tbuckley/cabot-search huggingface dataset:
A phase II study of erlotinib treatment in advanced non-small cell lung cancer after failure of gefitinib: Is a clinical benefit still achievable?
Authors: B. Cho, C. Im, H. Choi, S. Shin, J. Sohn, J. Kim, S. Kim, J. Moon, Y. Kim
Journal: Journal of Clinical Oncology (2007)

7609 Background: To evaluate the efficacy and toxicity of erlotinib in patients (pts) with advanced NSCLC who had progression after treatment with gefitinib. Methods: The study included stage IIIB/IV recurrent or metastatic NSCLC pts who have received 2 or 3 prior chemotherapy regimens and showed documented disease progression during or within 4 months after treatment with gefitinib. Pts received erlotinib 150 mg daily until disease progression or unacceptable toxicity. We analyzed EGFR mutations and other genetic abnormality from available tumor samples. Results: Pts and disease characteristics (n = 21) included median age 56 years; number of prior chemotherapy regimens (two, n=10; three, n=11); male (n=10); adenocarcinoma (n=15); and smoking status (never, n=11; former, n=3; current, n=7). Among the 17 pts with tumor samples available, EGFR mutation were detected in 5 (29.4 %). The DCR and RR for all pts were 28.6% (95% CI, 16.7 to 59.6%) and 9.5% (95% CI, 5.6 to 19.8%). All responders were EGFR nonmutants, with long duration of disease control on prior gefitinib therapy (&gt;180 days). The median duration of disease control was 125 days (95% CI, 73–261 days). The median progression-free survival and overall survival were 60 days (95% CI, 43–77 days) and 158 days (95% CI, 141–175 days), respectively. Pts who had SD on gefitinib showed significantly higher DCR (75% vs. 17.6% in non-SD pts, P= 0.050) and RR (50.0% vs. 0% in non-SD pts, P= 0.029). These pts also showed longer median PFS (140 vs. 37 days in non-SD pts, P= 0.005) and OS (not reached vs. 120 days in non-SD pts, P= 0.043). Among 17 pts with biomarker results available, EGFR nonmutants who had SD on gefitinib showed significantly higher DCR (100% vs. 21.4% in non-SD and/or EGFR mutants, P= 0.029) and RR (RR, 66.7 % vs. 0 % in non-SD and/or EGFR mutants, P= 0.022). Conclusions: Erlotinib seems to be a potential therapeutic option for the treatment of selected pts with gefitinib-nonresponsive, EGFR nonmutant, advanced NSCLC. No significant financial relationships to disclose. [Table: see text]
Upregulation of HER-2/neu is independent of the menopausal status of primary breast cancer patients: Plasma results from a prospectively randomized trial comparing dose-intense chemotherapy with G-CSF support to 3-weekly chemotherapy for adjuvant therapy of nodal-positive (1–3 LN) breast cancer (German Adjuvant Study Group ASG)
Authors: D. I. Luftner, S. Schildhauer, H. Eggemann, R. Geppert, K. Wernecke, M. Weigand, M. Budner, T. Zeiser, A. Kohls, K. Possinger, D. Elling
Journal: Journal of Clinical Oncology (2005)

