tbuckley/cabot-search huggingface dataset:
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Authors: Kyle S. McCommis, Jerry R. Colca, Brian N. Finck
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Colca is employed by, owns stock in, and holds intellectual property rights with MSDC. He consults for and owns stock in Octeta. Author names in bold designate shared co‐first authorship. We appreciate the interest of Drs. Musso and Gambino in our demonstration that MSDC‐0602 limited fibrosis in a mouse model of nonalcoholic steatohepatitis (NASH).1 MSDC‐0602 is a "next‐generation" thiazolidinedione (TZD) compound that has limited affinity for binding and direct activation of the peroxisome proliferator‐activated receptor γ (PPARγ). The mitochondrial pyruvate carrier (MPC) complex is an alternative target of all active TZD compounds, including rosiglitazone and pioglitazone.2 We also find it interesting that pioglitazone exhibits beneficial effects on NASH fibrogenesis in clinical trials, whereas the most potent PPARγ agonist of the clinically used TZDs, rosiglitazone, may have beneficial effects on some NASH endpoints, but does not affect fibrosis.3 One interpretation of this is that the limited dosing of rosiglitazone, attributed to potential PPARγ‐driven side effects, is insufficient to engage MPC and thus elicit the desired effects on fibrosis. Whereas the effects of MSDC‐0602 on fibrosis have only been examined in experimental models, an ongoing phase II clinical trial has been initiated (EMMINENCE; NCT02784444). Drs. Musso and Gambino bring up interesting points regarding the observation of PPARγ‐sparing TZDs eliciting less secretion of the antifibrotic adipokine, adiponectin, in a clinical trial.4 It should be noted that this next‐generation TZD still reduced fasting blood glucose and insulin sensitized. In addition, our studies found that genetic deletion of MPC2 in hepatocytes specifically or treatment of isolated stellate cells with MSDC‐0602 reduced stellate cell activation and collagen expression.1 This suggests that there are adiponectin‐independent effects of modulating MPC activity. Last, we agree that there are a number of significant metabolic adaptions with genetic inhibition of the MPC in liver. Specifically, amino acid catabolism is enhanced to maintain TCA cycle carbon flow.5 However, one must use caution when comparing these MPC knockout data to pharmacological MPC inhibition. To our knowledge, TZDs have not been reported to result in alterations in blood lactate or amino acid concentrations. Metabolomic studies need to be performed to identify whether similar metabolic compensations occur with prolonged MPC inhibition by TZDs.
Y<sup>90</sup>-ibritumomab tiuxetan (Y<sup>90</sup>-IT) and high-dose melphalan as conditioning regimen before autologous stem cell transplantation (ASCT) for elderly patients with lymphoma in relapse or resistant to chemotherapy: A feasibility trial (SAKK 37/05).
Authors: Michele Voegeli, Stephanie Rondeau, Simona Berardi, Erika Lerch, Luciano Wannesson, Thomas Pabst, Jochen Rentschler, Mario Bargetzi, Lorenz M. Jost, Nicolas Ketterer, Angelika Bischof Delaloye, Michele E. G. Ghielmini
Journal: Journal of Clinical Oncology (2013)

8560 Background: Standard conditioning regimens for ASCT are often not tolerated by elderly patients. Single agent high-dose melphalan has been shown to be safe and active in elderly patients with multiple myeloma. Y 90 -IT is a well-tolerated lymphoma treatment and feasible in the transplantation setting. We therefore investigated this combination of high-dose melphalan and Y 90 -IT as a conditioning regimen for elderly patients. Methods: Patients ≥65 years with relapsed or chemotherapy resistant CD20-positive lymphoma in PR or CR after salvage chemotherapy could be enrolled prior to stem cell mobilization. Myeloablation regimen consisted of standard dose Y 90 -IT followed by melphalan at escalating doses (100, 140, 170 and 200mg/m 2 , with a 3+3 phase I design) and by ASCT. The primary objective was to identify the MTD of melphalan in combination with standard dose Y 90 -IT (as defined &lt; 1 DLT in 3 patients); secondary endpoints were toxicity and CR rate 100 days after transplantation. Results: Between 2006-2012 twenty patients were included. Median age was 72 years (range 66-77). One patient was considered retrospectively ineligible and was evaluable for toxicity but not for DLT. Thirteen patients received the treatment and were transplanted. Eleven patients were evaluable for DLT. No DLT occurred. Non-hematological grade 3 or higher treatment related adverse events were: infection (n=6, including 2 cases of febrile neutropenia), diarrhea (n=3), mucositis, anorexia, viral hepatitis, hypokalemia, dehydration and multi-organ failure (n=1). Seven patients did not start treatment because of mobilization failure (n=3), progressive disease (n=2), worsening of cardiac failure (n=1) and grade 3 dyspnea (n=1). Seven patients achieved a CR/CRu and 2 patients were stable 100 days after transplantation. Conclusions: The combination ofstandard dose Y 90 -IT and high dose melphalan (200mg/m 2 ) is a safe and feasible conditioning regimen before ASCT for patients ≥65 years. The results show promising activity. Clinical trial information: NCT00392691.
