tbuckley/cabot-search huggingface dataset:
A phase 1 dose-escalation study of XL518, a potent MEK inhibitor administered orally daily to subjects with solid tumors
Authors: L. S. Rosen, P. Galatin, J. M. Fehling, I. Laux, M. Dinolfo, J. Frye, D. Laird, B. I. Sikic
Journal: Journal of Clinical Oncology (2008)

14585 Background: XL518 is a potent, selective, orally bioavailable inhibitor of MEK1, a component of the RAS/RAF/MEK/ERK pathway. XL518 inhibits proliferation and stimulates apoptosis in a variety of human tumor cell lines. In preclinical xenograft models, oral administration of XL518 results in sustained inhibition of pERK in tumor tissue, but not brain tissue, leading to tumor growth inhibition and regression at well tolerated doses. The purpose of this study is to define the maximum tolerated dose (MTD) and evaluate the pharmacokinetics (PK) and pharmacodynamic effects of XL518 Methods: Patients (pts) enrolled in successive cohorts receive XL518 PO QD on days 1 - 21 of each 28 day cycle. Tumor response is assessed Q 8 weeks. PK and pharmacodynamic blood samples are collected from all pts. Tumor biopsies and surrogate tissues are collected on an optional basis for pharmacodynamic analysis. Direct and indirect pharmacodynamic markers, e.g., phosphorylated ERK (pERK) and Ki67 are analyzed. Results: Thirteen pts (median age [range] = 63 yrs [38–78 yrs]) with advanced malignancies (3 CRC, 2 pancreatic, 2 NSCLC, 1 each with neuroendocrine, sarcoma, esophageal, adenoid cystic, ovarian, cervical) have been treated at 4 dose levels (0.05, 0.10, 0.20 mg/kg using suspension and 10 mg fixed using capsules). No DLTs or XL518- related serious adverse events have been reported. One pt with previously progressing NSCLC has had stable disease for 7 months and continues on therapy. PK analysis indicates rapid absorption (median tmax = 2 hrs) and ∼3.3-fold accumulation. The median steady state oral clearance was 29 L/hr. XL518 inhibited phosphorylation of ERK in 2 pre- and post-dose tumor biopsies by 29 and 52%, and similarly in hair bulbs from other pts by 26 and 42% including the aforementioned pt with NSCLC. In contrast, XL518 did not cause consistent inhibition of MEK in peripheral blood cells. Conclusions: XL518 has been very well tolerated and dose escalation continues. MEK signaling in tumor and hair samples was inhibited by XL518 suggesting that pERK may have utility as a clinical biomarker. The effects of XL518 on MEK signaling and downstream readouts are currently being evaluated in tissues from additional pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Exelixis Exelixis Exelixis Exelixis
Next-generation sequencing: Profiling gallbladder cancer (GBC).
Authors: Joanne Wing-Yan Chiu, Stefano Serra, Suzanne Kamel-Reid, Tong Zhang, Mairead Geraldine McNamara, Philippe L. Bedard, David W. Hedley, Malcolm J. Moore, Neesha C. Dhani, Tony Shek, Yok-Lam Kwong, Thomas Cheung Yau, Mark Doherty, Jennifer J. Knox
Journal: Journal of Clinical Oncology (2015)

286 Background: Molecular profiling data of GBC is scant and it is often included with other biliary cancers for analysis, which may hinder advancing drug discovery. Methods: Archival formalin fixed paraffin embedded (FFPE) tissue of GBC from 2 research hospitals in Toronto (n=21) and Hong Kong (n=21) were analyzed by MassARRAY Sequenom panel (23 genes, 279 mutations), or by next general sequencing (NGS) using Proton or Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons, ≥500x coverage). Results of other biliary cancer and ampullary cancer from an ongoing profiling project were also reported. Results: Twelve biliary cancer samples first analyzed with Sequenom revealed no mutations. Reanalysis with NGS of these yielded mutations in 5. All subsequent samples were analyzed with NGS (n=57). Mutations were identified in 80% [53 mutations in 42 GBC, 8 mutations in 9 intrahepatic cholangiocarcinoma (IHC), 7 mutations in 6 hilar/distal bile duct cancers (DBD)]. The most frequent mutations in GBC were TP53 and SMAD4, and KRAS mutation was found in 7% (Table). PIK3CA mutation was found in 5% of GBC but not the other biliary cancers, and IDH1 mutation was exclusive for IHC, in agreement with published literature. TP53 mutations in GBC patients did not correlate with gender, tumor grade, survival, or treatment response to gemcitabine-based chemotherapy. There was no difference in mutation patterns in GBC between 2 institutions/countries. Conclusions: NGS can be utilized for molecular profiling of biliary cancer, detecting potentially actionable targets in the majority of cases. Our preliminary data suggests GBC may have its own molecular profile, deserving special consideration in trial design for biliary cancer. To our knowledge the current study is the biggest cohort of NGS analysis for GBC. [Table: see text]
Efficacy and correlation with predictive markers of gefitinib in pretreated Chinese patients with advanced NSCLC
Authors: X. T. Zhang, L. Y. Li, X.-Y. Chang, X.-L. Mu, S.-L. Wang, M.-Z. Wang, W. Zhong, L. Zhang
Journal: Journal of Clinical Oncology (2005)

