tbuckley/cabot-search huggingface dataset:
E3803: Updated results on phase II study of a weekly schedule of BMS-247550 for patients with castrate refractory prostate cancer (CRPC)
Authors: G. Wilding, Y. Chen, R. P. DiPaola, M. A. Carducci, G. Liu
Journal: Journal of Clinical Oncology (2008)

5070 Background: BMS-247550 (ixabepilone) is an epothilone B analogue with activity in taxane-resistent cancer cell lines. Ixabepilone has been administered using an every 3 week schedule with significant neutropenia observed. Here we assess the activity and toxicity of ixabepilone, administered using a weekly schedule, in men with CRPC. Methods: Patients with metastatic CRPC were treated with ixabepilone at 20 mg/m2 IV weekly x 3, in 4 week cycles. This non-comparative study stratified patients to either a chemonaive (CN), prior-taxane (Tax) only, or two prior cytotoxic (TCx) chemotherapy arm. The trial was powered to detect a 50% PSA reduction using Consensus Criteria in at least 50% (91% power, α=0.10) for the CN stratum and 30% (power 90%, α=0.10) for the Tax and TCx strata. Results: In total, 96 pts were enrolled of which 92 were eligible (31 CN, 36 Tax, and 25 TCx) for the primary response determination in this study. PSA responses were seen in 10 (32.3%), and 8 pts (22.2%) for the CN and Tax arms respectively. An additional cohort of pts with measurable disease was subsequently registered in the CN and Tax arms to define the objective response with partial objective responses seen in 5 pts (20.8%) in the CN arm and 2 pts (7.1%) in the Tax arm. Significant (grade 3/4) neutropenia was seen in 6 (15.4%), 7 (14.6%), and 6 (23.1%), and grade 3/4 sensory neuropathy in 8 (20.5%), 13 (27.1%), and 7 (26.9%) for CN, Tax, and TCx respectively. Grade 3/4 thrombocytopenia was infrequent and seen in one pt on the TCx arm. Other common toxicities included fatigue (23.9%), motor neuropathy (11.5%), anorexia (9.7%), and nausea (6.2%) for all pts combined. Conclusions: BMS-247550 was found to have an acceptable toxicity profile when administered using a weekly schedule. Clinically significant myelosuppression in the no prior chemotherapy arm was slightly improved when compared with prior studies using the every 3 week schedule. Although single agent activity was observed, the overall response did not meet predetermined levels of activity. However, the response seen in the second-line setting are encouraging and meet or exceed current available therapies in this difficult patient population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb
Phase I study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer
Authors: J. P. Machiels, C. Sempoux, P. Scalliet, J. C. Coche, B. Coster, J. L. Canon, J. Kerger, E. Van Cutsem, M. Peeters, K. Haustermans
Journal: Journal of Clinical Oncology (2006)

3552 Background: Capecitabine has the potential to replace 5-FU as standard agent in combination with radiotherapy in rectal cancer. Cetuximab is a monoclonal antibody directed against the epidermal growth factor receptor. Both agents are active in the treatment of colorectal cancer and have demonstrated radiosensitising properties. The aim of this study was to assess the feasibility of combining cetuximab and capecitabine with concurrent radiation in the preoperative treatment of patients with rectal cancer. Methods: Twenty patients with rectal cancer (T3-T4 and/or N+, endorectal ultrasound) received radiotherapy (1.8 Gy, 5 days a week over 5 weeks, total dose 45 Gy, 3D conformal technique) in combination with cetuximab (initial dose 400 mg/m 2 given one week before the beginning of radiation followed by 250 mg/m 2 /week for 5 weeks) and 2 different doses of capecitabine for the duration of radiotherapy (650 mg/m 2 twice-daily, first dose level; 825 mg/m 2 twice-daily, second dose level, including weekends). During treatment all patients were scored weekly using the NCI-CTC v.2.0. Dose-limiting toxicity (DLT) was defined acccording to Dunst (JCO 2002). Six to 8 weeks after the end of chemoradiation surgery was performed. Results: Four and six patients were treated at the first and second dose level of capecitabine, respectively. No DLT occurred at either capecitabine dose. Ten additional patients were treated at the higher dose level. Out of these 20 patients, Grade 3 toxicity included diarrhea (n=2), rectal pain (n=5), ileitis (n=2), radiation dermatitis (n=1) and neutropenia (n=1). The most frequent grade 1/2 side effects were acneiform rash (n=16, 80%), fatigue (n=12, 60%), and diarrhea (n=12, 60%). Until now, 2 pathological complete responses were observed in 19 evaluable patients. Conclusions: Preoperative radiotherapy in combination with capecitabine and cetuximab is feasible and well-tolerated with promising efficacy results. The recommended doses for phase II evaluation are capecitabine 825 mg/m 2 twice-daily without interruption during the duration of radiotherapy and cetuximab at an initial dose of 400 mg/m 2 followed by 250 mg/m 2 /week. No significant financial relationships to disclose.
In Vivo Effects of Flt3/Flk2 Ligand on Mobilization of Hematopoietic Progenitors in Primates and Potent Synergistic Enhancement With Granulocyte Colony-Stimulating Factor
Authors: Thalia Papayannopoulou, Betty Nakamoto, Robert G. Andrews, Stewart D. Lyman, Minako Y. Lee
Journal: Blood (1997)
European benchmarking of lung cancer care
Authors: N. Wilking, D. Hogberg, B. Jonsson
Journal: Journal of Clinical Oncology (2008)