The impact of TP53 mutation on high-risk rectal cancer patients treated within the EXPERT-C trial, a randomized phase II study of neoadjuvant oxaliplatin/capecitabine (CAPOX) and chemoradiation (CRT) with or without cetuximab.
Authors: Alice Dewdney, Ian Chau, Jaume Capdevila, Bengt Glimelius, Andres Cervantes-Ruiperez, Diana M. Tait, Gina Brown, Andrew Wotherspoon, David Gonzalez de Castro, Sanna Hulkki Wilson, Yu Jo Chua, Rachel Wong, Yolanda Barbachano, Jacqueline Rose Oates, David Cunningham
Journal: Journal of Clinical Oncology (2012)

e14088 Background: The EXPERT-C trial randomised 165 patients into neoadjuvant CAPOX and CRT ± cetuximab and demonstrated a significant increase in radiological response (RR) and overall survival (OS) with cetuximab in KRAS/BRAF wild type (WT) rectal cancer (Dewdney et al JCO in press). TP53 mutation has been associated with worse CRT response and survival in rectal cancer and could lead to stimulation of PI3K signalling pathway, thus potential resistance to cetuximab. This analysis evaluates the impact of TP53 mutation in the EXPERT-C trial. Methods: FFPE tissue from biopsy (n=102) and resection specimens (n=99) were analysed for TP53 mutations (exons 5-8) using a multiplex PCR method followed by direct sequencing. If discordant results were encountered on paired biopsy and resection samples, analyses were repeated. Results: 53/102 (52%) biopsy and 24/99 (24%) resection samples harboured TP53 mutation, most commonly missense in exons 5 and 7. The vast majority had single TP53 mutations, only 4/53 biopsy and 1/24 resection samples had 2 mutations. 21/55 (38%) paired samples demonstrated discordant TP53 mutation status. In both all-treated and KRAS WT populations, presence of TP53 mutation had no impact on RR to neoadjuvant chemotherapy or CRT, regardless of treatment arm. A trend towards worse progression-free (PFS) (HR: 2.68; 95% CI: 0.85 - 8.43; p=0.08) and OS (HR: 4.04; 95% CI: 0.86 - 19.11; p=0.056) was observed in patients with TP53 mutation when treated with cetuximab, independent of the KRAS status. Conclusions: TP53 mutations were common in high-risk rectal cancer patients, the lower mutation rate in the resection samples was potentially due to lower tumour volume post CRT. The presence of a TP53 mutation at baseline had no impact on RR to treatment, however a trend towards worse PFS and OS was observed with the addition of cetuximab, consistent with the perceived biology.
A phase 1b study of ruxolitinib (Rux) + gemcitabine (G) ± nab-paclitaxel (N) in patients (pts) with advanced solid tumors.
