tbuckley/cabot-search huggingface dataset:
Factors influencing use of genetic tests in clinical practice among U.S. oncologists.
Authors: J. M. Peppercorn, E. P. Hamilton, L. Beskow, I. Lipkus, P. K. Marcom, G. H. Lyman
Journal: Journal of Clinical Oncology (2010)

6067 Background: Genetic tests in oncology may become commercially available while clinical evidence to guide their use in practice is still emerging. We surveyed U.S. oncologists regarding the factors effecting their decision to order genetic tests in conjunction with a survey of CYP2D6 testing for tamoxifen metabolism. Methods: A survey was mailed to all breast cancer oncologists identified at National Comprehensive Cancer Network (NCCNO) centers and a random sample of community based oncologists (CBO) identified from the American Society of Clinical Oncology directory. Oncologists were asked to rate from 1-10 the importance of factors that might influence their use of genetic tests in practice. Fisher's exact tests and unpaired T-tests were performed to test for significance. Results: 201 of 459 (44%) oncologists responded, including 97/173 (56%) of NCCNO and 104/286 (36%) of CBO. Evidence of survival benefit from randomized trials (mean 9.08) and professional guideline recommendations (mean 8.74) were rated the most important factors among all oncologists. Professional guidelines were rated more important among CBO than NCCNO (mean 9.01 vs. 8.47, p = 0.02). Insurance coverage was the third most important factor overall among CBO (mean 8.63 vs. 7.65 NCCNO, p = 0.001). Knowledge of how test results would guide therapy ranked third overall among NCCNO (mean 8.28) and fourth among CBO (mean 8.32). FDA approval was rated 8-10 among 67% of CBO vs. 44% of NCCNO (p = 0.002), with means of 7.81 and 6.69 respectively (p = 0.002). Lower levels of importance were assigned to retrospective evidence of the tests utility for prognosis, toxicity, or response. Overall, use of test among colleagues was considered least important among factors presented (mean 5.16 NCCNO vs. 5.77 CBO, p = 0.08). Third party requests for CYP2D6 appeared to influence “ever” use of test among CBO (64% vs. 22%, p = 0.006), not NCCNO (34% vs. 37%, p = 0.9). Conclusions: In addition to data from prospective randomized trials, professional guidelines appear to play an important role in use of genetic testing among oncologists. As novel genetic tests become available, professional guidelines should be established and kept up to date with emerging evidence. No significant financial relationships to disclose.
Phase I/II study of the tumor-targeting human L19-IL2 monoclonal antibody-cytokine fusion protein in combination with DTIC in metastatic melanoma patients
Authors: C. Garbe, A. Romanini, G. Spitaleri, L. Giovannoni, L. Zardi, D. Neri, A. Shaw, H. D. Menssen, F. deBraud, T. K. Eigentler
Journal: Journal of Clinical Oncology (2009)

9064 Background:L19-IL2 is a tumor targeted immunocytokine constituted by a single chain Fragment variable (scFv) format directed against the ED-B domain of fibronectin and the human cytokine interleukin-2 (IL2). The recommended dose (RD) for monotherapy of advanced solid cancer patients was established to be 22.5 Mio IU IL2 equivalent on day 1, 3, and 5 of a 21-day cycle. Here we report clinical results of the dose escalation part of a phase I/II study assessing L19-IL2 in combination with DTIC chemotherapy in metastatic melanoma patients. Methods: L19-IL2 was administered as an i.v. infusion at doses of 10 (n=3), 15 (n=3) and 22.5 MioIU IL2 equivalent dose (n=4) on days 1, 3 and 5 every 21 days in combination with DTIC 1000 mg/m2 on Day 1 for up to 6 treatment cycles. Serum samples for PK evaluation and induction of human antifusion antibodies to L19 (HAFA) were collected. Flow cytometry (T and NK/B cell panels) was performed. Data on safety and activity were evaluated using CTC v3.0 and RECIST criteria, respectively. Results: All 10 patients had progressive metastatic melanoma and the majority had already received prior systemic therapy. Median age at start of treatment was 62 years (52–74). There were no treatment related deaths and the treatment was well tolerated, details of CTC evaluation will be presented. The dose of 22.5 Mio IU day 1, 3, and 5 in combination with 1000 mg DTIC/m2 on day 1, repeated on day 22 was defined as the RD for up to 6 treatment cycles. 10 patients were evaluable for response. We observed 1 partial remission at the 15 Mio IL2 dose level after 4 treatment cycles. Immunophenotyping analysis showed transient stimulation of NK cells, T4 cells, and CTLs. Pharmacokinetic data will be presented. Conclusions: L19-IL2 at a dose of 22.5 Mio IU IL2 equivalent on days 1, 3, and 5 of a 3-weekly schedule can be safely combined with standard DTIC in metastatic melanoma patients. Toxicity was manageable and reversible. Preliminary evaluation suggests clinical activity of the L19IL2/DTIC regimen in metastatic melanoma patients. [Table: see text]
Amelioration of the Fitness Costs of Antibiotic Resistance Due To Reduced Outer Membrane Permeability by Upregulation of Alternative Porins
Authors: Michael Knopp, Dan I. Andersson
Journal: Molecular Biology and Evolution (2015)

