tbuckley/cabot-search huggingface dataset:
Levels of circulating endothelial cells (CECs) as early pharmacodynamic markers of activity of anti-angiogenic (AA) therapy in advanced pancreatic cancer (PC)
Authors: R. V. Iyer, M. M. Javle, A. U. Pande, J. Yu, D. Wilkinson, Y. Rustum, P. Wallace
Journal: Journal of Clinical Oncology (2006)

14080 Background: Clinical evaluation of targeted AA therapy may be enhanced by non-invasive biomarkers assessing relevant drug action. In this study we tested the hypothesis that AA therapy with bevacizumab (BV), may result in early release of mature CECs from the tumor vasculature into the peripheral circulation and that this change may serve as a surrogate pharmacodynamic marker of response. Methods: In an ongoing phase II study, patients with advanced PC received BV (15 mg/kg IV, d1), capecitabine (650 mg/m 2 twice daily × 14 days) and gemcitabine (1000 mg/m 2 IV d1 &amp; 8) given q21 days as first line therapy. CECs (CD34 + , CD31 + , and CD45 − cells) were assessed pre treatment on d1 and on d3 of cycle 1 by 4-color flow cytometry. Quality of life (QOL) was assessed prior to each cycle using the PAN26 questionnaire. Radiographic response by RECIST criteria and CA 19–9 were assessed every 8 weeks. Kendall’s tau, the Wilcoxon signed rank test and Mann-Whitney U-test were used to investigate an association between biomarkers (CEC and CA 19–9), paired data and independent data, respectively. Results: Twenty six of planned 34 pts have been accrued; 13 pts are assessable for change in CECs, 10 are evaluable for response, 3 are too early. Patient demographics: M/F: 4/9; median age 63 years (range 38–79). Best response in 10 pts: 2 PR, 7 SD and 1 PD. On day 3, CECs increased in 8 and decreased in 5 pts compared to baseline. During treatment CA19–9 decreased in 7 and increased in 6 pts. No significant association between CEC and CA 19–9 was detected (Kendall’s tau=-0.2, p=0.367). No significant differences of CEC levels or CA 19–9 were found pre and post-treatment, QOL improved and unimproved, and response and no-response groups. Conclusion: Preliminary analysis in 10 patients reveals no correlation between change in CECs and QOL or radiographic or tumor marker response. This may be due to delayed change (beyond day 3) or release of non-viable CECs that are not currently measured. The limited sample at this early analysis may also account for this finding. These results will be updated as accrual continues with refined CEC measurements which include a viability probe. This study was supported by a grant from NCCN and Genentec pharmaceuticals No significant financial relationships to disclose.
A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1<sup>st</sup> line or 2<sup>nd</sup> line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial
Authors: F. A. Shepherd, J. Pereira, T. E. Ciuleanu, E. H. Tan, V. Hirsh, S. Thongprasert, A. Bezjak, D. Tu, P. Santabárbara, L. Seymour
Journal: Journal of Clinical Oncology (2004)

7022 Background: In phase II studies, erlotinib has shown single agent activity in a number of tumor types, including NSCLC. NCIC CTG BR.21 is a randomized, placebo-controlled trial undertaken to determine if the Epidermal Growth Factor Receptor (EGFR) inhibitor erlotinib (Tarceva) prolongs survival in NSCLC patients after 1st or 2nd line chemotherapy. Methods: Eligibility criteria included stage IIIB/IV NSCLC, PS 0–3, 1–2 chemotherapy regimens (at least 1 combination regimen if < 70 yrs). Patients were stratified by center, PS (0,1 v 2,3), response to chemo (CR, PR v SD v PD), number of prior regimens (1 v 2), platinum (yes v no), and were randomized 2:1 to receive erlotinib 150 mg po/day or placebo. The 10 endpoint was survival with 20 endpoints of progression free survival (PFS), response, toxicity and QOL. Results: From Nov/01-Feb/03, 731 pts entered the study (median age 61y; 64% male; 67% PS 0,1). 50% had received 2 prior regimens, 93% had received platinum and 37% prior taxanes. Patient characteristics were well balanced. Overall response to erlotinib was 8.9% (95% CI: 6.6–12.0%, p < 0.001), median duration 34.2 wks. Statistically significant and clinically relevant differences were observed for overall survival and PFS. The planned primary QOL analysis, time to deterioration of patient reported symptoms (TTDS), showed statistically and clinically meaningful benefit for patients randomized to erlotinib. Rash and diarrhea were the most frequent symptoms; 5% of patients discontinued erlotinib for toxicity compared to 2% of patients on placebo. Conclusion: This is the first randomized trial to confirm that a Her1/EGFR inhibitor prolongs survival after 1st or 2nd line chemotherapy for NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI Pharmaceuticals OSI Pharmaceuticals OSI Pharmaceuticals partially funded by a grant to the National Cancer Institute of Canada Clinical Trials Group from OSI Pharmaceuticals
Association between different potential predictive markers from TRUST, a trial of erlotinib in non-small cell lung cancer (NSCLC)
Authors: E. Laack, C. Schneider, T. Gutjahr, E. Heinmöller, V. Lutz, J. Moecks, K. Rohr, C. Schmidtgen, O. Spleiss, M. Reck
Journal: Journal of Clinical Oncology (2007)

