, John W. M. Martens, Alex Sparreboom, Lena E. Friberg, Samira Elbouazzaoui, Erik A.C. Wiemer, Bronno van der Holt, Jaap Verweij, Ron H.N. van Schaik, Ron H.J. Mathijssen
Journal: Journal of Clinical Oncology (2013)

2597 Background: Paclitaxel (PTX) is a commonly used cytotoxic agent. It is metabolized by P450 cytochrome iso-enzymes CYP3A4 and CYP2C8 and has high interindividual variability in pharmacokinetics (PK) and toxicity. Here, we present a genetic prediction model to identify patients with low PTX clearance (CL) using the new Drug-Metabolizing Enzyme and Transporter (DMET; Affymetrix) platform, capable of detecting 1,936 genetic variants (SNPs) in 225 genes. Methods: In a PK study, 270 Caucasian cancer patients were treated with PTX. PK parameters were determined using a limited sampling strategy. HPLC or LC-MS/MS were used to determine PTX plasma concentrations and non-linear mixed effects modelling (NONMEM) was used to estimate individual unbound CL from previously developed PK population models. Subsequently, the cohort of patients was randomly split into a training and validation set. In all patients, the presence of SNPs in metabolic enzymes and transporters was determined using the DMET platform. Selected SNPs were subsequently validated in the validation set. Results: Baseline characteristics were comparable in both sets. The mean CL of the total cohort was 488 ± 149 L/h and the threshold for low CL was set at 339 L/h (1 SD &lt; total mean CL). 14 SNPs were selected to be included in the prediction model and validated in the validation set. For none of these 14 SNPs, evidence for a biological plausible link to taxane metabolism exists. The developed prediction model had a sensitivity of 95% to identify low PTX CL, a positive predictive value of 22% and remained significantly associated with low CL after multivariate analysis correcting for age, gender and Hb levels at start of therapy (P=0.024). Conclusions: This is the first considerably-sized application of the DMET platform to explain PK variability of a widely used anti-cancer drug. Although this validated prediction model for PTX CL had a high sensitivity, its positive predictive value is too low to be of direct clinical use. Likely, genetic variability in DMET genes alone does not sufficiently explain PTX CL, as for example environmental factors may also influence PTX metabolism.
Effect of CD37 small modular immuno-pharmaceutical (SMIP) on direct apoptosis in chronic lymphocytic leukemia cells via transcriptional up-regulation of the BH3 family member BIM
Authors: J. C. Byrd, R. Lapalombella, A. Ramanunni, L. A. Andritsos, J. M. Flynn, P. Baum, P. Thompson, N. Muthusamy
Journal: Journal of Clinical Oncology (2009)

3035 Background: CD37 is a tetraspan transmembrane family protein selectively expressed on normal and transformed B-cells. A novel CD37 SMIP was previously demonstrated to mediate superior direct apoptosis and NK-cell mediated killing of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Methods: Given the superior in vitro apoptosis observed with CD37 SMIP treatment and early clinical activity observed in highly refractory CLL patients, we hypothesized that a unique mechanism of cell killing was utilized by CD37 SMIP . This was pursued in preclinical studies outlined below. Results: Unlike many other agents utilized to treat CLL, death mediated by CD37 SMIP does not depend upon caspase activation. Nonetheless, CD37 SMIP treatment of CLL cells promotes time-dependent induction of mitochondrial membrane depolarization, mitochondrial translocation of Bax, and up-regulation of Bim protein. CD37 SMIP Bim protein induction occurred concomitantly with an increase in BIM mRNA levels. Electrophoretic mobility shift assay using oligonucleotides of the BIM promoter demonstrated increased protein binding activity in nuclear extracts derived from CD37 SMIP treated cells and the physical interaction of FoxO3a transcription factor with the FoxO3a responsive element in the BIM promoter was demonstrated using a “protein pull down” assay and confirmed by chromatin immunoprecipitation assays. Furthermore, CD37 SMIP treatment significantly increased BIM promoter regulated luciferase reporter expression in B-CLL cells. Consistent with a primary role of Bim up-regulation in mitochondrial membrane destabilization and apoptosis, transfection of CLL cells with BIM siRNA resulted in inhibition of CD37 SMIP -induced mitochondrial membrane depolarization and apoptosis. Conclusions: These studies demonstrate CD37 SMIP mediated apoptosis in CLL cells occurs via FoxO3a-dependent transcriptional up-regulation of BIM protein. This distinct mechanism of apoptosis utilized by CD37 SMIP contrasts it with other agents used for CLL treatment. Additionally, it provides a mechanism for the promising clinical activity of TRU-016 (humanized CD37 SMIP ) observed to date in refractory CLL patients. [Table: see text]
Six drugs induction chemotherapy for patients with localised Ewing sarcoma (ES): A pilot study
Authors: E. Palmerini, F. Bertoni, M. Mercuri, E. Barbieri, A. Longhi, P. Picci, G. Bacci, S. Ferrari
Journal: Journal of Clinical Oncology (2006)