The fitness cost of antibiotic resistance is a key parameter in determining the evolutionary success of resistant bacteria. Studies of the effect of antibiotic resistance on bacterial fitness are heavily biased toward target alterations. Here we investigated how the costs in the form of a severely impaired growth rate associated with resistance due to absence of two major outer membrane porins can be genetically compensated. We performed an evolution experiment with 16 lineages of a double mutant of Escherichia coli with the ompCF genes deleted, and reduced fitness and increased resistance to different classes of antibiotics, including the carbapenems ertapenem and meropenem. After serial passage for only 250 generations, the relative growth rate increased from 0.85 to 0.99 (susceptible wild type set to 1.0). Compensation of the costs followed two different adaptive pathways where upregulation of expression of alternative porins bypassed the need for functional OmpCF porins. The first compensatory mechanism involved mutations in the phoR and pstS genes, causing constitutive high-level expression of the PhoE porin. The second mechanism involved mutations in the hfq and chiX genes that disrupted Hfq-dependent small RNA regulation, causing overexpression of the ChiP porin. Although susceptibility was restored in compensated mutants with PhoE overexpression, evolved mutants with high ChiP expression maintained the resistance phenotype. Our findings may explain why porin composition is often altered in resistant clinical isolates and provide new insights into how bypass mechanisms may allow genetic adaptation to a common multidrug resistance mechanism.
Ixabepilone (BMS-247550) plus trastuzumab combination chemotherapy induces synergistic antitumor efficacy in HER2 dependent breast cancers and is accompanied by modulation of molecular response markers
Authors: F. Y. Lee, S. Castaneda, I. Inigo, D. Kan, B. Paul, M.-L. Wen, C. Fairchild, E. Clark, H. Lee
Journal: Journal of Clinical Oncology (2005)

561 Background: Ixabepilone (Ixa) belongs to a class of structurally novel, microtubule-stabilizing agents that exert their antimitotic action by binding to tubulin with a binding mode that is distinct from the taxanes. Ixa is non-cross-resistant with the taxanes in preclinical human primary tumor models. In Phase II trials Ixa exhibited robust activities in breast cancers, with or without prior taxanes. Here we determined the activity of combined treatment with Ixa plus trastuzumab in preclinical breast cancer models, and identified potential pharmacogenomic correlates that predict responsiveness to the trastuzumab/Ixa combination Methods: BT474 and KPL-4 human breast cancer cell lines were used; both express the receptor tyrosine kinase HER2 and are dependent on HER2 signalling for growth. Effects of drug treatments in vitro were determined by a vital dye uptake assay (MTS) or a colony formation assay. In vivo, BT474 and KPL4 were grown as SC tumors in mice. Gene expression profiling was performed using the Affymetrix HG-U133 arrays Results: In cell culture, trastuzumab was cytostatic and inhibited the proliferation of BT474 and KPL-4 in a dose-dependent manner from 0.1–5 μg/mL. Ixa in contrast was cytotoxic to both BT474 and KPL-4 cells with IC50s of 13.7 and 9.2 nM, respectively. Co-treatment of BT474 and KPL-4 cells with trastuzumab plus Ixa augmented the cytotoxic potency by more than 2-fold over Ixa alone (P<0.05). Treatment of KPL-4 tumored mice (n=8/group) with trastuzumab plus Ixa produced synergistic therapeutic effects. Trastuzumab treatment alone (10 mg/kg) produced no complete (CR) or partial (PR) response. Ixabepilone alone at its MTD (4 mg/kg) yielded 1 PR, 1 CR. The combined regimen produced 8 CR (4 of which were cured). Gene expression profiling revealed that trastuzumab treatment modulated the expression of several predictive marker genes, including the down-regulation of microtubule-associated proteins, tau Conclusions: Trastuzumab and Ixabepilone combination produced therapeutic synergism, which may be explained by changes in expression of predictive gene markers of drug response Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb
Change in symptoms after paracentesis for symptomatic malignant ascites
Authors: A. Easson, A. Bezjak, S. Ross, F. Sam, A. Newman, N. Bana, J. G. Wright
Journal: Journal of Clinical Oncology (2005)

