bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I pharmacokinetic (PK) study of the Epothilone B analogue, ixabepilone (BMS-247550) in patients (pts) with advanced malignancies and varying degrees of hepatic impairment. A SWOG Early Therapeutics Committee and NCI Organ Dysfunction Working Group Trial
Authors: Takimoto C. H. , Liu P. Y. , Lenz H. , Remick S. , Mulkerin D. , Mani S. , Synold T. W. , Ramanathan R. K. , Ivy P. , Davies A. M. 
Published: March 2020

2004 Background: Ixabepilone (Ix) is a semisynthetic Epothilone B derivative with antitumor activity in breast cancer pts previously treated with taxanes and in chemotherapy naïve prostate cancer pts. Because Ix is hepatically metabolized, the following study was performed to define dosing recommendations for pts with varying degrees of hepatic impairment. Methods: Pts were classified into hepatic dysfunction cohorts defined by a modified NCI Organ Dysfunction Working Group (NCI) schema. Starting doses were escalated in new pts independently in each cohort using a standard phase I design. Results: Overall, 71 pts were registered and 66 pts are evaluable for cycle 1 dose limiting toxicities (DLTs). Ix was administered at 10–40 mg/m2 as 10 minute infusions q3wks. Dose levels reached 40, 40, 30, and 20 mg/m2 for pts in Groups A, B, C and D, respectively. In group B, DLTs were observed in 2/12 pts treated at 30 mg/m2 (febrile neutropenia, grade (gr)3 mucositis, and gr3 diarrhea) and 3/8 pts at 40 mg/m2 (febrile neutropenia, gr3 nausea/vomiting, gr3 hyponatremia). In group C, DLTs were observed in 2/10 pts at 20 mg/m2 (gr3 dehydration, gr3 muscle weakness) and 2/3 pts at 30 mg/m2 (febrile neutropenia, gr 4 neutropenia). In group D, DLTs were observed in 2/9 pts at 10 mg/m2 (gr3 infection and gr3 renal failure) and 1/5 pts treated at 20 mg/m2 (gr3 infection). Otherwise, Ix was generally well tolerated. Pharmacokinetic parameters are currently being analyzed. No objective responses have been documented. Conclusions: Ix dose reduction is required in pts with moderate to severe liver dysfunction. The recommended Ix dose for group C patients is 30 mg/m2. To define the impact of mild liver impairment, Group B has been stratified further into B1 (Bili ≤ ULN and AST > ULN) and B2 (ULN < Bili ≤ 1.5 × ULN, AST any). Accrual continues to groups B1 and B2 at 40 mg/m2 and group D at 20 mg/m2. [Table: see text] [Table: see text]
Effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone
Authors: Goel S. , Goldberg G. , Iacono L. C. , Cohen M. , Griffin T. , Gollamudi R. , Desai K. K. , Chaudhary I. , Mani S. 
Published: March 2020

2005 Background: Ixabepilone (Ixa) is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixa has shown clinical activity in a broad range of tumors. Oxidative metabolism by CYP3A4/5 appears to be a prominent route of Ixa biotransformation in vitro. As a single agent, the recommended dose is 40 mg/m2 over 3 hours once every three weeks. Methods: This was an open-label, sequential study to assess the effect of CYP3A4/5 inhibition on the pharmacokinetics (PK) and pharmacodynamics (PD) of Ixa. Ketoconazole (K) was used as a model inhibitor of CYP3A4/5. Patients were administered a single 10 (n=4), 20 (n=12), 25 (n=7) or 30 (n=4) mg/m2 intravenous (iv) infusion of Ixa with K (400 mg/d orally x 6 days) during cycle 1, and a single 40 mg/m2 iv infusion of Ixa during Cycle 2. Cycles were repeated every 21 days. Detailed PK and PD analysis was performed in cycles 1 and 2. Results: The observed adjusted geometric mean of Ixa AUC for subjects with K was 2892 vs. 1628 ng/mL*hr in subjects without K. The ratio of the geometric means of normalized Ixa AUC and Cmax in Cycle 1/Cycle 2 were 1.78 and 1.07, respectively. The percent of peripheral blood mononuclear cells with tubulin bundle formation after administration of 20 mg/m2 Ixa with K was similar to that observed with single agent Ixa at a dose of 40 mg/ m2. The maximum tolerated dose of Ixa with K was 20 mg/m2. Dose limiting toxicities of Ixa with K were similar to those observed in previous Phase 1 studies of single agent Ixa and included prolonged neutropenia, febrile neutropenia, mucositis, elevated liver function enzymes, and fatigue. Conclusions: Oxidative metabolism by CYP3A4/5 appears to be a clinically important route of Ixa biotransformation. Inhibition of CYP3A4/5 by K affects the Ixa tolerable dose, increases the AUC and results in similar PD effects at half the recommended dose. [Table: see text]
Extent of bronchioloalveolar pattern and expression of the epidermal growth factor receptor in surgically resected lung adenocarcinomas
Authors: Dahabreh I. J. , Janinis J. , Karagiani E. A. , Dountsis A. , Vasilikos K. , Spiliadi H. T. , Dahabreh I. J. 
Published: March 2020