Authors: Todd Michael Bauer, Manish R. Patel, Tina Evans Wood, Thomas J. George, Fitzroy W. Dawkins, Kimberli J. Brill, Yining Du, Herbert Hurwitz
Journal: Journal of Clinical Oncology (2017)

439 Background: Aberrant activation of the JAK-STAT pathway has been associated with increased malignant cell proliferation and survival. Rux, a potent JAK1/2 inhibitor, was evaluated in combination with G±N in advanced solid tumors. Methods: This was an open-label study of Rux + G, without N (regimen A) or with N (regimen B) in advanced solid tumors. The objective of the dose-finding phase (reported here) was to identify MTDs of Rux + G and Rux + G/N. See Table for evaluated cohorts. Results: Among 42 pts enrolled, median age was 62.5 years, 81% had pancreatic cancer (PC), 50% had 1 prior regimen and 12% had 2 prior regimens. Discontinuations were mainly due to radiological or clinical disease progression (86% of pts). Median treatment durations: 55.5 d (A) and 97.5 d (B). 4 pts in B had DLTs: Grade (Gr) 3 pneumonia (n = 1, SAE), Gr 3 neutropenia (n = 1) and Gr 4 thrombocytopenia (n = 2). Table summarizes AEs. The most common Gr 3/4 hem AEs (lab) were anemia (88% A, 85% B) and thrombocytopenia (81% A, 89% B). SAEs occurring in ≥ 2 pts were abdominal pain (n = 4, A), sepsis (n = 2, A), dehydration, anemia and asthenia (n = 2 each, B). Rux + G was tolerated with standard doses of G. Rux + G/N was tolerated with reduced doses of G/N or concomitant GCSF. These combinations were not pursued further, therefore MTDs were not defined. ORRs were 2/16 (13%) in A and 10/26 (39%) in B. ORRs in PC pts: 8/34 (24%); 2/14 (14%) in A and 6/20 (30%) in B. Conclusions: Rux + G or Rux + G/N at the doses investigated were generally safe and well tolerated in pts with advanced PC and other solid tumors. ORRs were noted in multiple tumor types including PC. Clinical trial information: NCT01822756. [Table: see text]
What do adjuvant and metastatic cancer patients expect from their treatment, palliative care, and physicians? Results of a German survey on 607 patients.
Authors: Radoslav Chekerov, Thorsten Bock, Ernst Ulrich Mueller, Andreas Huebner, Andreas Lueck, Dietrich Kaempfe, Thorsten Edelmann, Rolf Richter, Jalid Sehouli
Journal: Journal of Clinical Oncology (2014)

e20658 Background: This study analyzes quality of life aspects, expectations and needs of cancer patients with special focus on doctor-patient communication. Methods: A questionnaire of 17 questions was developed, validated and administered to cancer patients in a print-version. Results: A total of 607 patients with a medium age of 67 years were interviewed, whereas 51.2% women and 46.8% men. The most common cancer types were: colon (21.3%), breast (17.1%), lung (8.4%), haematological (8.4%), prostata (5.1%), pancreas (4.6%), stomach (3.5%), ovary (2.8%) or other origins (28.8%). 21.9% of the patients were treated with the intention of cure, 78.1% had a metastatic disease. The investigation was done during patients received commonly chemotherapy, targeted or supportive treatment, and after surgery, radiation or cytostatic pretreatment. Therapy associated toxicity reflected mostly in fatigue (50.9%), alopecia (41%), vomiting/emesis (37.4%), anemia (32.2%), polyneuropathy (20.9%), pain (22.2%), dyspnea (17.8%) or skin disorders (12.1%). Support received by their family was of great importance for patients under treatment (74.5%), analog as the role of their treating physician (66.4%). The most effective and
A comparative proteomic approach for identification of putative biomarkers of neoadjuvant chemotherapy resistance in breast cancer.