6071 Background: Symptomatic malignant ascites is a significant problem for palliative patients with intraabdominal malignancy. Paracentesis is the most common therapeutic option. Although the main goal of paracentesis is symptom palliation, the best method of assessing symptom improvement is not known. The aim of our study was to compare existing and validated symptom and quality of life (QOL) questionnaires to assess their ability to detect a clinical improvement in symptoms after paracentesis. Methods: Patients with malignant ascites were asked to complete 4 symptom and QOL questionnaires before and 24 hours after therapeutic paracentesis. These included the Edmonton Symptom Assessment System, the Memorial Symptom Assessment Scale-SF and the EORTC Core and Pancreatic Cancer Module. Demographic data was collected, and the patient’s opinions about the questionnaires and the procedure elicited. Change scores were calculated by subtracting the baseline subscale scores from the follow-up scores. Results: 61 patients completed the baseline questionnaire and 44 completed follow-up questionnaire. Patients predominantly had ovarian (41%) and gastrointestinal cancer (25%); their ECOG performance status was 2 (26%) and 3 (49%). There was no systematic difference between respondents and non-respondents. Baseline questionnaires revealed a significant amount of baseline symptoms, with the worst scores in the symptom domains. The mean amount of fluid removed was 3.5 L (range 0.3–9.7 L); there were no complications. All questionnaires showed strong sensitivity, validity and reliability when applied to this patient population. Most patients (78%) reported that their symptoms had improved as a result of the procedure. Significant improvement was demonstrated for subscales that included the most distressing symptoms, such as abdominal bloating, anorexia, dyspnea, insomnia, fatigue, as well as overall QOL. The amount of fluid removed did not correlate with symptom improvement. Conclusions: Paracentesis provides relief of symptoms for patients with malignant ascites. The existing symptom and quality of life questionnaires are valid and sensitive to change and could be suitable for clinical trials of new interventions for paracentesis. No significant financial relationships to disclose.
Phase II study of cyclophosphamide, etoposide and estramustine in patients with androgen independent prostate cancer
Authors: M. A. Choudry, D. A. Laber, C. Crump, V. R. Sharma, R. V. Larocca, L. Bhupalam, G. H. Kloecker, A. C. Mehta, F. J. Hendler, D. M. Miller
Journal: Journal of Clinical Oncology (2005)

4757 Background: Oral therapy offers the tremendous advantage of independence and avoids all the catheter-related complications. Cyclophosphamide (C), etoposide (E) and estramustine (E) are active against androgen-independent prostate cancer (AIPC). The optimal dose and schedule of these agents have not been defined. Methods: Objectives are to evaluate the efficacy and safety of this triple drug regimen (CEE). Each treatment cycle consists of cyclophosphamide 50 mg/m2 p.o., etoposide 50 mg/m2 p.o. and estramustine 280 mg p.o. administered on days 1–14, every 28 days. Response was assessed by changes in size of measurable and non-measurable lesions (RECIST JNCI 92(3):205–216, 2000), and PSA levels (JCO 17(11):3461–7, 1999). Results: From October 2001 to August 2004, 24 subjects with AIPC were enrolled. 21 patients, who completed at least 2 cycles, are evaluable for toxicity and response. Median baseline characteristics: age 67.8 years (52–86); ECOG performance status 1.6 (0–3); PSA 302 ng/ml (26–2268); prior hormonal manipulations 3.7 (1–11), and 4/21 had prior chemotherapy. Total number of cycles administered: 95 with median of 4.5 cycles/patient. Response: 14/21 patients are still alive. Median survival has not been reached. PSA response: Out of 21 subjects, 6 (28%) had > 50% decrease and 5 (23%) had >75% decrease. Measurable disease: 7/21 patients had measurable lesions by RECIST criteria. Six had SD (86%) and 1 PD. 48% of the subjects experienced an improvement in their ECOG performance status and 71% reported improvement in their level of pain. Toxicity: Grade 3–4: 28% neutropenia, 5% thrombocytopenia, 5% anemia. 4 patients (27%) developed a thrombotic event. 3 with DVTs, two spontaneous and one after a 14-hours car trip. 1 subject with a strong history of cardiac complications had a myocardial infarction. Neutropenic fever requiring antibiotic use occurred in 2 patients. Grade 1–2: 90% fatigue, 71% alopecia, 71% nausea, 33% vomiting, 28% transaminitis, 19% anorexia and 14% breast tenderness. Conclusions: CEE is a well-tolerated, all oral, easy to administer and effective triple drug therapy for patients with metastatic androgen-independent prostate cancer. No significant financial relationships to disclose.
Multidirectional Myocardial Strain Analysis in Severe Aortic Stenosis Patients: Two-Dimensional Speckle Tracking Assessment Before and After Aortic Valve Replacement
Authors: Victoria Delgado, Rutger R. van Bommel, Frank van der Kley, Arnold C. T. Ng, Nina Ajmone Marsan, Laurens F. Tops, Michel I. M. Versteegh, Robert J. Klautz, Eduard R. Holman, Eernst E. van der Wall, Martin J. Schalij, Jeroen J. Bax
Journal: Journal of the American College of Cardiology (2009)
ERCC-1 gene expression as a predictor of outcome following platinum-based chemotherapy in epithelial ovarian cancer (EOC)
Authors: C. O. Michie, J. S. Clark, A. C. Hoffman, K. D. Danenberg, M. E. Stewart, T. Rye, C. M. McLachlin, A. R. Williams, D. J. Harrison, C. M. Gourley
Journal: Journal of Clinical Oncology (2008)