17535 Background: In Europe, lung cancer is the third most common form of cancer following breast cancer and colorectal cancer. Poor survival rates make lung cancer the most common cause of cancer death. Method: We have studied management and organization of lung cancer care in 20 European countries: Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, The Netherlands, Norway, Poland, Portugal, Russian Federation, Spain, Sweden, Switzerland and the United Kingdom. We have compared outcomes of lung cancer care, measured by dividing incidence with prevalence using data from the GLOBOCAN 2002 database. We have also analyzed policies promoting and restricting patient access to the most appropriate treatment. Results: There are large variations between countries in terms of incidence and mortality and the outcome of lung cancer care. United Kingdom, Denmark, Poland, the Czech Republic, Ireland, Russia, Hungary and Norway perform below the average of countries in the study. There are several determinants of outcomes of lung cancer care, and the direct correlation and causation must be interpreted with caution. The countries with best outcome have a higher expenditure on health care, with the exception of UK, Ireland and Denmark standing out as having among the poorest outcomes in spite of overall health expenditures at the median. Lack of investments have also led to a serious shortage of radiation facilities in many countries. The organization of cancer care in many of the poorest performing countries is fragmented and treatment unevenly accessible to patients. Policies, procedures, budgeting systems and economic conditions delay market introduction and restrict patient access to modern lung cancer drugs (docetaxel, gemcitabine, paclitaxel, and vinorelbine). The uptake and use of these drugs (sales/ per lung cancer death) is below the European average in countries with poorer outcome. The same is true for the most recent drugs introduced, erlotinib and pemetrexed. Conclusions: The high burden of the lung cancer diseases urges for improvement of lung cancer care. Regulations, priorities, funding, and organization of lung cancer care must be coordinated to provide all patients with the most appropriate treatment alternative. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche
Mutation supply and relative fitness shape the genotypes of ciprofloxacin-resistant <i>Escherichia coli</i>
Authors: Douglas L. Huseby, Franziska Pietsch, Gerrit Brandis, Linnéa Garoff, Angelica Tegehall, Diarmaid Hughes
Journal: Molecular Biology and Evolution (2017)

Ciprofloxacin is an important antibacterial drug targeting Type II topoisomerases, highly active against Gram-negatives including Escherichia coli. The evolution of resistance to ciprofloxacin in E. coli always requires multiple genetic changes, usually including mutations affecting two different drug target genes, gyrA and parC. Resistant mutants selected in vitro or in vivo can have many different mutations in target genes and efflux regulator genes that contribute to resistance. Among resistant clinical isolates the genotype, gyrA S83L D87N, parC S80I is significantly overrepresented suggesting that it has a selective advantage. However, the evolutionary or functional significance of this high frequency resistance genotype is not fully understood. By combining experimental data and mathematical modeling, we addressed the reasons for the predominance of this specific genotype. The experimental data were used to model trajectories of mutational resistance evolution under different conditions of drug exposure and population bottlenecks. We identified the order in which specific mutations are selected in the clinical genotype, showed that the high frequency genotype could be selected over a range of drug selective pressures, and was strongly influenced by the relative fitness of alternative mutations and factors affecting mutation supply. Our data map for the first time the fitness landscape that constrains the evolutionary trajectories taken during the development of clinical resistance to ciprofloxacin and explain the predominance of the most frequently selected genotype. This study provides strong support for the use of in vitro competition assays as a tool to trace evolutionary trajectories, not only in the antibiotic resistance field.
Abstract 16142: Grad 3-Ischemia (QRS Complex Distortion) as a Predictor of Myocardial Damage as Assessed by Cardiac Magnetic Resonance Imaging and Clinical Prognosis in Patients With ST-Elevation Myocardial Infarction
Authors: Karl-Philipp Rommel, Hadil Badarnih, Steffen Desch, Matthias Gutberlet, Gerhard Schuler, Holger Thiele, Ingo Eitel
Journal: Circulation (2014)