Authors: Tasadooq Hussain, Lucy Scaife, Victoria Hodgkinson, Vijay Agarwal, Tapan Mahapatra, Peter John Kneeshaw, Penelope Louis McManus, Michael Lind, Philip Drew, Lynn Cawkwell
Journal: Journal of Clinical Oncology (2013)

e22123 Background: Neoadjuvant chemotherapy is a standard treatment for locally advanced breast cancer however chemoresistance can be a major obstacle in ER+ cancers. Using comparative proteomic approaches (antibody microarray/AbMA and 2D-PAGE with MALDI-TOF/TOF MS) to investigate a pilot series of breast cancer samples we recently identified 14-3-3 theta/tau, tBID and BcL-XL as putative biomarkers of response to neoadjuvant chemotherapy (Hodgkinson et al. J Prot 2012, 75:1276-1283 and 75:2745-2752). Here we aimed to analyse further samples using the AbMA approach and to re-analyse the combined data. Methods: Samples from chemoresistant and chemosensitive breast cancers were selected following anthracycline-taxane chemotherapy and 4 experiments were performed using ductal ER+ tumours. Differential protein expression was compared between chemoresistant and chemosensitive samples using the Panorama XPRESS Profiler725 AbMA kit. The combined data from 9 AbMA assays and 3 2D-PAGE/MS experiments was then analysed using Ingenuity Pathway Analysis (IPA; Ingenuity Systems). Results: 89 differentially expressed proteins (DEPs) were seen in the 4 further AbMA experiments. Sixteen proteins (DR4, E2F6, ILK, MeCP2, MyD88, PI19INK4d, PRMT2, ID, FANCD2, FAKpTyr577, Pinin, Zyxin, 14-3-3 theta/tau, BcL-xL, Pancytokeratin and RIP) were found in at least 2/4 experiments. In the combined dataset (12 experiments from 2 proteomic platforms), 8 DEPs were seen in at least 3 experiments. These were 14-3-3 theta, 14-3-3 epsilon, 14-3-3 gamma, Bcl-xl, Bid, Phosphokinase B, Vimentin and FAK. 121 DEPs from the combined data were analysed using IPA; 12 DEPs were mapped onto the PI3K/AKT pathway. Conclusions: We have identified at least 8 proteins which could play a role in chemoresistance and clinical validation of these putative biomarkers is currently underway.
Prevention of thrombocytopenia using thrombopoietin in high-dose cytarabine treatment of non-Hodgkin lymphoma.
Authors: He Huang, Zhao Wang, Huangming Hong, Chengcheng Guo, Xueying Li, Mengping Zhang, Xiaoting Lin, Xiaojie Fang, Xiaohong Fu, Ying Tian, Shanshan Li, Tingzhi Liu, Chaoyong Liang, Jia Tian Lin, Dr.Prem Raj Shrestha, Jian Xiao, Hongyu Zhang, Yabing Cao, Linzhu Zhai, Tongyu Lin
Journal: Journal of Clinical Oncology (2014)

e19532 Background: High-dose cytarabine treatment of non-Hodgkin lymphoma most likely cause severe thrombocytopenia which may be fatal. Thrombopoietin (TPO) specifically stimulates megakaryopoiesis and platelet production. This study tries to find out the optimal mode of using TPO to reduce the toxicity of thrombocytopenia. Methods: Patients more than 18 years old with NHL who need high dose cytarabine (4g/m2/cycle) treatment were enrolled. They were administered 10 doses of TPO (15,000U/dose) daily by two modes randomly: TPO injection at Day 2-11 (standard preventive cycle, SP cycle) or injection at Day -4/-2/2-9 (ahead preventive cycle, AP cycle), and then switched in subsequent cycles as a self-controlled design. The platelet counts and the need of platelet transfusion were assessed to analyze their hematopoietic response. Results: A total of 30 patients with aggressive NHL were enrolled (40±16 years, 63% male) from March 2012 to September 2013. The incidence of thrombocytopenia of different degrees in AP cycles and SP cycles were: PLT≤100×109/L: 83.3% (25/30) versus 86.7% (26/30) (P=0.500); PLT≤50×109/L: 50% (15/30) versus 63.3% (19/30) (P=0.217); PLT≤25×109/L: 13.3% (4/30) versus 36.7% (11/30) (P=0.036), respectively. The lasting period of severe thrombocytopenia (PLT≤25×109/L) was shorter in AP cycles (1.2 days versus 3.5days, P=0.029), and recovery to baseline platelet count was achieved earlier (7.1 days versus 9.2 days, P=0.024). The median nadir platelet count was 40.8±15.5×109/L versus 25.1±10.8×109/L (P= 0.013). The need of platelet transfusions in AP cycles was significantly lower compared with in SP cycles. TPO was well tolerated: only one patient developed temporal throbocythemia, and no serious adverse events occurred in all patients. Conclusions: Giving thrombopoietin ahead of high dose cytarabine chemotherapy effectively prevents severe thrombocytopenia and reduces platelet transfusion which indicates a superior prevention mode.
Phase I/II study of rilotumumab (R) and erlotinib (E) in previously treated patients (pts) with metastatic NSCLC.