7240 Background: Gefitinib has shown meaningful antitumor activity with tolerable toxicity for refractory non-small-cell lung cancer (NSCLC) in western and Japanese. The aim of the study was to evaluate the efficacy and to identify markers of response to Gefitinib in Chinese patients with pretreated advanced NSCLC. Methods: Patients with NSCLC who failed at least one platinum-based regimen received Gefitinib 250mg once daily until disease progression or unacceptable toxicity. Tissues at the time of diagnosis were collected for detection of p-EGFR expression by immunohistochemistry and gene mutation of EGFR. Results: 98 patients enrolled in the study from October 2002 to February 2004. The response rate (RR) was 31.6%. Disease control rate (DCR) was 67.3%. Objective response was correlated with adenocarcinoma and female. Median progress free survival(PFS)was 6.1 months and overall survival(OS) was 8.5 months. The PFS improvement was associated with adenocarcinoma and objective response. The OS improvement was associated with adenocarcinoma and non-smokers. Immunohistochemistry was performed in 38 patients and EGFR mutation was performed in 24 patients. The positive expression rate of p-EGFR was much higher in responders (8/10) than in non-responders (5/28). 9 out of 13 patients with positive p-EGFR expression were female. The sensitivity and specificity of mutation rate of 19 or 21 exons were 78%(7/9) and 80% (12/15) respectively. 7 out of 9 patients who have EGFR gene mutation were female. All positive p-EGFR expression and activating mutation of EGFR were detected in adenocarcinoma. Conclusion: Gefitinib demonstrated significant antitumor activity for pretreated Chinese patients with advanced NSCLC. The positive expression of p-EGFR and activating mutation of EGFR were highly associated with response. They might be used as predictive markers for response of Gefitinib. No significant financial relationships to disclose.
Interferon beta in multiple sclerosis
Authors: A. Burnfield, C Price, J. C Napier, J. Holmes, G. Winyard, P. Cardy, J. Peltola, T. Keranen
Journal: BMJ (1997)

# Reducing frequency and severity of relapses will be of great clinical benefit {#article-title-2} Editor-Richard G Richards's editorial on interferon beta in multiple sclerosis deals with the “clinical cost effectiveness” of the drug in the disease, but it lacks a fair balance, emphasising the cost effectiveness and minimising the clinical effectiveness of the drug.1 Richards states that “the studies showed no evidence of any reduction in the more clinically relevant endpoint-the progression of disability, which should be the goal of treatment.” This is his personal judgment and does not reflect the needs and wishes of patients with multiple sclerosis and their families. Multiple sclerosis is a distressing, humiliating, and often long drawn out disease with no cure. For this reason, quality of life, for the patients and their families, is paramount. A drug that can reduce the frequency and severity of relapses, whether or not it diminishes the progression of the disease, will be of great clinical benefit to many patients, improving their situation physically, psychologically, and socially. Surely happiness, feeling better, and increased health have great value. This is what many of us believe that the practice of our profession is about. 1. 1.↵1. Richards RG .Interferon beta in multiple sclerosis.BMJ1996; 313:1159. (9 November.) [OpenUrl][1][FREE Full Text][2] # Current policy is sensible {#article-title-4} Editor-The NHS Executive's position on interferon beta allows individual hospital doctors, working within certain parameters, to decide with a patient with multiple sclerosis whether to start treatment with the drug. This sensible standpoint comes in for varying degrees of criticism in three recent articles, mainly on the grounds of health economics.1,2,3 The authors are all proponents of evidence based policymaking but are happy to assert that an effect on disability is the most important outcome measure in this disease without producing any evidence to support their view. Many people with multiple sclerosis would consider a reduction in the number of relapses to be valuable. We do not withhold treatments that give important symptomatic relief in … [1]: {openurl}?query=rft.jtitle%253DBMJ%26rft.stitle%253DBMJ%26rft.issn%253D0007-1447%26rft.aulast%253DRichards%26rft.auinit1%253DR.%2BG%26rft.volume%253D313%26rft.issue%253D7066%26rft.spage%253D1159%26rft.epage%253D1159%26rft.atitle%253DInterferon%2Bbeta%2Bin%2Bmultiple%2Bsclerosis%26rft_id%253Dinfo%253Apmid%252F8916730%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=FULL&journalCode=bmj&resid=313/7066/1159&atom=%2Fbmj%2F314%2F7080%2F600.2.atom
Induction of myeloma cell apoptosis by polyclonal rabbit anti-thymocyte globulin (rATG)
Authors: M. S. Zand, J. J. Ifthikharuddin, C. Abboud, J. L. Liesveld
Journal: Journal of Clinical Oncology (2004)