7651 Background: Recent studies have examined potential predictive markers in NSCLC patients (pts) treated with EGFR tyrosine kinase inhibitors. However, few data are available on inter-relationships between different markers. Clinical and molecular markers were analyzed for patients from TRUST, an open label, non-randomized trial initiated to provide erlotinib access to pts with advanced NSCLC. Methods: 393 German pts (99% Caucasian) with stage IIIb/IV NSCLC were included. Markers/characteristics assessed were: EGFR (282 pts) and phosphorylated MAPK (pMAPK; 109 pts) using immunohistochemistry (IHC; positive status was defined as: ≥10% of tumor cells with any membrane staining for EGFR; and H-score ≥200 for pMAPK), EGFR gene copy number (135 pts) using fluorescence in-situ hybridization (FISH), EGFR mutations (86 pts), KRAS mutations (108 pts), tumor type (281 pts), smoking status (392 pts) and gender (393 pts). Results: EGFR FISH+ pts were likely to also be EGFR IHC+: 92.9% (26/28) of EGFR FISH+ pts were EGFR IHC+, and 92.6% of EGFR IHC- pts were also EGFR FISH- (p&lt;0.1). pMAPK expression status was not related to other markers. 15.7% (17/108) pts had KRAS and 7.0% (6/86) had EGFR mutations; no pts had mutations in both genes, indicating that these mutations might be mutually exclusive. Both KRAS mutations and histology were associated with smoking status. 94.1% (16/17) pts with KRAS mutations and 91.6% (87/95) pts with squamous-cell carcinoma were smokers. In female pts, the occurrence of adenocarcinoma was significantly higher (73.6% vs 55.4% in males; p&lt;0.001), possibly influenced by a lower incidence of smokers in this group (51.3% vs 92.2% in males; p&lt;0.001). Conclusions: The availability of a large number of tumor samples from the TRUST study, and assessment of a broad range of markers allows investigation of relationships between various tumor/patient characteristics. Understanding these complex inter-relationships may shed light on the role of each marker. Specific combinations of markers may prove useful in predicting clinical benefit from erlotinib. As the study is ongoing, additional data will be available and presented. No significant financial relationships to disclose.
Retrospective comparison between conventional-dose chemotherapy and high-dose chemotherapy for the treatment of relapsed or metastatic germ cell tumors.
Authors: A. M. Alencar, J. Rinck, L. L. Cezário, T. B. de Oliveira, V. C. de Lima, L. T. Chinen, F. N. Santos, M. F. Fanelli
Journal: Journal of Clinical Oncology (2010)