Authors: Ahmad A. Tarhini, Imran Rafique, Phu Tran, William E. Gooding, Liza Cosca Villaruz, Timothy Francis Burns, David Friedland, Grace R. Tarabay, Andrew D. Laman, Dhaval R. Mehta, Matthew Gerard Sulecki, Daniel P. Petro, Mark S. Georgiadis, Kevin M. Kane, Sajid M. Peracha, Kiran K. Rajasenan, Alexis Megaludis, Lijun Dai, Mark A. Socinski
Journal: Journal of Clinical Oncology (2015)

8092 Background: MET is frequently overexpressed in NSCLC. Amplification of MET and its ligand (HGF), are mechanisms of resistance to EGFR inhibitors. R is an IgG2 human mAb that targets HGF. This phase I/II trial evaluated the safety and recommended phase 2 dose (RP2D) of R combined with E for pts with metastatic previously treated NSCLC (Phase I) and whether efficacy is high enough to warrant further interest (Phase II). Methods: Phase I adopted a dose de-escalation design with R starting at 15 mg/kg IV every 3 weeks and E 150 mg orally daily (dose level 0). If dose de-escalation was needed it would proceed according to Narayana k-in-a-row design where a selected dose was estimated by isotonic regression. RP2D was the maximum below the dose associated with a 25% DLT rate. Phase II intended to test whether disease control rate (stable disease or response, DCR) of 50% for E could be improved by adding R. A Simon 2 stage design was used to select the optimal sample size for type I and II error of .10. Twenty-seven of 45 pts were required to have disease control for evidence of a statistically significant improvement over E alone. Response was assessed by RECIST every 6 weeks. Results: In the absence of need for de-escalation among the first 8 pts, the RP2D was defined as dose level 0. Overall, 45 response-evaluable pts with stage IV were enrolled (13 squamous and 32 adenocarcinoma; 2 EGFR and 7 KRAS mutant). Median age was 65 years. A median of 4 cycles (range 1-18+) were administered. Four pts had partial response (one with EGFR and one KRAS mutation), 23 had SD, and 18 had progression, for a response rate of 8.9% (90% CI, 3.9 - 18.1) and DCR of 60% (90% CI, 47.1 - 71.3). Median PFS 2.6 months (90% CI 1.4- 2.7). At a median follow up of 15 months, median OS was 6.6 months (90% CI, 5.6 - 8.9). Probability of surviving one year was .33 (90% CI, .23 - .47). Among grade 3/4 AEs that were considered at least possibly related were rash (3), oral mucositis (1), elevated alkaline phosphatase (3) and bilirubin (1), thromboembolic event (3), diarrhea (5). Conclusions: The combination of R and E in this study was found to have an acceptable safety profile and the DCR rate met the study’s pre-specified criteria for success. Further investigation of this regimen is warranted. Clinical trial information: NCT01233687.
Use of a SNP panel to refine risk estimates in women at high risk of breast cancer: Results from two randomized tamoxifen prevention trials.