638 Background: The ASG is completing recruitment into an adjuvant trial in which breast cancer patients (pts) either receive conventional ECP (Arm A; epirubicin (E): 90 mg/m2 + cyclophosphamide (C) 600 mg/m2 x4 q3w, followed by paclitaxel (P) 175 mg/m2 x4 q3w) or dose-dense EP + G-CSF on days 5–13 (Arm B; E: 120 mg/m2 x4 q2w, followed by P: 175 mg/m2 x4 q2w). Plasma for circulating HER-2/neu, EGFR and CA 27.29 levels is prospectively collected at baseline, at the end of chemotherapy and at relapse. Methods: Circulating HER-2/neu is measured using a standardized ELISA assay (Bayer Diagnostics/Oncogene Science, Cambridge, USA). The nonparametric analysis of variance for repeated measurements is used to detect significant influences of treatment arm, menopausal status and time effects, and to determine interactions. Results: Longitudinal plasma results (baseline and end of chemotherapy) are available from 415 pts of which 53% are postmenopausal. HER-2/neu concentrations increased from 9.4/9.3 ng/mL (Arm A/B) at baseline to 11.2/11.0 ng/mL (Arm A/B) at the end of chemotherapy for pre- and postmenopausal pts equally with a significant time effect (p<0.00001). In contrast to circulating HER-2/neu, CA 27.29 increased to a greater extent over time (p<0.00001) in the dose-dense Arm B from 21.3 U/mL to 37.2 U/mL as compared to Arm A from 20.5 U/mL to 25 U/mL. At the same time, circulating EGFR levels decreased significantly over time (p=0.0012) in the dose-dense Arm B only. Conclusions: These are the first results that show that HER-2/neu levels increase significantly in postmenopausal breast cancer pts. Identical results were published for premenopausal pts only (Lüftner et al., Breast Cancer Res Treat 2003). Circulating EGFR is known to be lower in postmenopausal pts than in premenopausal pts, which could reflect the faster ovarian ablation in the dose-intense arm. The pronounced increase of CA 27.29 in Arm B may be explained by cell death of minimal residual disease during intensified chemotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Diagnostics
Angiographic Cystoid Macular Edema and Outcomes in the Comparison of Age-Related Macular Degeneration Treatments Trials
Authors: Neepa Shah, Maureen G. Maguire, Daniel F. Martin, James Shaffer, Gui-Shuang Ying, Juan E. Grunwald, Cynthia A. Toth, Glenn J. Jaffe, Ebenezer Daniel
Journal: Ophthalmology (2016)
Design, synthesis and biological evaluation of Ruthenium (II) polypyridyl complexes with redox active ligands.
Authors: Abhishek Yadav, Sanjay Awasthi, Frederick MacDonnell
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

LB-191 

Purpose:    Tumor cells under hypoxic stress are among the most resistant to radiotherapy and chemotherapy and are also most susceptible toward metastasis, making this subpopulation a particularly attractive chemotherapeutic target.    We are interested in the development, toxicology and pharmacology of a new class of redox-active drugs that show potentiated DNA- cleavage activity under hypoxic conditions. These drugs are all based on a tetraazapentacene heterocycle which is the pharmacophore. Metal complexation of the drug provides solubility and imparts a cationic charge that helps the drug to tightly bind to DNA (Kb ~ 109 M-1) and this DNA damage is enhanced in presence of common cellular reductants like glutathione. The present paper presents structural design, studies in cultured malignant and normal cells, as well as animal toxicity and antitumor studies of this new pharmacophore.    Experimental Design:    A structure-activity relationship for a series of Ru(II) complexes has been established by synthesizing and screening them for its biological activity.    Cytotoxicity studies were performed to determine the IC50 using a standard MTT drug sensitivity assay on non-small cell lung cancer (NSCLC) H358 and H226. The control experiments for this were also carried out in normal healthy cells HUVEC and HAVSMC.    An initial animal toxicity screen was determined in a dose ranging study by intraperitoneal injection in C57BL/6NTac mice to calculate the maximum tolerable dose (MTD). The animals were also autopsied after interval of 0, 24 and 48 hr and the organs liver, spleen, intestine, kidney, heart, lung and brain collected and analyzed for studying the pharmacokinetics of the complex using Atomic Absorption Spectroscopy.    The in vivo antitumor activities of the most promising complexes were performed using an orthotopic syngeneic mouse melanoma model. For each complex 4 male C57BL/6NTac mice were injected with 1 million B16 mouse melanoma cells subcutaneously. The tumor volume and regression was monitored for the group.    Results:    The results of the drug sensitivity assay were determined for a total of 17 complexes (racemic/chiral). The most antipromising activity was shown by complex with a longer bridging redox active ligand tatpp with an IC50 value of about 10 μM, very rare for this class. The complex also showed low animal toxicity in the screen with MTD as high as 100 mg/Kg. Also we found that the complex had a measurable inhibitory effect on tumor growth as measured by the tumor volume.    Conclusions:    We report synthesis and biological activity of a novel molecule with anticancer properties that support a potential clinical utility for advanced human cancer.    Supported by National Cancer Institute grant CA 113747
A pilot study of gemcitabine (g), oxaliplatin (o), cetuximab (c) for locally advanced or metastatic pancreatic cancer
Authors: J. R. Merchan, A. Venkatraman, J. Macintyre, K. Ciombor, J. Levi, A. Ribeiro, D. Sleeman, F. Aurea, M. Vulfovich, C. M. Rocha-Lima
Journal: Journal of Clinical Oncology (2008)