Introduction: Predicting the extent of myocardial damage on early electrocardiographic (ECG) findings could be helpful for improved risk stratification in patients with acute reperfused ST-elevation myocardial infarction (STEMI). Distortion in the terminal portion of the QRS complex (so called grade 3 ischemia, G3I) has been associated with adverse outcomes in STEMI patients. The correlation of G3I with infarct size and microvascular injury is not well defined. Objective: To studied the relation of G3I with myocardial damage as assessed by CMR and the association of G3I with adverse clinical outcomes in a STEMI population treated by primary percutaneous coronary intervention (PCI). Methods: We analyzed the ECGs of 572 consecutive STEMI patients regarding the presence or absence of G3I. G3I was defined as: 1) complete loss of S waves in 2 adjacent leads with typical Rs configuration (i.e. V1-V3), or 2) ST-J point to R wave amplitude ratio &gt;0.5 in other leads with qR configuration. CMR was performed within 1 week after infarction for comprehensive assessment of myocardial damage using a standardised protocol. The primary clinical end-point was major adverse cardiac events (MACE) defined as death, reinfaction and readmission for congestive heart failure within 12 months after the index event. Results: G3I was present in 186 (32%) patients. The presence of G3I was associated with larger infarct size (18.3%LV [10.4 to 27.6] versus 16.5%LV (8.2 to 23.5), p=0.01), late microvascular obstruction (0.4%LV [0 to 2.7] versus 0%LV [0 to 1.5], p= 0.05, presence of intramyocardial hemorrhage (41 versus 32%, p=0.04) and less myocardial salvage (47 [28 to 64] versus 53 (35 to 68), p=0.01). G3I was associated with a significant higher incidence of MACE (p=0.01) and was identified as an independent predictor of MACE in Cox regression analysis (Hazard ratio 2.19 [1.10 to 4.38], p=0.03). Conclusions: This largest study to date correlating G3I on the admission ECG with CMR markers of myocardial damage demonstrates that G3I is significantly associated with infarct size, myocardial salvage and reperfusion injury in a STEMI population reperfused by primary PCI. Moreover, G3I was independently associated with MACE.
Renal cell carcinoma of end-stage renal disease
Authors: M D Hughson, L Schmidt, B Zbar, S Daugherty, A M Meloni, F G Silva, A A Sandberg
Journal: Journal of the American Society of Nephrology (1996)

Renal cell carcinomas (RCC) are responsible for the deaths of 3% to 4% of patients with ESRD. The clear cell carcinoma of the kidney, which comprises 80% of sporadic RCC within the general population, shows a deletion of gene sequences in the short arm of chromosome 3 (3p) in as many as 100% of cases. The von Hippel-Lindau tumor suppressor gene at 3p25-26 is found to be mutated in the nondeleted allele in 57% of these sporadic clear cell carcinomas. This study was undertaken to determine the histopathologic types of RCC occurring in ESRD patients in the United States and to investigate the frequency with which 3p genetic changes can be found in these ESRD tumors. Seventeen end-stage kidneys containing RCC were collected from 15 ESRD patients at ten US medical centers. The tumors were classified by Thoenes' histopathologic typing. DNA extracted from paraffin blocks of tumor and nontumorous tissue was analyzed by single-stranded conformational polymorphism analysis for von Hippel-Lindau mutations and by microsatellite amplification for deletion of 3p gene sequences. Twenty-one RCC were identified in the 18 kidneys. The 21 RCC were classified histopathologically as follows: clear cell, compact, three cases; chromophilic, tubulopapillary, 15 cases; chromophilic, compact, three cases. Among the three clear cell carcinomas, one showed 3p genetic loss. None of the chromophilic RCC showed a 3p deletion and none of 19 tumors studied by single-stranded conformational polymorphism analysis disclosed von Hippel-Lindau mutations. In contrast to the general population, clear cell RCC with 3p abnormalities represent only a small proportion of the renal carcinomas in this collection of ESRD tumors. The findings indicate that the genetic changes underlying the development of most ESRD tumors are different from those occurring in sporadic clear cell RCC and do not characteristically involve the inactivation of a 3p tumor suppressor gene.
Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer.
Authors: F A Holmes, T Madden, R A Newman, V Valero, R L Theriault, G Fraschini, R S Walters, D J Booser, A U Buzdar, J Willey, G N Hortobagyi
Journal: Journal of Clinical Oncology (1996)