2552 Background: Myelomatous plasma cells have a variable surface phenotype which depends on the stage of differentiation arrest. Polyclonal anti-thymocyte globululin (rATG) is generally thought of as an anti-T cell lineage reagent, although it has potent activity against many cell surface antigens expressed on B cells. We describe the use of rATG to induce in vitro apoptosis of CD19+ plasmablasts, CD138+ cell lines and freshly isolated myeloma cells. Methods: We tested the ability of rATG (Thymoglobulin; Sangstat), anti-CD20 (rituximab), and anti-CD52 (Campath-1H) to induce apoptosis in human plasmablasts, myeloma cell lines (RPMI 8226, NCI-H929, U266) and freshly isolated myeloma cells from bone marrow aspirates of 5 untreated patients isolated by CD138 magnetic bead affinity columns. Surface marker phenotyping was performed for all cells. Cells were incubated with rATG (0.01 - 1000 mcg/ml), anti-CD20 (0.01–10 mcg/ml) anti-CD52 (0.01–100 mcg/ml), and pooled rabbit immunoglobulin in media containing heat inactivated sera. Apoptosis was assessed at 18 hours post-exposure by annexin-V plus TOPRO-3 staining, nuclear fragmentation, caspase 3/8/9 staining, mitochondiral membrane potential, and sub-diploid DNA quantitation. Results: All myeloma cells and cell lines were phenotyped by FACS and found to express surface at least 3 antigens known to have reactivity with rATG (MHC class I, CD80, CD38, CD40, CD45). No myeloma cells, cell lines, or pre-plasmablasts expressed significant expression of the target antigens for rituximab (CD20) or campath-1H (CD52). Compared with controls, rATG at 100 mcg/ml induced significant apoptosis of naive B cells (94±11%, p<0.001), CD40L stimulated plasmablasts (99±12%, p<0.001), all myeloma cell lines (93±7%, p<0.001), and myeloma cell isolates (91±24%, p<0.001). Neither CD40L stimulated pre-plasmablasts, myeloma cells or cell lines had apoptotic levels statistically different from controls. Conclusions: These results indicate that rATG, but not campath-1H or rituximab, is an active agent against multiple myeloma tumor cells. Further testing in a rigorous clinical trial to determine in vivo efficacy is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sangstat
Abstract 13901: Metformin Stimulates Ischemia-Induced Revascularization through an AMPK/eNOS-Dependent Pathway
Authors: Noriko Takahashi, Rei Shibata, Noriyuki Ouchi, Toyoaki Murohara, Kimihiro Komori
Journal: Circulation (2012)

Background: Type2 diabetes causes increased morbidity of coronary and peripheral artery diseases due to microvascular rarefaction and impaired collateral vessel growth under ischemic conditions. Me...
Presurgical comparative imaging evaluation in patients with colorectal cancer liver metastasis (PROMETEO Study)
Authors: F. Rojas Llimpe, F. Di Fabio, G. Ercolani, E. Giampalma, C. Serra, P. Castellucci, S. Pini, V. Mutri, R. Golfieri, C. Pinto, A. Martoni
Journal: Journal of Clinical Oncology (2009)