15510 Background: Little progress has been made in the treatment of advanced pancreatic cancer (PC). Preclinical data suggest synergism between a platinum + G, and G + C. The combination of G and erlotinib is a standard. The combination of G and platinums is associated with higher RR and PFS to G alone. Methods: The study primary endpoint was to determine the progression free survival (PFS) of GOC in patients with locally advanced or metastatic pancreatic cancer. It was expected that GOC would extend PFS from 5.8 months to 7.54 months (relative increase of 30%). Chemotherapy naïve patients with locally advanced (LA) or metastatic (M) PC with PS 0–2 and good organ function were eligible. Treatment: G, 1000 mg/m2 over 100 minutes and C, at a loading dose of 400 mg/m2 on day 1 (250 mg/m2 on day 8 and subsequent cycles), and O,100 mg/m2 on day two, every two weeks (one cycle). Patients were treated until disease progression, intolerable toxicity, or patient refusal. Efficacy evaluation was performed every 4 cycles. Results: A total of 41 evaluable patients were enrolled from June 2006 to July 2007. Median age was 62 years, (range: 44–82). Male/female: 19/22. Twenty patients (48.8%) had metastatic disease. Median PFS time was 6.9 months (95% CI=3.9–9.2). Median PFS in LA patients was 7.5 months vs. 4.5 months in M patients. Confirmed RR= 24% (95% CI=12–40%), with one (2.4%) CR and 9 (22%) PR. Clinical benefit rate (CR, PR and SD) was 75, 6% (95% CI=59.7–87.6%). One year survival was 53% (95% CI=30–71%). Median OS was 6.5 months in the M group and not reached yet in the LA group. 1-year survival for LA: 75% (95% CI=37–92%), M: 33% (95% CI=7–62%). Most frequent grade 3/4 AEs (≥ 10% of patients) included neutropenia, infection, liver enzyme elevation, fatigue, diarrhea, peripheral neuropathy, hypokalemia and thrombosis. Conclusions: GOC is an active combination with a favorable toxicity profile. The study did not meet its primary endpoint. Updated information on the primary and secondary endpoints and correlative studies on available tumor specimens will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ImClone Systems Incorporated, Lilly Oncology, Pfizer Oncology, sanofi-aventis
Prediction of treatment response in anemic patients with cancer using darbepoetin alfa (DARB)
Authors: O. Camara, M. Hartmann, A. Egbe, I. Koch, I. Runnebaum
Journal: Journal of Clinical Oncology (2009)