To determine whether a schedule-dependent interaction occurs when paclitaxel and doxorubicin are administered sequentially.Ten patients with metastatic breast cancer received paclitaxel 125 mg/m2 over 24 hours either immediately before or after doxorubicin 48 mg/m2 over 48 hours as the initial chemotherapy treatment. Two such courses were given, and the sequence of administration was reversed after course 1. In cohort 1, paclitaxel preceded doxorubicin for course 1. In cohort 2, doxorubicin preceded paclitaxel for course 1. Doxorubicin levels were measured serially during the infusion and for 24 hours following it. Patients were assessed clinically for the occurrence of stomatitis and infection and granulocyte counts were measured twice weekly.Eight patients had complete pharmacokinetic sampling for both courses. The mean end-of-infusion plasma doxorubicin concentrations (Cmax) were 70% higher in the paclitaxel-doxorubicin sequence compared with the reverse sequence (45 +/- 8 ng/mL v 26 +/- 5 ng/ mL). The mean doxorubicin clearance was 32% lower in the paclitaxel-doxorubicin sequence (34.3 +/- 10.3 L/h v 51.6 +/- 16.1 L/h, P < .01). Clinically, hematologic and mucosal toxic effects were worse in the paclitaxel-doxorubicin sequence. The median absolute granulocyte count was 0.2/microL in the paclitaxel-doxorubicin sequence and 1.3/microL in the doxorubicin-paclitaxel sequence. Seven of 10 patients who received the paclitaxel-doxorubicin sequence had grade 2 (n = 4) or 3 (n = 3) stomatitis, while only one of 10 patients who received the doxorubicin-paclitaxel sequence had grade 2 stomatitis and none had grade 3.When paclitaxel by 24-hour infusion precedes doxorubicin by 48-hour infusion, doxorubicin clearance is reduced by nearly one third, which results in grade 2 and 3 stomatitis. To prevent this effect when paclitaxel (by 24-hour infusion) and doxorubicin are administered sequentially, doxorubicin should be given first. The mechanisms for this effect are under investigation.
Characterization of new Ashkenazi Jewish founder mutations in MSH6 causing Lynch syndrome.
Authors: L. Raskin, F. Schwenter, M. Freytsis, M. Tischkowitz, D. A. Levine, S. Narod, S. Gallinger, G. Rennert, W. Foulkes, S. B. Gruber
Journal: Journal of Clinical Oncology (2010)

1514 Background: Founder mutations are an important cause of Lynch syndrome and facilitate genetic testing in specific ethnic populations. Two recently described mutations in MSH6 are putative founder mutations, warranting careful clinical and genetic analysis. Methods: MSH6 exon 9 insertion and deletion mutations were analyzed in 2,660 colorectal cancer (CRC) cases and 3,270 healthy controls of Ashkenazi Jewish (AJ) descent from population-based and hospital-based case-control studies in Israel, Canada and the USA. Microsatellite markers and single nucleotide polymorphisms were analyzed in carriers from case-control studies and clinical series. Age of the mutation was estimated using a Bayesian MCMC linkage disequilibrium mapping approach (DMLE+ software). Results: We characterized two recently described mutations in MSH6 exon 9, c.3984_3987dupGTCA (MSH6 dup) and c.3959_3962delCAAG (MSH6 del). MSH6 dup was found in 8 of 2,660 cases and 1 of 3,270 controls, consistent with a very high risk of CRC (odds ratio [OR] = 9.8, 95% confidence interval [CI] = 1.2-78.7, Fisher's exact p = 0.0136). Of note, the only control carrying MSH6 dup had a remote history of endometrial cancer (age 61) and developed cecal cancer at age 76, several years after being ascertained as a control without CRC. The MSH6 del was less common, identified in 3 of 2660 cases and no controls. Survival analysis indicates a trend of better overall survival among CRC patients with MSH6 dup or del (hazard ratio [HR] = 0.7, 95% CI = 0.5-1.1) compared to CRC patients without MMR mutations. Haplotype analysis demonstrated separate conserved haplotypes for each mutation. Four recombination events in MSH6 dup carriers allowed estimation of the age of the mutation, which arose ∼650 years ago in the fourteenth century. No carriers of either mutation were identified in 450 Sephardi Jewish cases or 490 Sephardi Jewish controls. Conclusions: MSH6 truncating mutations c.3984_3987dupGTCA and c.3959_3962delCAAG are founder mutations in Ashkenazi Jews that cause Lynch syndrome. Although less common than other Jewish founder mutations, these mutations substantially contribute to CRC in this ethnic group and are relevant for the diagnosis and management of AJ Lynch syndrome patients. No significant financial relationships to disclose.
1024 RELAXIN IS A RENAL VASODILATOR IN EXPERIMENTAL MODELS OF CIRRHOSIS AND A POTENTIAL NOVEL THERAPY FOR HEPATORENAL SYNDROME (HRS) IN HUMANS
Authors: V.K. Snowdon, A. Pellicoro, P. Ramachandran, W. Mungall, R. Lennen, M. Jansen, R. Aucott, T. Kendall, M. Bailey, J. Hughes, J.P. Iredale, J.A. Fallowfield
Journal: Journal of Hepatology (2013)
Abstract 13521: C-Terminal Pro Endothelin 1 Precursor Fragment Plasma Levels Correlate with Hemodynamic Parameters in Patients with Scleroderma-Associated Pulmonary Arterial Hypertension
Authors: Daniel Dumitrescu, Sonja Schnorbach, Pia Moinzadeh, Nicolas Hunzelmann, Stephan Rosenkranz
Journal: Circulation (2012)
The impact of specific treatment patterns on survival for children with low and high grade gliomas: analysis of the 1973–2002 SEER data
Authors: W. Woods-Swafford, J. F. Kuttesch Jr., J. Barnholtz-Sloan
Journal: Journal of Clinical Oncology (2008)