e15105 Background: Although metastatic and relapsed germ cell tumor (GCT) can be cured with conventional dose salvage chemotherapy (CDCT), 20% to 30% do not achieve durable complete response. High dose chemotherapy (HDCT) has been studied in phase II trials and demonstrated improved relapse-free survival (RFS) and overall survival (OS) compared with historical control. This study compares CDCT to HDCT in a retrospective series of patients with relapsed and metastatic GCT treated at Hospital A. C. Camargo, São Paulo, Brazil. Methods: Fifteen patients with relapsed GCT treated with HDCT were retrospectively compared to 13 patients treated with CDCT. RFS and OS curves were produced by Kaplan-Meier method and compared by log-rank test. Results: All 28 patients had primary gonadal tumors. In the CDCT group, 38% had pure seminomatous GCT and 61% had low risk at diagnosis according to IGCCCG, while 92% of patients in HDCT group had nonseminomatous tumors and high risk in 80%. HDCT was administered as second line salvage treatment in 53.3% of the patients, third line in 33.3% and fourth line in 13.3%. In CDCT group, 38% received prior chemotherapy (adjuvant or for metastatic disease at diagnosis), 15% received adjuvant radiation therapy and 46% received no adjuvant treatment after primary surgery. In a median follow up of 34.5 months (range, 02 to 102), 8 (61%) patients the CDCT were alive and disease-free, all of them with low risk. Eight (53.3%) patients in the HDCT group were alive and disease-free, 7 with high risk. Two of them had recurred after HDCT and underwent salvage chemotherapy. The RFS (p = 0.80) and OS (p = 0.63) did not differ in both groups. Grade 3 and 4 toxicity occurred in 46.2% of patients in CDCT group and 53.8% in HDCT group (p = 0.84). There was one treatment-related death in the HDCT group (alveolar bleeding due to prolonged grade 4 trombocytopenia), and no one on the CDCT group. Conclusions: Despite the higher number of high risk patients on the HDCT group, the current analysis did not show difference in RFS and OS among patients with relapsed GCT who were treated with HDCT and CDCT. High dose chemotherapy remains a real treatment option to be discussed for high risk patients. No significant financial relationships to disclose.
Paroxysmal atrial fibrillation (PAF) associated with high-dose melphalan (HDM) in autologous peripheral blood stem cell transplantation (APBSCT)
Authors: J. A. Warren, L. A. Solberg, J. H. Chesebro, A. Moreno-Aspitia
Journal: Journal of Clinical Oncology (2004)

6649 Background: Conditioning with HDM and APBSCT are offered to patients with severe hematologic malignancies. While toxicities such as myelosuppression and mucositis are well-documented in the literature, there is little mention of a possible relationship between HDM and acute cardiotoxicity. We hypothesized, from clinical experience, that HDM is associated with increased incidence of PAF in patients undergoing APBSCT. Such data would be useful to clinicians in planning of care for patients to be administered HDM prior to APBSCT. Methods: The study design is a case-control series from a retrospective review. The medical records of 119 patients undergoing APBSCT were reviewed for demographics, past medical history, and hospital and bone marrow transplantation (BMT) records. Patient undergoing BMT were divided into two groups: Group 1 received HDM alone or in combination with other chemotherapy or radiation therapy, and Group 2 received no melphalan in their conditioning regimen. Patients were transplanted at the Mayo Clinic in Jacksonville, Florida between January 1996 and August 2003. Patients were aged 37 or greater. Fischer's exact test was used for statistical analysis. Results: Seven (9.2%) of 76 patients in Group 1 developed PAF during their hospital admission in the absence of predisposing factors. Zero of 43 patients in Group 2 developed PAF. Comparing patients who received HDM versus those who did not, we observed a cause and effect relationship between HDM and PAF (p = 0.048). A difference was demonstrated also for manifestation of PAF in subset of patients receiving HDM = 200mg/m2 (five of 39, or 13%) versus those receiving no melphalan (p = 0.02). Conclusions: There is a statistically significant relationship between BMT patients receiving HDM (total dose ≥ 140 mg/m2) alone or in combination, and the appearance of PAF. Likewise, there is a greater relationship between PAF following APBSCT in patients conditioned with HDM at doses of 200 mg/m2. Further studies will be required to confirm true dose-related acute cardiotoxicity, and whether prophylaxis against arrhythmia in such patients is effective. No significant financial relationships to disclose.
Responding to Patients Requesting Physician-Assisted Death
Authors: Timothy E. Quill, Anthony L. Back, Susan D. Block
Journal: JAMA (2016)

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Adaptive Response of T and B Cells in Atherosclerosis
Authors: Daniel F.J. Ketelhuth, Göran K. Hansson
Journal: Circulation Research (2016)