20065 Background: An increasing number of studies are exploring relations between the bronchioloalveolar differentiation of adenocarcinomas and clinical, radiological and molecular parameters. We investigated the potential relation between the extent of the bronchioloalveolar carcinoma (BAC) component of adenocarcinomas and the expression of the epidermal growth factor receptor (EGFR) protein. Methods: We retrospectively reviewed data from all patients who underwent surgery for lung cancer in our hospital between February 1, 2001 and May 31, 2005 (n = 366), and in whom pathologic analysis had revealed an adenocarcinoma histologic subtype. Paraffin embedded tissue samples were retrieved and re-examined. Samples exhibiting either a pure BAC histology or a mixed adenocarcinoma histology with a >50% BAC component (n = 46) were selected for EGFR expression analysis by immunohistochemical staining. Patient demographics, stage and tumor differentiation data were recorded. Histological analysis was carried out using the WHO 1999/2004 criteria for lung cancers. For EGFR expression evaluation, samples were assigned a score ranging from 0 to +3. Expression was considered positive when the score was +1 or higher. Statistical analysis was performed using the chi-square test. Results: Of the 46 tumor samples examined, 10 had a BAC component of 50–79% (group A), 18 had BAC component of 80–99% (group B) and 18 exhibited a pure BAC histology (group C). Male/female ratio was 61.3%/38.7%. Mean age at presentation was 61.6 years. Among group A, 4 patients were EGFR positive and 6 were EGFR negative. 16 group B patients were EGFR positive and 2 were EGFR negative. Similarly, 16 group C patients were EGFR positive and 2 were EGFR negative. This distribution suggests that EGFR is more often expressed with increasing BAC component (p = 0.0041). No correlation was observed between demographics and EGFR expression or the extent of BAC pattern. Conclusions: EGFR expression is related to the extent of the BAC component in adenocarcinomas, with statistical significance. Study of a larger number of patients and correlation of this finding with EGFR and Ras mutational status and responsiveness to therapy are warranted. No significant financial relationships to disclose.
Ki-67/MIB-1 as prognostic factor for locoregional recurrence after adjuvant radiation therapy in early breast cancer: A population-based study
Authors: Mucciarini C. , Giovanardi F. , Masoni F. , Cirilli C. , Artioli F. , Cagossi K. , Sarti S. , Hakim R. , Iop A. , Federico M. 
Published: March 2020

20074 Background: Adjuvant radiotherapy (RT) has been shown to decrease the risk of locoregional recurrence (LRR) in women with infiltrating early breast cancer, with or without an associated systemic treatment. RT is more effective on high proliferating cells and we could evaluate the proliferative activity of any cancer through Ki-67/ MIB-1 antibodies. Adjuvant RT for breast cancer could show a greater efficacy to prevent LRR in the higher proliferating cancers. Methods: We conducted a retrospective analisys on all the 5004 cases of infiltrating early breast cancer diagnosed in the Province of Modena between 1989 and 2004 and registered in the Modena Cancer Registry. Beneath them we were able to find data about 1885 women who underwent adjuvant RT. We analyzed the data concerning this population on the basis of number of LRR and Ki-67 labeling index. Since the lack of a worldwide agreed Ki-67 cut off value representing an high proliferation rate of cell activity, we examinate our data in an univariate analisys establishing for the Ki-67 three different cut offs values ( 20%, 30% and 50%). Results: Between 1885 women who underwent RT, 91 ( 4.8%) had a LRR. Median follow-up was 6 years (range 1–15 years). Using a cut off for the Ki-67 of 20% to fix an high cell proliferation, 67 women had a Ki-67 < 20% and 24 ≥ 20%. The p-value was 0.176. Increasing the cut off to the 30%, 75 women had a Ki-67 < 30% and 16≥ 30%. The p-value was 0.048. Finally, considering the Ki-67 value to 50%, 87 women had a value < 50% and 4 ≥ 50%, with a p-value of 0.992. In our analisys, it doesn’t seem that an increasing Ki-67 value would be correlated with a higher LRR. We are considering in a further analisys the weight of the different sistemic therapies on our results. Conclusions: The Ki-67 expression doesn’t seem to be considered a statistically significant prognostic factor for LRR in early breast cancer after adjuvant RT. No significant financial relationships to disclose.
Homocysteine (HC) level as possible predictor of pemetrexed efficacy
Authors: Symanowski J. , Simms L. , Melemed A. 
Published: March 2020