e20643 Background: Malignant diseases along with chemotherapy or radiotherapy often result in anemia. Anemia is adversely correlated with the patient quality of life. Darbepoetin alfa (DARB) is an erythropoietic protein that works in a similary way as the body´s natural erythropoietin. The aim of this prospective study is to assess factors that are predicitive of treatment response under DARB. Methods: Between November 2002 and November 2007 overall 116 patients out of 120 projected were included in this trial. Patients with breast cancer, ovarian cancer or cervical cancer who were treated with chemotherapy, chemoradiation entered in the study. The initial hemoglobin level had to be less than 6.8 mmol/l. The primary endpoints were the evaulation of the effect of DARB(2.25 ug/kg/week) on erythropoietin level,on the hemoglobin level, on the transferrin receptor, on ferritin and creatinine. Secundary endpoints were the number of non responders and the effect of iv. iron. Patients were considered responders if hemoglobin increased by greater than 1.24 mmol/l or up to 7.44 mmol/l without red blood cells transfusion during a four week treatment. Results: 116 patients were recruited. The median age was 61(range 28–79). 44% were breast cancer patients, 39% suffered from ovarian cancer and 17% had cervical cancer. Overall 46% had adjuvant treatment. The median duration of DARB treatment was 6.1 weeks(range 0.1–37.6). 47% of the patients responded. Hemoglobin level increase more than 1.24 mmol/l was detected in 9 patients. 6 patients meet the criteria hemoglobin level more than 7.44 mmol/l. Both criteria had 29 patients.The median hemoglobin increase was 1.8 mmol/l(range 0.8–4) in responders and 0.5 mmol/l(-0.9–2.1) in non responders. Responders had significantly lower serum creatinin levels as non responders(p= 0.037). Hemoglobin increase was within the first 3 weeks significantly faster in responders as in non responders(p=0.0020). The transferrin receptor increase was also significant faster in responders(p=0.0036). Conclusions: An early hemoglobin increase was the most predictive factor for response to DARB. [Table: see text]
Drug-induced antibodies during 2-N-methyl-9-hydroxyellipticinium acetate (NSC-264137) treatment: schedule dependency and relationship to hemolysis.
Authors: J M Mondesir, J M Bidart, A Goodman, G F Alberici, P Caille, F Troalen, J Rouesse, C Bohuon, R J Gralla, A I Einzig
Journal: Journal of Clinical Oncology (1985)

Drug-dependent antibodies were investigated in patients treated with elliptinium acetate, a cytostatic drug with activity in advanced breast cancer. Retrospective analysis of 83 patients, receiving weekly intravenous elliptinium, showed a high incidence of anti-elliptinium antibodies (20%). Hemolysis occurred among antibody-positive patients, apparently related to the antibody titer. The predictability of anti-elliptinium antibodies for hemolysis and the schedule dependency of antibody development was examined prospectively. Among 42 patients treated weekly for at least three courses, 40% developed antibodies. Of 30 patients receiving elliptinium daily for three days every three weeks, none developed either antibodies or hemolysis. Only antibody positive patients, with titers greater than or equal to 32 were at risk for hemolysis. The possible mechanisms are discussed.
Efforts should be made to find boy with cancer after his removal from hospital, UK court orders
Authors: Clare Dyer
Journal: BMJ (2015)

A 10 year old boy with cancer of the jaw, whose parents are thought to have taken him to Poland, should have an operation to save him from a “brutal and agonising” death, a High Court judge has ruled.

Mr Justice Mostyn said that an urgent operation to remove the craniofacial osteosarcoma and reconstruct the jaw would be in the boy’s best interests, although both he and his parents oppose it.

The …
A phase II trial of UFUR plus gemcitabine in non-small cell lung cancer patients failing previous platinum-based chemotherapy
Authors: Y.-M. Chen, R.-P. Perng, C.-M. Tsai, J. Whang-Peng
Journal: Journal of Clinical Oncology (2005)