e15010 Background: The aim of the study was to define the specific diagnostic accuracy of different imaging techniques in patients (pts) with resectable colorectal cancer liver metastasis (CLMs). Methods: Consecutive pts with, potentially resectable CLMs afferent to the Multidisciplinary Liver Team of Bologna Sant’Orsola Malpighi Hospital performed, in the 3 weeks prior to liver surgery, computed tomography scan (CT), magnetic resonance diffusion-weighted (MR-DW), and liver contrast-enhanced ultrasonography (CEUS1). Liver contrast-enhanced ultrasonography was also performed intra-operatively (CEUS2). All the imaging exams were performed according to the standard operative procedures. Results: From December 2007 to December 2008, twenty-nine out of 50 pts enrolled in the PROMETEO study underwent liver resection. The pt characteristics were: 18 (62%) males, 11 (38%) females; 18 (62%) synchronous metastasis, 11 (38%) metachronous metastasis; 15 (51.7%) neoadjuvant chemotherapy; 7 (24.1%) previous liver surgery; 3 (10.3%) previous loco-regional treatment. Ninety-three liver lesions were resected; the median number lesions per patient was 2 (range 1- 10). All lesions were studied with CT and CEUS1, 90 (96.8%) with CEUS2, 83 (89.2%) with PET and 85 (91.4%) with MR-DW. Five lesions at pathological examination were non-metastasis (1 hamartoma, 1 steatosis, 1 giant-cell reaction, 2 necrosis). Only 3 lesions were not detected by all imaging techniques (in one pt. previously treated with chemotherapy and radiofrequency). Conclusions: These results show that CT, CEUS1 and MR-DW have a good accuracy in the detection of liver metastasis in patients who are candidates for resection. CEUS2 presents the best pathological predictive value. [Table: see text] No significant financial relationships to disclose.
Evaluation of cognitive function and quality of life in breast cancer patients receiving adjuvant dose dense chemotherapy.
Authors: Michael B. Dabrow, Christine E. Szarka, Joanne Moore, Michael R Chernick
Journal: Journal of Clinical Oncology (2012)

e19519 Background: Breast cancer therapy related neurocognitive dysfunction, such as memory impairment and “chemo-brain”, has been reported by many women during and after receiving adjuvant chemotherapy. Studies evaluating this effect have had mixed results regarding its validity. No study has evaluated a specific regimen and none have examined dose dense therapy. We have serially evaluated the cognitive and quality of life changes in patients receiving dose dense adjuvant adriamycin/cyclophosphamide followed by pactitaxel (DD AT-P) chemotherapy. Methods: Patients with early stage breast cancer (Stages I, II) who were treated at a single community hospital cancer center and were given dose dense AC-P adjuvant chemotherapy were asked to participate in this trial. 45 patients were enrolled and 43 were eligible for evaluation with the following instruments: FACT-F, FAS test, MMSE, MNA and BDI. Tests were administered at the start of chemotherapy, at the completion of chemotherapy, at 6 months and 12 months after completing chemotherapy. The tests were administered by oncology nurses. Scores were evaluated using repeated measures analysis of variance testing whether or not the change from baseline test scores had a trend over time. Results: 43 patients were evaluated. Age range was 34-72 years with a median age of 52. 34 patients completed 4 evaluations, 6 completed 3 evaluations, 3 completed 2 evaluations. The only measures demonstrating significant trends were the FAS test (p=0.022) and the Functional Well-Being (p=0.002) and Physical Well-Being (p&lt;0.0001) portions of the FACT-F. The changes over time for these measures all indicated improved performance over baseline at the completion of the trial. The remainder of the tests showed no significant change over time. Conclusions: Dose dense adjuvant chemotherapy with AC-P for breast cancer does not result in decreased cognitive or quality of life measures over time. Patients can be reassured that this specific program of therapy will not lead to long term decreases in mental function and quality of life.
Phase I study of picoplatin and docetaxel (D) with prednisone (P) in patients (pts) with chemotherapy-naive metastatic hormone refractory prostate cancer (HRPC)
Authors: L. Roman, P. Karlov, A. Kaprin, O. Gladkov, H. Breitz
Journal: Journal of Clinical Oncology (2007)