5564 Background: The excision repair cross-complementation group 1 (ERCC1) enzyme is a crucial component of the nucleotide excision repair pathway which removes cisplatin-induced DNA adducts. High ERCC1 mRNA expression has been associated with platinum resistance in several tumor types. We assessed the relationship between ERCC1 expression and survival in EOC treated with platinum-based chemotherapy. Methods: The Edinburgh Ovarian Cancer Database contains prospectively collected clinical data for all EOC patients treated in SE Scotland. This was screened for patients treated with platinum-containing chemotherapy. 145 archival formalin-fixed, paraffin-embedded (FFPE) tumor samples were recovered and microdissected. mRNA was isolated and quantitative Real Time- PCR was performed for ERCC1. The maximal chi-squared method was used to determine optimal ERCC1 cut-points. Differences in survival between patients whose tumors expressed high/low ERCC1 levels were then compared by Kaplan-Meier analysis. Results: First-line chemotherapy consisted of single agent platinum (69%), platinum-taxane combinations (30%) or a platinum-topotecan combination (1%). Using an ERCC1 cut-point at the 80th percentile to define high expression was found to predict a significantly worse progression-free survival (PFS; p=0.005) and overall survival (p=0.040). In addition, for patients treated with carboplatin and paclitaxel, it was shown that high ERCC1 expression was associated with a worse PFS (p=0.018). Conclusions: ERCC1 gene expression predicts the outcome following platinum-based chemotherapy in EOC. Contrary to the findings of the only other study with >100 patients addressing this issue, the relationship holds for carboplatin and paclitaxel as well as for platinum alone. These findings go some way towards identifying a patient group that is less responsive to standard platinum-based chemotherapy. Alternative treatment strategies should be sought in these patients and tested in the setting of a randomised trial of biomarker guided versus standard therapy. The fact that gene expression analysis can be performed on FFPE tissue increases the applicability of this technology. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Response Genetics Inc, Response Genetics Ltd Response Genetics Inc, Response Genetics Ltd Response Genetics Inc
A phase I pharmacokinetic study of PR-104, a hypoxia-targeting agent, in patients with solid tumors
Authors: M. B. Jameson, D. Rischin, M. Pegram, J. Gutheil, A. Patterson, W. Denny, W. Wilson
Journal: Journal of Clinical Oncology (2007)