7296 Background: Both UFUR (Tegafur/Uracil) and gemcitabine (G) are effective agents against chemo-naïve NSCLC. The effectiveness of combination of these two agents in NSCLC patients failing previous chemotherapy is unknown.Our aim was to evaluate the efficacy of oral UFUR plus G in NSCLC patients who failed previous platinum-based chemotherapy. Methods: Treatment consisted of oral UFUR 200 mg/m2/day from days 1 to 14 and G 1000 mg/m2 intravenous infusion on days 1 and 8, of every 3 weeks. Results: Between June and November 2004, 31 patients were enrolled into the study, and 22 patients went off-study during that period. The present treatment was second-line treatment in 54.5%, and third-line or higher in 45.5%. Analyses of these 22 patients showed: mean age: 66.6, median cycles received: 3.5, and objective response rates of 22.7%. Treatment-related toxicities were mild and few. Grade 3 or 4 haematological toxicities included neutropenia in 3 patients and anemia in 3 patients. No neutropenic fever occurred. Non-haematological toxicities were all less than grade 3, except for grade 3 pneumonitis in 1 patient and grade 3 fatigue in 2 patients. Median time to disease progression was 3.8 months. Conclusions: This study demonstrated that UFUR plus gemcitabine salvage chemotherapy in NSCLC patients who have failed previous platinum-based chemotherapy produces a relatively lower toxicity profile, and a better compliance and response rate than conventional salvage chemotherapy, such as docetaxel treatment, and deserves further study. Updated data will be shown at the meeting. No significant financial relationships to disclose.
2-Chlorodeoxyadenosine dose escalation in nonhematologic malignancies.
Authors: A Saven, H Kawasaki, C J Carrera, T Waltz, B Copeland, J Zyroff, M Kosty, D A Carson, E Beutler, L D Piro
Journal: Journal of Clinical Oncology (1993)

We performed a dose-escalation study of 2-chlorodeoxyadenosine (2-CdA) in solid tumors to determine the maximum-tolerated dose (MTD) and define its toxicity profile at higher doses.Twenty-one patients, seven with malignant astrocytoma, twelve with metastatic melanoma, and two with metastatic hypernephroma, were enrolled onto the study. Patients were entered onto cohorts that received 0.10, 0.15, or 0.20 mg/kg/d of 2-CdA by continuous intravenous infusion for 7 days every 28 days. 2-CdA levels were determined by radioimmunoassay. In tumor tissue samples, deoxycytidine kinase (dCK) levels were measured by both enzyme activity and immunoreactive protein analysis.Of seven patients treated with 2-CdA at 0.1 mg/kg/d, one experienced grade 3 or 4 myelotoxicity. Of 11 patients treated at 0.15 mg/kg/d, four experienced myelotoxicity, two after a single course of 2-CdA. All three patients who received 2-CdA at 0.2 mg/kg/d experienced myelosuppression. Neurologic events occurred in two patients, both with malignant melanoma. Two of seven patients (28.6%) with astrocytomas obtained partial responses with a median duration of 8 months. 2-CdA penetrated the blood-brain barrier. An association was found between dCK levels as measured by enzymatic activity and immunoreactive proteins, but this did not correlate with 2-CdA tumor responsiveness.The MTD for 2-CdA delivered as a 7-day intravenous infusion in patients with nonhematologic malignancies was determined to be 0.1 mg/kg/d, the same as the MTD for patients with hematologic malignancies. There was no clinical correlation with dCK expression and response to 2-CdA. The responses noted in patients with malignant astrocytoma warrant further phase II study.
Definition of Dendritic Cell Subpopulations Present in the Spleen, Peyer’s Patches, Lymph Nodes, and Skin of the Mouse
Authors: Fabienne Anjuère, Pilar Martı́n, Isabel Ferrero, Marta López Fraga, Gloria Martı́nez del Hoyo, Natalia Wright, Carlos Ardavı́n
Journal: Blood (1999)
Abstract P2-07-01: EMT activates PERK-eIF2α signaling and sensitizes cells to perturbations in endoplasmic reticulum function
Authors: Yuxiong Feng, Ethan S Sokol, Catherine A Del Vecchio, Sandhya Sanduja, Jasper HL Claessen, Theresa A Proia, Dexter X Jin, Ferenc Reinhardt, Hidde L Ploegh, Qiu Wang, Piyush B Gupta
Journal: Cancer Research (2015)

