tbuckley/cabot-search huggingface dataset:
Application of pharmacodynamic assays in a phase Ia trial of Apo2L/TRAIL in patients with advanced tumors
Authors: Y. Pan, R. Xu, M. Peach, C. Huang, D. Branstetter, B. Durbin, R. Herbst, G. Eckhardt, D. Mendelson, P. Holland
Journal: Journal of Clinical Oncology (2007)

3535 Background: Recombinant human (rh) Apo2L/TRAIL is a dual pro-poptotic receptor agonist (PARA) that induces apoptosis by binding to pro-apoptotic receptors DR4 and DR5, which recruit a death inducing signaling complex upon ligand binding. This results in activation of the effector caspase 3/7, that subsequently cleaves intracellular substrates to execute cellular apoptosis. A Phase1a trial is underway to evaluate the safety and tolerability of rhApo2L/TRAIL in patients with advanced tumors. The aim of this study was to develop and validate high-throughput pharmacodynamic assays to monitor rhApo2L/TRAIL activity in easily accessible patient samples such as serum. Methods: To monitor rhApo2L/TRAIL activity in patients, we optimized assays to measure the release of the apoptotic markers caspase 3/7, cytokeratin 18 (CK18), and genomic DNA (gDNA) in serum. Serum caspase 3/7 levels were monitored using the Caspase Glo kit, which generates a luminescent signal upon cleavage of a caspase 3/7 substrate; cleavage of the caspase substrate CK18 was measured using an optimized form of the M30 ELISA assay; gDNA was measured using a β-actin-specific TaqMan real-time PCR assay. Mice bearing Colo205 xenografts were treated with rhApo2L/TRAIL and sera were collected and assayed for apoptotic markers. Upon validating these assays, we monitored the levels of apoptotic markers in cancer patients who received rhApo2L/TRAIL. Results: We detected transient increases in apoptotic markers in mouse sera 8–24 hr after treatment with rhApo2L/TRAIL. This increase was dose-dependent and correlated with active caspase 3 detected by IHC in Colo205 tumors. In the phase Ia study, increases in serum caspase 3/7 and gDNA levels were observed in &gt;50% of colorectal, lung and sarcoma patients evaluated. Preliminary analyses show the percentage of increase correlates using both analytes and is dose-dependent. Conclusions: These findings support the use of serum-based pharmacodynamic assays as a means to monitor rhApo2L/TRAIL activity in patients with advanced tumors. A complete analysis of all patient serum samples from the ongoing phase Ia trial will be reported. No significant financial relationships to disclose.
Salvage therapies in women who fail to respond to first-line treatment with fluorouracil, epirubicin, and cyclophosphamide for advanced breast cancer.
Authors: K Porkka, C Blomqvist, P Rissanen, I Elomaa, S Pyrhönen
Journal: Journal of Clinical Oncology (1994)

PURPOSE We studied all salvage therapies given until death or the end of follow-up evaluation in women who failed to respond to the same first-line cytotoxic therapy for metastatic breast cancer. PATIENTS AND METHODS The study cohort consisted of 140 women who had received the fluorouracil, epirubicin, and cyclophosphamide (FEC) regimen for metastatic breast cancer. Eight patients were excluded. No exclusions with respect to disease site, performance status, or biochemical abnormalities were made. The median follow-up time was 29 months for surviving patients. RESULTS Most patients (88%) died during the follow-up period. Patients received a median of three salvage therapies (range, zero to eight) during the course of disease. Most courses (52%) were not assessable for response. Fifty-percent of courses consisted of chemotherapy: 35% of hormonal and 15% of combination of cytotoxic and hormonal therapies. The median duration of therapy (DT) ranged from 4 to 1 months, and decreased with advancing stages of therapy. Similarly, median time to treatment failure (TTF) ranged from 3 to 0.5 months. For unknown causes, patients who received second-line hormonal therapy fared better than those who received other forms of therapy. Of 366 analyzed courses, only one complete response (CR) and 18 partial responses (PRs) were observed (response rate, 11% for assessable and 5% for all courses). Stable disease for at least 3 months was found in 20% to 25% of courses. Most responses (n = 10) occurred during first salvage therapy, and no responses were observed after third salvage therapy. CONCLUSIONS Response rates for salvage therapies were low, and median treatment times short. The value of offering more than two salvage chemotherapy regimens to an unselected group of patients is questionable.
Glomerulonephritis with associated hypocomplementemia and crescents
Authors: D B Adey, B R MacPherson, G C Groggel
Journal: Journal of the American Society of Nephrology (1995)