10016 Background: Gliomas account for greater than 50% of all pediatric CNS tumors. Investigations into treatment effects and long-term prognosis are limited to single institutional reviews with small sample sizes. We examined trends in survival of pediatric gliomas in the United States using population-based data from the Surveillance, Epidemiology and End Results (SEER) program. Methods: Study subjects from the SEER Public-use database included 2,799 pediatric and adolescent patients diagnosed with microscopically confirmed primary glial tumors from 1973–2002 with follow-up through 2004. Frequencies of prognostic variables of interest were assessed for differences by time period (1973–79, 1980–89, 1990–02) using chi-square tests. Survival analyses were performed using Kaplan Meier and Cox regression models. Results: Evaluation of histologic types over time indicated a shift in distribution from astrocytoma, NOS to WHO Grade I/II and oligodendroglial tumors. WHO grade III/IV and Glioma histology types had worse survival when compared to those with astrocytoma, NOS for all periods. In the most recent period, Blacks had an increased risk of death compared to Whites (HR=1.51, CI 1.06,2.14). Surgical management alone was consistently and significantly associated with improved survival (35% decreased risk of death in 1973–79 improving to a 77% decreased risk of death in 1990–02) whereas radiation alone following biopsy (∼2 fold increased risk of death in all time periods) and biopsy alone were associated with worse survival when compared to a combination of radiation and surgery. Subset analyses evaluating extent of resection on survival showed any surgical intervention significantly decreased the risk of death (∼80% decreased risk of death) but the addition of radiation counteracted this decrease. Conclusions: Gliomas treated with radiation alone following biopsy had increased risk of death. Surgical resection, regardless of extent, decreased the risk of death significantly. However, combining radiation with surgery eliminated this survival advantage. In a therapy era focused on reducing neuropsychological deficits, these findings mandate further investigation into the role of radiation therapy in this population. No significant financial relationships to disclose.
Recontact and Recruitment of Young Adults Previously Enrolled in Neonatal Herpes Simplex Virus Research
Authors: Holly A. Taylor, Ellen Kuwana, Benjamin S. Wilfond
Journal: The American Journal of Bioethics (2015)

"Recontact and Recruitment of Young Adults Previously Enrolled in Neonatal Herpes Simplex Virus Research." The American Journal of Bioethics, 15(10), pp. 56–57
Breast Cancer — Patient Choice of Treatment: Preliminary Communication
Authors: J J Ashcroft, S J Leinster, P D Slade
Journal: Journal of the Royal Society of Medicine (1985)

Forty patients who have undergone treatment for breast cancer (mastectomy or lumpectomy plus radiotherapy) were assessed, both preoperatively and at intervals up to one year following surgery, using tests of anxiety, depression, body satisfaction, marital adjustment, self-esteem, sociability and life change. The women were also interviewed to assess degree of concern about the disease, appearance and treatment. Wherever appropriate, patients were given a choice of treatment. Very little adverse psychosocial reaction has been found. It would appear that this is largely because most patients could opt for treatment which resulted in minimal disfigurement.