Abstract Epithelial-to-mesenchymal transition (EMT) plays an important role in cancer progression. By undergoing an EMT, cancer cells acquire a spectrum of malignant properties, including invasiveness, multi-drug resistance and stem-like traits. Although they play an important role in tumor progression and resistance, few vulnerabilities of EMT cancer cells have been reported to date. To identify specific vulnerabilities of EMT cells, Using small molecule and RNAi screens, we have discovered that induction of EMT greatly sensitizes cells to agents that perturb endoplasmic reticulum (ER) function. This unexpected sensitivity to ER stress is mainly due to the expression and secretion of large amount of extracellular matrix (ECM) proteins by cells that have undergone an EMT. In line with their increased secretory load, EMT cells display a branched ER morphology and constitutively activate the PERK-eIF2α branch of the unfolded protein response (UPR). Using a PERK-specific inhibitor, we found that PERK activation is also required for EMT cells to invade and metastasize. In human tumor tissues, EMT gene expression correlates strongly with both ECM and PERK-eIF2α genes. In summary, our findings identify a novel vulnerability of cells that have undergone an EMT, and demonstrate that the PERK branch of the UPR is required for their malignancy. Citation Format: Yuxiong Feng, Ethan S Sokol, Catherine A Del Vecchio, Sandhya Sanduja, Jasper HL Claessen, Theresa A Proia, Dexter X Jin, Ferenc Reinhardt, Hidde L Ploegh, Qiu Wang, Piyush B Gupta. EMT activates PERK-eIF2α signaling and sensitizes cells to perturbations in endoplasmic reticulum function [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-07-01.
Adjuvant methotrexate escalated to toxicity for resectable stage III and IV squamous head and neck carcinomas--a prospective, randomized study.
Authors: R E Rentschler, D W Wilbur, G H Petti, G D Chonkich, D A Hilliard, E S Camacho, R B Thorpe
Journal: Journal of Clinical Oncology (1987)

To determine if adjuvant methotrexate (MTX), escalated weekly to toxicity, could improve disease-free survival (DFS) and overall survival by preventing recurrent disease, 60 patients with potentially resectable stage III or IV squamous head and neck carcinomas were stratified by primary site, stage, and nutritional status, then randomized by pairs to receive or not receive adjuvant MTX. All received standard surgery and postoperative radiation therapy. Five patients were taken off study because of unresectability at the time of surgery, leaving 55 evaluable patients. There were no statistically significant imbalances in known prognostic factors between the two treatment arms. MTX was begun at 40 mg/m2 and escalated 10 mg/m2 weekly (four doses preoperatively; four doses postoperatively, preradiation therapy; eight doses postradiation therapy) to mucosal or hematologic toxicity. The median peak MTX dose achieved was 80 mg/m2. Although three patients were hospitalized with MTX toxicity, none died of MTX toxicity. No patient receiving MTX had disease progression during treatment, and there was no increase in postoperative complications. Thirty-two patients died (median survival, 19 months); 23 patients are alive with median follow-up of 43 months. There was no statistically significant difference in actuarial DFS (P = 1.0) or overall survival (P = .61). Although patients on the MTX arm appeared to have less local and regional recurrences at first recurrence (thus more distant metastases), this did not reach statistical significance (P = .06). There was no significant difference between the sites of recurrence at death or last follow-up (P = .38).
P-334 Radiological assessments for select patients in neoadjuvant setting in rectal cancer: monoinstitutional experience
Authors: R. Murialdo, S. Scabini, L. Tixi, A. Massobrio, E. Romairone, E. Rimini, R. Gonella, L. Mastracci, F. Grillo, C. Marrone, G. Cittadini, A. Bacigalup, G. Zoppoli, A. Ballestrero
Journal: Annals of Oncology (2015)
Effects of granulocyte-macrophage colony-stimulating factor and erythropoietin on leukemic erythroid colony formation in human early erythroblastic leukemias
Authors: MT Mitjavila, JL Villeval, P Cramer, A Henri, J Gasson, G Krystal, M Tulliez, R Berger, J Breton-Gorius, W Vainchenker
Journal: Blood (1987)