15546 Background: Picoplatin is a sterically hindered platinum analogue specifically developed to overcome platinum resistance and to improve on the safety and efficacy of other platinum-based drugs. In &gt;600 pts, picoplatin had single-agent activity in prostate, lung, ovarian and other malignancies with rare clinically significant nephro-, oto-, or neurotoxicity (∼2% grade 3 and 0% grade 4), even in platinum pretreated pts. An objective response rate of 20% and a PSA response rate of 25% were observed following 120 mg/m 2 picoplatin q 3 wk in 20 chemotherapy-naïve pts with HRPC. D + P leads to superior survival, increased PSA response and improved quality of life in HRPC pts. Picoplatin has demonstrated synergy with taxanes in pre-clinical studies. Thus the current study is designed to investigate D + P + picoplatin in chemotherapy-naïve pts with metastatic HRPC. Methods: Pts with documented progression of metastatic disease during adequate hormonal therapy, ECOG performance status of 0 or 1 and preserved organ function received D, 60 mg/m 2 q 3 wks + P, 5 mg, po bid + picoplatin. Picoplatin has been given to date to sequential cohorts of subjects at 60 mg/m 2 , 80 mg/m 2 and 100 mg/m 2 . Results: 16 pts have been enrolled and have received up to 8 cycles of therapy. Therapy has been well tolerated. No dose limiting toxicity has been observed. Dose reduction for thrombocytopenia has been required in 1 pt, but there has been no cumulative myelotoxity. 7 pts in the first 3 dose cohorts have been evaluated for efficacy after 4 cycles (12 weeks): at doses below the maximum tolerated dose, there were 3 PSA responses and 1 objective partial response. Dose escalation continues. Conclusion: Picoplatin can be safely administered with D + P in chemo-naïve pts with HRPC. A phase 2 study of this combination will begin when an optimal, safe dose is defined. No significant financial relationships to disclose.
Duration of the first off treatment period is associated with time to androgen independence (AI) and survival in men with localized or biochemical relapse of prostate cancer treated on a prospective trial of intermittent androgen deprivation (IAD)
Authors: D. Telesca, C. S. Higano, E. Y. Yu, R. B. Montgomery, S. L. Tam, K. J. Russell, P. S. Nelson, R. B. Etzioni
Journal: Journal of Clinical Oncology (2007)

5146 Background: Patients (pts) with localized prostate cancer or biochemical relapse who are treated with AD eventually develop AI and die. In an effort to better understand the natural history of this population, various characteristics of the patients and the first cycle of IAD were analyzed. Methods: Eligible pts had histological diagnosis of prostate cancer, no evidence of bone metastases by bone scan or visceral disease by CT scan, and at least 2 consecutive rising PSA = 2 weeks apart after diagnosis, radical prostatectomy (RP), or radiation therapy (XRT). Pts were treated with IAD consisting of 9 months of leuprolide acetate and an anti-androgen. Subsequently AD was stopped and monthly PSA and testosterone levels were followed during the off treatment period (Toff) until the PSA reached a threshold value (1 ng/mL if prostate removed or 4 ng/mL if prostate intact). At that time AD was resumed as before in a new cycle. Pts were treated until AI, defined as two rising PSAs while on AD with a castrate level of testosterone. Results: To date, 57 of 88 accrued pts are evaluable for this analysis. The median age at diagnosis is 62.2 yrs (range 43.9–77.4 yrs), median Gleason sum is 7. For the 49 pts with biochemical relapse after prior RP or XRT, median time from diagnosis to PSA relapse is 3.2 yrs (0–14.7 yrs) and from diagnosis to IAD was 4.9 yrs (range 0.1–14.9 yrs). For the 8 pts with no prior therapy, median time from diagnosis to IAD is 0.2 yrs (range 0–3.9 yrs). The median PSA value for all pts at study entry is 16 ng/mL (range 4–175 ng/mL); the value at study entry or after 3, 5, or 7 months of AD is not associated with time to AI or survival. Entry PSA is predictive of length of first Toff, and the length of the first Toff is associated with both time to AI (P&lt;0.010) and survival (P&lt;0.01). Conclusions: The duration of the first Toff in other studies of IAD should be evaluated for similar associations with time to AI and survival. No significant financial relationships to disclose.
Evidence for the Involvement of Both Retinoic Acid Receptor- and Retinoic X Receptor-Dependent Signaling Pathways in the Induction of Tissue Transglutaminase and Apoptosis in the Human Myeloma Cell Line RPMI 8226
Authors: Bertrand Joseph, Olga Lefebvre, Claude Méreau-Richard, Pierre-Marie Danzé, Marie-Thérèse Belin-Plancot, Pierre Formstecher
Journal: Blood (1998)
Concurrent or sequential letrozole with adjuvant breast radiotherapy: final results of the CO-HO-RT phase II randomized trial
Authors: C. Bourgier, S. Kerns, S. Gourgou, C. Lemanski, M. Gutowski, P. Fenoglietto, G. Romieu, N. Crompton, J. Lacombe, A. Pèlegrin, M. Ozsahin, B. Rosenstein, D. Azria
Journal: Annals of Oncology (2015)