Fibrillary glomerulonephritis is an unusual, but not rare cause of glomerulonephritis. Hypocomplementemia in association with fibrillary glomerulonephritis has been reported only once previously. A patient with hypocomplementemia and fibrillary deposits as demonstrated by electronmicroscopy is reported. The clinical and pathologic features of fibrillary glomerulonephritis and immunotactoid glomerulopathy are reviewed.
Low-level amplifications of the human telomerase gene (TERC) regularly is associated with vulvar intraepithelial neoplasia
Authors: G. Gebauer, J. Schleibaum, S. Aulmann, P. Schirmacher, C. Sohn, P. Sinn
Journal: Journal of Clinical Oncology (2006)

20060 Background: Invasive squamous carcinomas of the vulva frequently harbor gains on the long arm of chromosome 3, including the human telomerase gene locus (TERC). Vulvar cancer develops from precursor lesions known as vulvar intraepithelial neoplasia (VIN) which frequently occur simultaneously in multiple locations and have a considerable risk or recurrence during follow-up. We investigated TERC gene copy number in a series of vulvar intraepithelial neoplasias to determine the risk of progression in these lesions. Methods: A total of 20 cases of high grade vulvar intraepithelial neoplasias (VIN 3) were analyzed using a two-color fluorescence in situ hybridization (FISH) assay detecting the human telomerase gene locus (3q26) on paraffin embedded tissue sections. Two samples were excluded for technical reasons. Results: In 11 cases, gains of chromosomal material at 3q26 were detected with an average of 1.48 copies per chromosome. In another patient a high level amplification was found. The remaining two cases, four centromere and 3q26 hybridization signals were observed, consistent with a tetraploidy of chromosome 3. No changes in DNA copy number on chromosome 3q were detected only in four lesions. Conclusions: Our findings demonstrate high frequency of gains on chromosome 3q in the majority of high grade vulvar lesions. This suggests an involvement of the human telomerase gene locus in the pathogenesis of vulvar cancer. No significant financial relationships to disclose.
Investigating large and small airway epithelial cell senescence in COPD and bronchiectasis
Authors: Jodie Birch, Gail Johnson, Kasim Jiwa, Chris Ward, John Taylor, Paul Corris, Andrew Fisher, Anthony De Soyza
Journal: European Respiratory Journal (2013)

Introduction : Accelerated ageing and cellular senescence have been implicated in the pathogenesis of COPD but data comparing senescence in the large and small airways remains limited. The role of senescence in bronchiectasis is currently unknown.

Aims : To evaluate expression of senescence markers in large and small airway epithelial cells of patients with COPD or bronchiectasis.

Methods : Lung tissue was obtained from 11 smokers (controls), 19 patients with COPD (GOLD III-IV) and 14 patients with bronchiectasis. Expression of the anti-ageing molecule human sirtuin (SIRT1), the proliferation marker Ki-67 and senescence markers γH2AX, p16 and p21 were investigated by immunohistochemistry and airway epithelial expression quantified by a semi-quantitative method.