9537 Background: Vincristine (V), doxorubicin (A), cyclophosphamide (C), ifosfamide (I), actinomycin-D (Ac) and etoposide (E) are the standard drugs active against ES. Feasibility and efficacy of a six drugs induction treatment were investigated in a monoinstitutional study. Methods: Between March 1998 and May 1999, nonmetastatic ES aged ≤ 50 years were enrolled. Induction treatment: VAC (V 2 mg, A 80 mg/m 2 , C 1200 mg/m 2 , weeks 0 and 6), IVAc (I 9 g/m 2 , V 2 mg, Ac 2 mg, week 3), IE (I 9 g/m 2 , E 450 mg/m 2 , week 9). Local treatment, surgery whenever possible, was planned on week 12. Maintenance treatment: alternating courses of VAC-IVAc-IE (three times). In surgically treated patients, chemoinduced necrosis was evaluated and graded: grade III (complete necrosis), II (persistence of microfoci of viable tumor cells) and I (persistence of macrofoci of tumor cells). Results: 34 patients were enrolled; median age was 19 years (6–50); 22 were males and 12 females. Site: extremity 22 (65%), axial location 12 (35%). Despite a large use of G-CSF (94% of cycles), grade IV leukopenia was common (60% of cycles). Nevertheless, febrile neutropenia was observed in only 10.6% of cycles. Grade IV thrombocytopenia occurred in 12.5% of cycles. Platelet and red blood cell transfusions were required in 4% and 11% of cycles, respectively. No toxic deaths were recorded. Local treatment: surgery in 24 patients (70%), followed by post operative radiation (RT) in 6 of them; RT in 10 patients (30%). Chemoinduced necrosis was grade III in 29% of patients, grade II in 34% and grade I in 37%. With a median follow-up of 80 months (1–69) 5 years overall survival (OS) was 62%. 5 years Event free survival (EFS) was 56%. 5 years EFS according to site was: extremity 68%, axial location 33% (p &lt; 0.02); according to local treatment was: surgery 61% (with RT 67%), RT 30% (p = 0.027); according to chemoinduced necrosis: grade III 86%, II 50%, I 55% (p = 0.26). Conclusions: The treatment is feasible. Surgery was possible in 70% of patients with a high cure rate for patients with a grade III chemoinduced necrosis. No significant financial relationships to disclose.
Intra tumoral CD8-mediated type 1 anti-tumor responses and differentiated triple negative (TN) and HER-2 advanced breast cancer under neoadjuvant chemotherapy
Authors: H. C. Marana, L. Benevides, D. G. Tiezzi, J. M. Andrade, L. G. Brito, V. F. Schiavon, J. S. da Silva
Journal: Journal of Clinical Oncology (2009)

e22106 Background: To determine the predictive value of CD8 T cells tumor infiltrated lymphocytes (TIL) for treatment response in locally advanced breast cancer (LABC) primarily submitted to neoadjuvant chemotherapy. CD8 T cell-mediated immune responses fall into two distinct types based on effector cell-derived cytokine production. Type I CD8 T cells (Tc1) produce IFN-γ, whereas type 2 cells (Tc2) secrete IL-4, IL-5, IL-10, and GM-CSF. Methods: CD8 T cell, FoxP3 and stimulated anti-CD3 production of IFN-γ were quantitatively measured in the TIL sample from 22 consecutive patients with LABC using a FACS cell analyzing and enzyme immunoassay. Neoadjuvant treatment was given to all patients as Docetaxel 75 mg/m 2 and Epirubicin 60 mg/m 2 i.v. infusion, for one day, each 21/21 days. Results: Univariate analysis showed that CD8 T cell, FoxP3 and production of IFN-γ are more pronounced in Triple Negative (TN) tumor (39±4.1%, 44,15±11.2% and 17.66±9.18% respectivilly) than HER-2 tumor (30.2±3.4%; 31,7±2.62% and 9.69±6.07%) and this difference was not significantly changed by the neoadjuvant chemotherapy. Conclusions: The results suggest that mammary tumor growth and progression were dependent, in part, on effector cell-derived IFN-γ. Here we postulated that this condition was associated to response to neoadjuvante chemotherapy and was distinct expressed by different gene type of tumor breast. This suggested that CD8-mediated type 1 antitumor responses cannot only promote accumulation of distinct endogenous CD8 T cell subpopulations, but also facilitate and preferentially modulate their localization kinetics, persistence, states of activation/differentiation, and function within the primary tumor environment of tumor response/regression. The TN tumor was more chemo-sensitive and had high IFN-γ production. The action way could be done by CD44 high, FoxP3 and TGFβ 1 and the activatioin of Treg in TIL that help in the tumor progression. The chemotherapy breaks this and facilitated the tumor regression. These studies offer insight into potential mechanisms for enhancing T cell-based immunotherapy in breast cancer. [Table: see text]
Coping and survival in breast cancer patients evaluated in a 5-year follow-up
Authors: E. Andritsch, G. Dietmaier, G. Hofmann, V. Ladinek, S. Zloklikovits, E. Petru, H. Samonigg
Journal: Journal of Clinical Oncology (2006)