3516 Background: PR-104 is a novel pre-prodrug (precursor of a prodrug) designed to form a cytotoxic nitrogen mustard (alkylating agent) in hypoxic regions of tumors. Following IV administration, PR-104 is converted by systemic phosphatases to the alcohol intermediate PR-104A, which, under hypoxic conditions, is reduced to form the active DNA-crosslinking mustard species PR-104H. This phase I trial defines a Maximally Tolerated Dose (MTD) and pharmacokinetics (PK) for this schedule. Methods: Patients (pts) with relapsed/recurrent solid tumors received PR-104 as a 1-hour IV infusion every 3 weeks with PK sampling on days 1–2 of cycle 1. Cohorts of ≥3 pts were treated starting at 135 mg/m 2 . Results: 23 pts have been enrolled: median age 51 years (range 29–72); 13 (57%) male. Most pts had received prior radiation or chemotherapy and had metastatic disease. Six dose levels (135, 216, 354, 550, 770, and 1,100 mg/m 2 ) have been evaluated. Dose-limiting toxicity (DLT) was observed in one patient at 1,100 mg/m 2 (grade 3 fatigue) and this dose level was expanded to 6 pts. In the first 4 cohorts, 54 adverse events (AEs) were considered drug-related by the investigator including nausea (26% of all AEs), fatigue (19%), vomiting (11%) and anorexia (6%); remaining AEs each constituted &lt; 3% of the total. Of 16 grade 3 AEs, 3 were considered drug-related by the investigator (anemia, dehydration and vomiting). Prophylactic anti-emetics largely prevented nausea and vomiting at higher doses, at which dose-related decreases in neutrophils and platelets were seen. Conclusions: PR-104 has shown manageable toxicities similar to other cytotoxic agents, with no serious mucositis, diarrhea or alopecia. DLT is likely to be myelosuppression based on preclinical and current clinical data, with the MTD close to 1,100 mg/m 2 . The preclinical PK target for the alcohol intermediate has been exceeded at higher doses and, while no objective responses have been documented, reductions in tumor volume have been seen at these doses. [Table: see text] No significant financial relationships to disclose.
Phase II intergroup study of sorafenib (S) in advanced soft tissue sarcomas (STS): SWOG 0505
Authors: C. W. Ryan, M. von Mehren, C. J. Rankin, J. R. Goldblum, G. D. Demetri, V. H. Bramwell, E. C. Borden
Journal: Journal of Clinical Oncology (2008)

10532 Background: S is an oral multi-kinase inhibitor of VEGFR, PDGFR, Raf, Flt-3 and c-KIT. STS of vascular derivation (VS: angiosarcoma, hemangiopericytoma) express VEGFR and VEGF mRNA. Prognosis for high grade liposarcomas (LPS) and leiomyosarcomas (LMS) has been correlated with levels of serum VEGF. We therefore studied S in patients (pts) with advanced VS, LPS and LMS. Methods: Pts with advanced VS, LPS and LMS with 0–1 prior chemotherapies for advanced disease were treated with S 400 mg BID. Solitary fibrous tumors were included as VS because of morphologic similarity to hemangiopericytoma. Pts were required to have adequate blood parameters, PS of 0–1, and no uncontrolled hypertension or history of thromboembolic disease. Prohibited medications included therapeutic anticoagulation, combination anti-retroviral therapy, and prior VEGFR or MAPK inhibitors. 15 pts were accrued to each of three strata: VS, LPS, LMS. If ≥1 RECIST responses were seen in a stratum, an additional 10 pts were to be added to that stratum. Results: 51 pts were accrued between 3/2006 and 2/2007. 12 pts were ineligible due to: abnormal lab data (6), >1 prior chemotherapy (2), and incorrect diagnosis on pathology review (4). One pt did not receive any therapy. 38 pts are evaluable for toxicity and 37 for response. Most common AEs were hand-foot, fatigue and diarrhea. Grade 3–4 AEs included amylase/lipase (7), hand foot/rash (6), liver function tests (4), diarrhea (4), electrolytes (4), fatigue (2), hypertension (2), and nausea, vomiting, constipation, abdominal pain, pancreatitis, hemoglobin, platelets (1 each). There were no RECIST responses, but unconfirmed responses were observed. Of note, 7/9 patients in the VS cohort had SD or better and 2 remained on treatment >1 year. With 13 patients deceased, overall median PFS and OS were 3 and 13 months, respectively. Conclusions: S monotherapy did not result in RECIST responses in VS, LPS or LMS. Favorable PFS was observed in pts with advanced VS and further study in these tumors is warranted. VS (n=9) LPS (n=10) LMS (n=19) Response PR/SD 1*/6 0/2 1*/6 PFS (95% CI) 4.7 mo (3.8–6.5) 1.7 mo (1.6- 2.1) 1.8 mo (1.7–8.1) OS (95% CI) 13.5 mo (7.3–13.5) 11.7 mo (5.2-NR) 14.3 mo (13.2- 14.3) * unconfirmed Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Ariad, Bayer, Infinity, Johnson and Johnson, Novartis, Onyx, Pfizer, PharmaMar Bayer, Novartis, Onyx, Pfizer, PharmaMar Amgen, Ariad, Bayer, Bristol-Myers Squibb, Infinity, Johnson and Johnson, Novartis, Onyx, OSI, Pfizer, PharmaMar Ariad, Infinity, Johnson and Johnson, Novartis, Pfizer, PharmaMar