Results : Epithelial SIRT1 expression was decreased in both large (3-fold, p < 0.001), and small (2-fold, p < 0.05) airways of patients with COPD compared to controls. SIRT1 levels were decreased only in large airways of patients with bronchiectasis (1.5-fold, p < 0.01). Ki-67 expression was reduced in large airways of patients with COPD (2-fold, p < 0.05) in comparison to patients with bronchiectasis and controls. We observed increased expression of γH2AX in small airways of patients with COPD (2-fold, p < 0.01) and patients with bronchiectasis (1-fold, p < 0.05). A similar increase in p16 expression was observed (p < 0.05). Cytoplasmic staining for p21 was documented, however no difference in nuclear staining was observed between patient groups.

Conclusions : These results suggest that large and small airway epithelial cell senescence occurs in COPD and prompt further investigation into the potential role of senescence in bronchiectasis.
Comparison of the antiemetic effect of high-dose intravenous metoclopramide and high-dose intravenous haloperidol in a randomized double-blind crossover study.
Authors: S M Grunberg, K V Gala, M Lampenfeld, D Jamin, K Johnson, P Cariffe, D Strych, M Krailo
Journal: Journal of Clinical Oncology (1984)

Metoclopramide is an effective antiemetic for cisplatin-induced vomiting when given in parenteral high-dose regimens but not oral low-dose regimens. Metoclopramide was compared to haloperidol, also given in a high-dose parenteral regimen. Patients received two cycles of cisplatin at a dose greater than or equal to 70 mg/m2. Metoclopramide (2 mg/kg intravenous) was given every two hours for five doses beginning one half hour before cisplatin. Haloperidol (3 mg intravenous) was given on the same schedule. A randomized double-blind crossover design was used to control subjective bias and to compare the same patient's experiences. Twenty-eight patients completed both study arms. Excellent control of vomiting was achieved with both drugs. Metoclopramide resulted in 1.92 vomiting episodes (range, 0-5) with 36% having no vomiting. Haloperidol resulted in 3.04 vomiting episodes (range, 0-8) with 20% having no vomiting. Significantly fewer vomiting episodes were noted with metoclopramide rho = .006, paired sign test). However, responses to the two drugs were well correlated (Spearman's rho = .39, P = .03). Metoclopramide and haloperidol are both excellent antiemetics when given in sufficient dosage by an effective route. Metoclopramide does show a mild advantage. However, the positive correlation in response to these agents suggests a common mechanism of action. The ability to identify related antiemetics will be useful in the design of rational combination antiemetic therapy.
Ethnicity and return to work in breast cancer survivors: An exploratory qualitative study
Authors: V. S. Blinder, M. Mahadeo, L. T. Vahdat, H. T. Gold, I. De Melo-Martin, M. K. Hayes, R. J. Scheff, A. Moore, E. Chuang, M. Mazumdar
Journal: Journal of Clinical Oncology (2008)