18624 Background: A notable amount of studies investigated possible relations between the kind of coping with the disease and the survival in cancer patients. There is some evidence that distress is a predictor of shortened survival and that active coping is related to better chances. Nevertheless many of those studies were limited by small sample sizes or a retrospective design and the published data are inconsistent. Methods: This investigation of 212 breast cancer patients (stage I and II) in an adjuvant, disease free situation started 5 years ago about 3 years after the initial diagnoses and was carried out at three different measuring times (5 and 4 years ago and at present). It was an attempt to explore whether the preferred coping styles implicate survival. Results: At present 3.8% (N = 8) of the patients have died because of their cancer and 10.8% (N = 23) are suffering from a relapse. Significant relations between recurrence and avoidance (F 1;178 = 3.973; p = 0.048) measured with the IES (Impact of Event Scale) five years ago and between recurrence and avoidance (F 1;164 = 6.788; p = 0.010) and aggression (F 1;164 = 3.277; p = 0.038) measured with the BSI (Brief Symptom Inventory) four years ago were found with MANOVAs. Patients, who stated a higher level of avoidance and aggression, were at higher risk to become a relapse or metastases. Patients having a progressive course of disease tended to be younger (57.2 years) than patients being free of disease (61.3 years, F 1;179 = 3.294; p = 0.070). Regarding the 8 year survival those patients, who had died, stated a higher level of anxious preoccupation measured with the MAC (Mental Adjustment to Cancer Scale) 5 years ago (M-W-U = 397.5; p = 0.48). Conclusions: The results of this study provide an essential aspect for psychological support and of the necessity to include psychooncological elements in physician-patient-communication. No significant financial relationships to disclose.
A sensitive exosome-based biosignature for the diagnosis of prostate cancer.
Authors: C. Kuslich, T. L. Pawlowski, T. Deng, T. Tinder, J. Kim, J. Kimbrough, D. Spetzler
Journal: Journal of Clinical Oncology (2010)

4636 Background: The screening and diagnosis of prostate cancer (PCa) would be significantly improved by identifying biomarkers that are not only highly specific and sensitive but also surveyed easily from the blood or urine. Exosomes are endosome-derived vesicles between 40-100 nm in diameter that are secreted by many cell types including prostate epithelial cells in both normal and neoplastic states. The quantity and molecular composition of exosomes shed from cancer cells differs considerably from those shed by normal cells. This study explored whether plasma- derived exosomes can be utilized as a robust blood-based biosignature for PCa and other disease states. Methods: A novel multiplexed platform for quantifying and profiling exosomes from plasma was used to develop an exosome-derived biosignature comprised of seven surface membrane protein biomarkers. Antibodies used to capture and detect these targeted biomarkers are specific to membrane proteins for: exosomes generally (CD9, CD81, and CD63), exosomes from prostate epithelial cells (PSMA and PCSA), and tumor-associated exosomes (EpCam and B7H3). A training set comprised of 29 PCa patients and 31 age-range matched men from the general population was used to generate an exosome-specific PCa biosignature. The training set results were subsequently confirmed with a blinded pilot validation comprised of 30 PCa and 30 age-range matched men. Results: The blood-based exosome PCa assay correctly identified PCa patients in the training set with a sensitivity of 83% and specificity of 90%, AUC = 0.881. Furthermore, the assay distinguished between PCa and BPH samples (n=15), with a sensitivity and specificity of 83% and 85%, respectively, with an AUC = 0.844. The blinded validation cohort confirmed the sensitivity and specificity of the assay. Conclusions: This preliminary study demonstrates the ability of an exosome-associated biosignature to distinguish PCa from both unaffected and BPH samples. Exosome profiling could provide a powerful tool to monitor PCa progression and therapeutic response from a blood sample. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Caris MPI