Atherosclerosis is a chronic inflammatory disease that is initiated by the retention and accumulation of cholesterol-containing lipoproteins, particularly low-density lipoprotein, in the artery wall. In the arterial intima, lipoprotein components that are generated through oxidative, lipolytic, and proteolytic activities lead to the formation of several danger-associated molecular patterns, which can activate innate immune cells as well as vascular cells. Moreover, self- and non-self-antigens, such as apolipoprotein B-100 and heat shock proteins, can contribute to vascular inflammation by triggering the response of T and B cells locally. This process can influence the initiation, progression, and stability of plaques. Substantial clinical and experimental data support that the modulation of adaptive immune system may be used for treating and preventing atherosclerosis. This may lead to the development of more selective and less harmful interventions, while keeping host defense mechanisms against infections and tumors intact. Approaches such as vaccination might become a realistic option for cardiovascular disease, especially if they can elicit regulatory T and B cells and the secretion of atheroprotective antibodies. Nevertheless, difficulties in translating certain experimental data into new clinical therapies remain a challenge. In this review, we discuss important studies on the function of T- and B-cell immunity in atherosclerosis and their manipulation to develop novel therapeutic strategies against cardiovascular disease.
Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach
Authors: Douglas M Ruderfer, Alexander W Charney, Ben Readhead, Brian A Kidd, Anna K Kähler, Paul J Kenny, Michael J Keiser, Jennifer L Moran, Christina M Hultman, Stuart A Scott, Patrick F Sullivan, Shaun M Purcell, Joel T Dudley, Pamela Sklar
Journal: The Lancet Psychiatry (2016)
Ex-vivo analysis of the isoform selective histone deacetylase inhibitor entinostat in triple-negative breast cancer tumors
Authors: P. Ordentlich, L. Tee, Y. Huynh, S. Mee, H. Mamuszka, G. Lee
Journal: Journal of Clinical Oncology (2009)

e14597 Background: Triple-negative (ER, PR, HER2 negative) breast cancer represents an unmet need for which novel agents and approaches are essential. Entinostat is an orally available, class 1 isoform selective histone deacetylase inhibitor currently in multiple phase 2 clinical studies including advanced NSCLC and breast cancer. Studies in vitro and in vivo in the triple negative cell line model MDA-MB-231 have established single agent activity of entinostat in inhibiting tumor growth as well preventing bone metastases. In addition, entinostat induces expression of ERα in MDA-MB-231 in vivo and is synergistic with endocrine therapy agents to inhibit tumor growth of ER negative cancer cells. The aim of these studies was to confirm the activity of entinostat in triple negative breast cancers using human breast tumor explants. Methods: Cytotoxicity of entinostat was determined by the Oncotech Extreme Drug Resistance (EDR) proliferation assay using ten cryopreserved breast tumor explants known to lack estrogen receptor, progesterone receptor and HER2/neu expression (i.e. Triple negative) by immunohistochemistry. Results: Dose response curves of entinostat were analyzed and compared to paclitaxel at 2.45 μM in ten triple negative breast tumor explants in the EDR assay. Entinostat was broadly effective in all of the tumors tested, with most samples showing dose-dependent response for the range of concentrations analyzed (0.003 - 10 μM). Two of the breast tumors that were most sensitive to entinostat (IC 50 30- 100nM) were also sensitive to paclitaxel. In contrast, entinostat effectively inhibited (IC 50 10–270nM) the growth of eight of the tumors that were resistant to paclitaxel (i.e. &lt; 50% growth inhibition). Overall, all breast tumors tested were sensitive to entinostat at clinically achievable concentrations regardless of paclitaxel resistance indicating entinostat may improve the treatment outcome of triple negative breast cancer patients. Conclusions: Entinostat is an effective agent at inhibiting the growth of triple negative breast tumors with clinically relevant IC 50 's ranging from 10nM to 270nM. A pre-surgical clinical study to assess the activity of entinostat in triple negative breast cancer patients is planned. [Table: see text]
A phase III study of VMPT versus VMP in newly diagnosed elderly myeloma patients
Authors: A. P. Palumbo, S. Bringhen, D. Rossi, S. Berretta, V. Montefusco, J. Peccatori, M. Galli, A. Carella, P. Omedè, M. Boccadoro
Journal: Journal of Clinical Oncology (2009)