20532 Background: Employment status after breast cancer is related to treatment recovery and quality of life (QoL). While correlates of return to work (RTW) have been previously identified in primarily Caucasian populations (eg. health status and perception of employer discrimination vs. accommodation), limited data exist regarding RTW and its relationship with QoL in ethnic minority breast cancer survivors (BCSs). Methods: Our aims were to improve our understanding of RTW in ethnically diverse BCSs and to pilot test a modified version of a previously used RTW Questionnaire. We conducted a qualitative study of RTW in BCSs from 6 ethnic groups: African-Americans, African-Caribbeans, Caucasians, Chinese, Filipinas, and Latinas. We used a sampling strategy designed to enrich for ethnic minorities and patients experiencing work problems after diagnosis. We organized ethnically cohesive focus groups of 4–6 BCSs who had completed treatment for stage I-III disease and were employed 3 mos. prior to diagnosis. Focus group discussions were audio- and video-recorded, transcribed, and analyzed for content and themes. Participants also completed the RTW questionnaire and gave written feedback. Results: We interviewed 24 subjects in 6 groups. Participants mentioned fear of gossip and/or pity, lack of schedule flexibility for doctors’ visits, cancer-related discrimination, stress, and unpleasant associations with medical equipment at work. Self-image was important among the Caucasian BCSs, while privacy at work was a common theme among all but the Chinese and Latina BCSs. For some, the entire year after diagnosis was a time of perceived treatment, even if all medical therapy had been completed. Those with a strong family history of breast cancer worked through their treatment and said work helped them cope. Positive aspects of early RTW included feelings of independence and wellness and finding a support system among coworkers. The average time for questionnaire completion and feedback was 25.8 min. Conclusions: Ethnically diverse BCSs experience an array of barriers to RTW, some of which may be influenced by ethnicity and culture. A quantitative study using an ethnically sensitive and translated RTW questionnaire is needed to better understand RTW in BCSs of different ethnicities. No significant financial relationships to disclose.
Target identification of natural and traditional medicines with quantitative chemical proteomics approaches
Authors: Jigang Wang, Liqian Gao, Yew Mun Lee, Karunakaran A. Kalesh, Yong Siang Ong, Jaehong Lim, Joo-Eun Jee, Hongyan Sun, Su Seong Lee, Zi-Chun Hua, Qingsong Lin
Journal: Pharmacology & Therapeutics (2016)
A phase I/II study of bexarotene (B) and erlotinib (E): A novel targeted combination therapy for lung cancer and other aerodigestive tract (ADT) tumors
Authors: K. H. Dragnev, W. J. Petty, V. Memoli, W. Black, I. Williams, J. R. Rigas, E. Dmitrovsky
Journal: Journal of Clinical Oncology (2004)

3092 Background: We reported (Proc AACR, 2701a, 2003) two important pathways in lung carcinogenesis. Treatment of BEAS-2B human bronchial epithelial cells (HBEC) with tobacco carcinogens enhanced cyclin D1 and epidermal growth factor receptor (EGFR) expression. All-trans-retinoic acid (RA) suppressed their expression through a transcriptional mechanism for EGFR and post-transcriptional proteasome-dependent proteolysis for cyclin D1. Similar effects were noted with the rexinoid (B), bypassing the need for intact RAR-β signaling often deregulated in lung cancer. We found additive cooperation in HBEC between B and EGFR tyrosine kinase inhibitor E (OSI-774) repressing G1 cyclins via non-cross-resistant pathways. Methods: Phase I/II trial of B and E in advanced ADT tumors. Primary objective - maximum tolerated dose. Secondary objectives - toxicities, efficacy, and surrogate markers of response (cyclin D1, Ki-67, EGFR, phospho-EGFR) in buccal swabs from patients (pts) at the highest dose. 3 dose levels - 1: B 300 mg/m2, E 100 mg; 2: B 300 mg/m2, E 150 mg; 3: B 400 mg/m2, E 150 mg. All pts received Lipitor for elevated triglycerides. Results: Eight pts were enrolled, accrual continues –stage IV NSCLC (6), laryngeal (1), salivary gland (1). Median age was 61 (53–70), 50% women, median performance status 80 (70–90). 7 patients had prior chemotherapy. 7 pts were treated on level 1, 1 on level 2. Three pts had grade (gr) 3 hypertriglyceridemia, 1 pt on warfarin had gr 3 INR prolongation without bleeding, 1 pt had pneumonia requiring hospitalization. One pt on level 1 died early with a pre-existing pericardial effusion. No gr 3/4 toxicities were seen on level 2. There was 1 partial response for over 7 months (NSCLC), 1 minor response (bronchoalveolar), 1 stable disease (NSCLC), 3 progression (2 NSCLC, 1 salivary), 1 too early for evaluation and 1 nonevaluable. Conclusions: Preliminary results indicate this is a well-tolerated regimen with activity in lung cancer. Updated results will be presented along with findings from surrogate markers analysis. Supported in part by NCI CA23108, Ligand and Genentech. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ligand Ligand Ligand; Genentech
A phase II study of docetaxel and gemcitabine in the treatment of recurrent ovarian, peritoneal, and fallopian tube cancer
Authors: M. S. Shahin, P. Hanjani, S. Nolte
Journal: Journal of Clinical Oncology (2006)