Authors: Jack M. Cuzick, Adam Brentnall, Corrinne Segal, Ivana Sestak, Roseann Kealy, Anthony Howell, Trevor J. Powles, Nicholas Orr, William G. Newman, Mitchell Dowsett
Journal: Journal of Clinical Oncology (2014)

1519 Background: An assessment of how panels of single-nucleotide polymorphism (SNP) breast cancer risk factors might improve risk assessment among high-risk women is needed for better targeting of preventive therapy and other risk reduction measures. Methods: A case-control study was designed using leukocytic or tissue DNA from two tamoxifen prevention trials (IBIS-I and Marsden). SNPs were assayed on the Sequenom platform and a relative risk score for 15 SNPs (SNP15) was formed using the most recent iCOGS SNP risk estimates. Baseline questionnaires were used to estimate 10-year relative risks from the Tyrer-Cuzick model (TC). Conditional logistic regression was used to assess performance. An updated panel using all validated risk SNPs (approx. 70) is also being evaluated and will be presented at the meeting. Results: 440 cases and 686 controls had median age at baseline of 49 (inter-quartile range 45 - 54). Hardy-Weinberg equilibrium was verified. SNP15 and TC appeared uncorrelated (Spearman 0.037, P=0.209). The odds ratio (OR) between 25th, 75th percentiles of SNP15 was 1.24 (95% CI 1.05 - 1.46) with AUC 0.568; TC had OR 1.41 (1.21 - 1.64), AUC 0.578; combined OR 1.54 (1.30 - 1.83), AUC 0.600. The observed risk was 48% (11 – 84) of predicted for SNP15 and 77% (42 – 110) for TC. SNP15 was more predictive for estrogen receptor (ER) positive tumours (318 cases, OR 1.36 (1.12 – 1.64), AUC 0.587, 67% (25-109) of predicted) but not for estrogen-receptor (ER) negative cancer (122 cases, P = 0.76); TC was significantly associated with both ER types. Little difference in performance was seen between tamoxifen and placebo treatment arms. The proportion of untreated women with 10-yr predicted risk above 8% was <1% for SNP15, 18% for TC and 25% for the combined risk score. Conclusions: A SNP panel is useful for refining risk estimates in women with phenotypic risk factors for breast cancer, and adds important information to classic phenotypic factors but does not appear to vary according to potential to benefit from tamoxifen. Clinical trial information: ISRCTN91879928 (ref: CCT-NAPN-14839).
First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors.
Authors: Johann Sebastian De Bono, Lida A. Mina, Michael Gonzalez, Nicola J. Curtin, Evelyn Wang, Joshua W. Henshaw, Manpreet Chadha, Jasgit C. Sachdev, Daniela Matei, Gayle S. Jameson, Michael Ong, Bristi Basu, Zev A. Wainberg, Lauren Averett Byers, Rashmi Chugh, Andrew Dorr, Stanley B. Kaye, Ramesh K. Ramanathan
Journal: Journal of Clinical Oncology (2013)

2580 Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC 50 &lt;1nM). In tumors genetically dependent on DNA repair by homologous recombination PARP inhibition induces synthetic lethality. Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage dose-escalation study with 3-6 patients (pts)/dose level. In dose escalation (Stage 1) cycle 1 was 6 wks, with drug taken on days 1 and 8-35, for PK and PD assays, followed by daily continuous dosing in 4-wk cycles. Stage 2 (expansion at MTD) recruits pts with tumors defective in DNA repair: Ewing sarcoma, small cell lung cancer or tumors associated with BRCA mutation (mut). Results: 39 pts (33F/6M) were enrolled in 9 cohorts from 25 to 1100 µg/d that defined a MTD of 1000 µg/d. Median (range) age was 58 (19-81), PS 0 (0-1) and # of prior therapies 4 (1-13). Tumors (# with deleterious BRCA 1/2 mut) included 23 ovarian/primary peritoneal (17); 8 breast (6); 3 pancreas; 2 colon; 1 prostate (1), and 1 mullerian carcinosarcoma. 17 and 8 pts had BRCA 1 and 2 mut, respectively. Dose-limiting thrombocytopenia occurred in 1/6 and 2/5 pts at 900 and 1100 µg/d, respectively. Potentially-related adverse events in &gt;10% of pts (# grade 1 and 2/grade 3 and 4) included fatigue (10/0); nausea (10/0); flatulence (4/0); anemia (5/2); neutropenia (4/3); thrombocytopenia (1/3); and grade 1 alopecia (10). Inhibition of PARP activity in PBMCs was observed at doses ≥ 100 µg/d. BMN 673 plasma concentrations peaked 1-2 hrs post-dose; exposure increased dose proportionally. Steady state plasma concentrations were reached by the end of the 2 nd week of daily dosing; mean C max : 0.30 - 25.4 ng/mL and AUC 0-24 : 3.96 - 203 ng-hr/mL across the 25 to 1100 µg/d dose range after 28d of daily dosing. RECIST and/or CA-125 responses occurred at doses ≥ 100 µg/d in 11/17 BRCA carrier ovarian/peritoneal cancer pts. Objective responses occurred in 2/6 BRCA-carrier breast cancer pts. Conclusions: BMN 673 is well tolerated with impressive anti-tumor activity in pts with BRCA mut with a single agent recommended Phase II trial dose of 1000 µg/d due to dose-limiting thrombocytopenia. Clinical trial information: NCT01286987.