8515 Background: In MM patients VMP is superior to MP. In relapsed-refractory patients the 4 drug combination VMPT induced a high proportion of complete responses (CR). Methods: 500 newly diagnosed MM patients ≥ 65 years were randomly assigned to receive VMPT (N=247) or VMP (N=253). Patients were treated with nine 5-week cycles of VMPT (bortezomib 1.3 mg/m2 days 1, 8, 15, 22; melphalan 9 mg/m2 days 1–4; prednisone 60 mg/m2 days 1–4 and thalidomide 50 mg days 1–35) or VMP (bortezomib, melphalan and prednisone at the same doses and schedules previously described). Primary end-point was progression-free survival (PFS). Assuming the hazard ratio (VMP vs VMPT) of 1.35, the total sample size is 500 (250/arm) subjects (power 80%, 2-side alpha 0.05). Results: 354 patients (median age 71 years), who received at least 1 cycle were evaluated: 177 VMPT and 177 VMP. Data were analyzed in intention-to-treat. The VGPR rate was 55% in the VMPT group and 45% in the VMP group (p&lt;0.001). After a median follow-up of 14.5 months, the 3-year PFS was 74% in the VMPT group and 70% in the VMP group (HR=0.75, 95% CI 0.45–1.26, p=0.28). The 3-year overall survival (OS) was 88% in the VMPT group and 87% in the VMP group (HR=0.89, 95% CI 0.42–1.87, p=0.75). Subgroup analyses did not show any statistical difference between responses/PFS and either ISS or chromosomal abnormalities (t(4;14) or t(14;16) or del17) in both groups. Age &gt; 75 years was associated with lower VGPR rate (p=0.02) in VMPT but not in VMP. Factors predictive of longer PFS were age ≤ 75 years (p=0.003) and the achievement of VGPR (p=0.0005) in VMPT but not in VMP. The incidence of grade 3–4 adverse events (AEs) was similar in both groups. In the VMPT patients and in the VMP patients, the more frequent AEs were neutropenia (36% vs 31%), thrombocytopenia (20% vs 19%), peripheral neuropathy (18% vs 12%) and infections (14% vs 10%), respectively. Conclusions: VMPT is superior to VMP in terms of response rates. Longer follow-up is needed to assess their effects on PFS and OS. Both regimens appeared to overcome the poor prognosis of ISS and chromosomal abnormalities. An update of these data will be presented. [Table: see text]
Sunitinib in combination with docetaxel and prednisone in patients with metastatic hormone-refractory prostate cancer (mHRPC) - preliminary results
Authors: D. J. George, G. Liu, G. Wilding, T. E. Hutson, I. Chen, E. Chow Maneval, C. J. Logothetis, A. J. Zurita
Journal: Journal of Clinical Oncology (2008)

5131 Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET. VEGF and PDGF overexpression have been implicated in disease progression and bone metastases. By targeting VEGFR and PDGFR, SU may improve the efficacy of chemotherapy in patients (pts) with mHRPC. This multicenter phase I/II study is investigating the safety and efficacy of 1st-line SU in combination with docetaxel (D) and prednisone (P) in pts with mHRPC. The optimal combination dose in this population was previously established in phase I (Zurita et al, ECCO 2007). Methods: In phase II, pts receive SU 37.5 mg daily po on Days 1–14, D 75 mg/m2 iv on Day 1, and P 5 mg bid po on Days 1–21 of a 21-day cycle. Dose reductions are permitted in cases of treatment-related toxicity. Following a Simon’s Minimax 2-stage design, 31 pts were planned to be treated at Stage 1. If 9 or more PSA responses (≥50% confirmed decline in PSA from baseline) occurred in the 1st 31 eligible pts, the study would be expanded to a total of 54 pts. In addition to PSA kinetics, pts with measurable disease are assessed for tumor responses (RECIST). Other secondary endpoints include safety, exploratory analyses of potential biomarkers of treatment outcomes, and patient-reported outcomes. Results: 31 pts were enrolled in Stage 1. Results are available for 18 pts to date (median age 65 yrs, entry PSA 46.6, Gleason score 8) who have been on study for a median of 2 cycles (range 1–8). Five pts (28%) discontinued the study: 1 due to disease progression and 4 due to adverse events (1 death due to Pseudomonas infection leading to sepsis, 1 case of hyperbilirubinemia, 2 pts with febrile neutropenia). The most common treatment-related AEs were diarrhea (50%), neutropenia (44%), fatigue (33%), nausea (33%), and dysgeusia (28%). To date, PSA responses occurred in 9 pts (50%; another 2 are to be confirmed), allowing Stage 2 to proceed. In 13 pts with measurable disease, 5 (39%) have an initial partial response (to be confirmed) and 7 (54%) have stable disease. Conclusions: Sunitinib in combination with DP appears to be safe and well-tolerated in mHRPC pts, with encouraging efficacy measured by both PSA and objective response rates. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer, sanofi-aventis Pfizer Pfizer, sanofi-avenis Pfizer