15006 Background: The aim of this trial was to investigate the efficacy and toxicity of weekly combination of docetaxel (D) and gemcitabine (G) in the management of recurrent ovarian, peritoneal, or fallopian tube cancer. Methods: D (30 mg/m 2 ) was given as a one-hour IV infusion followed by G (650 mg/m 2 ) as a 30 minute IV infusion on Day 1, 8 &amp; 15 of a 28-day cycle. Results: Thirty pts were enrolled. Mean age was 67.4 (range 47–85). Twelve (40%) pts had Platinum sensitive disease, and 18 (60%) had Platinum resistant disease. One hundred eighteen cycles were evaluable for toxicity. The mean number of cycles was 4 (range 1–7). Twenty-six (22%) of the cycles were incomplete due to toxicity (day # 15 not given in 25 of the incomplete cycles). Dose delay was observed in 4 (13.3%) pts, and a one-dose level reduction was required in 11 (36.7%) pts. Hematologic toxicity included grade 3 neutropenia in 13 (11%) cycles, grade 3 thrombocytopenia in 11 (9.3%) cycles. No grade 4 neutropenia, thrombocytopenia or neutropenic fever was encountered. Bone marrow support with erythropoiten (36.6% pts), and filgrastim (13.3% pts) were utilized. Blood transfusions were given in 10 (8.5%) cycles. Elevated LFT grade 1/2 was seen in 7 (23.3%) pts and 3 (10%) pts, respectively. Nonhematologic grade 3 toxicites occurred in 4 pts (including one seizure). Mean follow-up interval was 19.6 months (mos) (range 1–36.6). To date, 14 (46.6%) pts are alive with disease, and 16 (53.4%) have died of disease. The overall response rate was 32% (1 CR and 8 PR in 28 evaluable pts). Ten pts (33.3%) had SD and 5 had ID. Median progression-free interval (PFI) was 3.8 mos (95% CI: 1.65–5.97). Overall survival was 19.6 mos (95% CI: 14.23–24.96), and no significant differences in PFI and survival between the Platinum-sensitive and resistant pts (P = 0.5, P = 0.08, respectively). Conclusions: Weekly docetaxel plus gemcitabine is an active and tolerable regimen with minimal toxicity in this older population of pts (9 ≥ 80 years of age). No significant difference in response between Platinum sensitive and resistant pts was observed. Overall response rate appears to be better than single agent regimens currently available. Elimination of the third week of treatment may not affect efficacy and will be more acceptable to pts with less toxicity. No significant financial relationships to disclose.
Abstract 17072: Marked Increases of Large HDL Particles Induced by Exercise-based Cardiac Rehabilitation Are Strongly Associated With Improved Cardiopulmonary Fitness in Patients With Acute Coronary Syndrome
Authors: Yuya Yokota, Shinji Koba, Makoto Shoji, Youichi Kobayashi
Journal: Circulation (2013)

Background: Exercised-based cardiac rehabilitation (CR) can increase HDL-cholesterol (HDL-C). However it remains unclear how elevated HDL-C and changes of HDL subfractions are correlated with the i...
The practice of early palliative care: A qualitative study of patient-clinician encounters.
Authors: Christopher Taekyu Lim, Avia Tadmor, Daisuke Fujisawa, James John MacDonald, Emily R. Gallagher, Jennifer S. Temel, Joseph A. Greer, Elyse R. Park
Journal: Journal of Clinical Oncology (2014)

2 Background: Studies have shown that palliative care (PC) integrated early in the course of metastatic cancer, shortly after diagnosis, leads to improved patient outcomes. Unlike PC in the inpatient setting, PC initiated early, in the ambulatory setting, had not been well studied. Our aim was to elucidate the practice of early PC through analysis of PC clinic visit transcripts. Methods: As part of an ongoing study of early PC in patients with advanced lung and gastrointestinal cancers at the Massachusetts General Hospital, we are audio-recording patients’ outpatient PC clinic visits. To capture the range of PC content, we randomly selected five patients and analyzed three clinic transcripts per patient: early, midway, and late in each patient’s clinical course. We performed thematic analysis on these clinic transcripts using NVivo 10. Results: Our analysis suggests that the elements of early PC that occur most frequently across the disease course are managing symptoms, facilitating coping, and developing the relationship with patients and their family caregivers. Elements that tend to occur during clinical transitions include advising treatment decision-making, facilitating medical understanding, and advance care planning. Our analysis also identifies four broad approaches to PC that are applied longitudinally, over the course of the patient-clinician relationship: 1) eliciting versus commenting on patients’ perspectives, 2) alluding to and preparing for the future, 3) transitioning between managing symptoms and facilitating coping, and 4) transitioning between developing the relationship and facilitating coping. Lastly, we observe three specific techniques applied by PC clinicians: 1) coordinating with oncologists, 2) providing referrals, and 3) addressing family dynamics. Conclusions: Our study identifies the predominant elements, four longitudinal approaches, and three specific techniques of early PC. These novel insights can be applied to care delivered by both PC and non-PC clinicians, well before patients approach the end of life. The longitudinal approaches in particular may help explain the significance of early integration of PC into cancer care.
A phase I dose-escalation study of weekly IMC-1121B, a fully human anti-vascular endothelial growth factor receptor 2 (VEGFR2) IgG1 monoclonal antibody (Mab), in patients (pts) with advanced cancer
Authors: D. R. Camidge, S. G. Eckhardt, S. Diab, L. Gore, L. Chow, C. O’Bryant, E. Temmer, A. Ervin-Haynes, T. Katz, F. Fox, R. B. Cohen
Journal: Journal of Clinical Oncology (2006)

3032 Background: Anti-VEGFR2 antibodies are effective in a variety of preclinical leukemia and solid tumor models. IMC-1121B is a fully human anti-VEGFR2 IgG1 Mab. Methods: Cohorts of 3–6 pts (ECOG PS ≤ 2) with advanced cancer and no significant cardiovascular, thrombotic or bleeding disorders received escalating doses of IMC-1121B. A single initial dose with extended PK sampling was followed by 4 x weekly infusions per treatment cycle starting at 2mg/kg. 7 dose levels up to a maximum of 16 mg/kg are planned. Human anti-human antibodies (HAHA) directed against IMC-1121B were assessed at baseline and before each Week 4 dose. Tumor response was assessed every 2 cycles. PD analyses include DCE-MRI, serum VEGF and sVEGFR1/2 levels, and peripheral blood mononucleocyte gene expression profiling at baseline and post-dosing. Results: 12 pts (8 M; 4 F), median age 58 years (range: 36–76), have entered the study: cohort 1 (2mg/kg) n=6, cohort 2 (4mg/kg) n=4 and cohort 3 (6mg/kg) n=2. No toxicities ≥ grade 2, considered definitely or probably related to study drug, have occurred. Toxicities ≥ grade 2 possibly drug-related include anorexia, vomiting, anemia, depression, fatigue, and insomnia. To date, there has been one unconfirmed partial response (melanoma) and 5 pts with stable disease for &gt;3 months (colon: 2, breast, gastric, thyroid). Preliminary non-compartmental PK analysis reveals dose-dependent elimination and non-linear exposure, consistent with saturable clearance mechanism(s): mean t1/2 = 63.62, 93.46, 99.63 hrs, mean Cmax = 43.67, 80.25, 264 ug/mL, and AUC0-Inf = 3860, 9242, 27437 hr*ug/mL, at the 2, 4, and 6 mg/kg dose levels, respectively. Conclusions: Weekly administration of IMC-1121B is well tolerated at doses up to 6mg/kg/week. There is early evidence of a non-linear dose-PK relationship. Dose escalation continues. Updated safety, PK, PD, HAHA, and efficacy data will be presented. [Table: see text]