20078 Background: Pemetrexed is a novel anticancer agent clinically active in several solid tumors, including malignant pleural mesothelioma (MPM), non-small cell lung cancer (NSCLC), and breast cancer. Pemetrexed’s anticancer activity is believed to be related to its inhibition of 3 enzymes involved with folate metabolism and DNA synthesis. Some side effects associated with its clinical activity are more pronounced if a patient (pt) has a folate deficiency and high HC levels (Niyikiza et al, Ann Oncol 1998). Given this connection, we hypothesized that high HC levels might predispose a pt to pemetrexed anticancer activity. In a related question, we examined if baseline HC levels varied among different cancers. Methods: To investigate these hypotheses, plasma HC levels were examined from pts in the pemetrexed-containing arm of a phase III MPM trial (N = 226; Vogelzang, JCO 2003); a phase III NSCLC trial (N = 265; Hanna, JCO 2004); and a phase II breast cancer trial (data pooled from 600 and 900 mg/m2 groups) (N = 92; Llombart, ASCO 2006). For each study, HC (high vs low) was used as a prognostic indicator variable for overall survival (OS) and progression-free survival (PFS). Different cut points distinguished pts with high vs low HC, and final analysis results were based on the optimal cut point that yielded the largest Wald chi-square value (smallest p-value). Results: Average baseline HC levels were similar for each trial: 11.0, 10.6, and 10.6 μmol/L for the MPM, NSCLC, and breast trial, respectively. The MPM data suggested that high HC pts had longer OS (all hazard ratios [HRs] <1). The NSCLC data showed comparable OS times regardless of HC level. MPM and NSCLC data for PFS was similar to OS results. PFS from the breast cancer study was also similar for both HC groups (HR ∼1). Conclusions: Average baseline HC level did not suggest differences in nutritional status of the 3 pt populations. Data examination from the 3 studies yielded contradictory results, suggesting that high HC level is not a predictor of a better efficacy response to pemetrexed. [Table: see text] [Table: see text]
The analysis of NBS-1 gene mutation [657del(5)] in exon 6 in the population of 472 sporadic breast cancer patients in the Czech Republic
Authors: Melter J. , Pazdrova G. , Janku F. , Kleibl Z. , Novotny J. , Petruzelka L. 
Published: March 2020

20087 Background: Nijmegen breakage syndrome (NBS) caused by mutation [657del(5)] in exon 6 of NBS-1 is an autosomal recessive disorder with microcephaly, immunodeficiency, radiosensitivity, and predisposition to lymphoid malignancies. Recently, high frequency of NBS-1 mutation was found in some Slavic populations. Because NBS-1 heterozygotes may have high incidence of neoplastic changes, there is an urgent need to clarify the role of NBS-1 mutation in breast cancer carcinogenesis. Methods: We analyzed the NBS-1 status in 472 sporadic breast cancer patients treated in the Department of Oncology, Charles University Prague. DNA was extracted from peripheral blood monocytes. Subsequently two PCRs for each sample were carried out. Reaction was visualized using electrophoresis on agarose gel. Agarose gel wells with both the NBS-1 gene-specific band and internal control band were interpreted as positive. Wells with internal control only were interpreted as negative. PCR from samples giving neither an internal control band nor specific band were repeated. DNA samples obtained from a previously typed NBS family were used as a positive control. Results: Based on previously published data we expect to find at least 5 mutation carriers. Surprisingly, in our population of 472 subjects there was no mutation identified. Conclusions: Based on results of this study there is no relationship between NBS-1 mutation and breast cancer incidence. Acknowledgment: The study was supported in part by the RASO grant from Czech Society of Oncology, and MSM0021620808. No significant financial relationships to disclose.
Deletion polymorphism of the GSTM1 gene in lung cancer patients from the Lake District in Turkey
Authors: Coskun Ari F. , Bosgelmez G. , Coskun H. S. , Polat M. , Kisioglu N. , Ergurhan Ilhan I. 
Published: March 2020

20089 Background: Association of glutathione-S-transferase M1 (GSTM1) polymorphisms and cancer has been demonstrated. Especially the deletion polymorphism of GSTM1 has been related to risk for lung cancer in some studies. We thus investigated the frequency of GSTM1-null genotype in lung cancer patients and healthy individuals from the Lake District in Turkey. Methods: Cases were recruited among patients with clinically and histologically confirmed diagnosis of lung cancer patients from the Lake District. Controls were selected among the nonsmoking healthy blood donors applied to hospital in same region. DNA samples were extracted from whole blood using proteinaz K (20 mg/mL) digestion in lysis buffer (10 mM Tris-HCl, 400 mM NaCl, 2 mM EDTA, % 10 SDS). Homozygous deletion of the GSTM1 gene was determined by PCR using the primers E4F: 5′-CTGCCCTACTTGATTGATGGG-3′, E5R: 5′-CTGGATTGTAGCAGATCATGC-3′, corresponding to exons 4 and 5 of the GSTM1 gene. PCR products were analyzed by 1% agarose gel electrophoresis and UV transilluminator was then used to evaluate the product content. Individuals carrying the GSTM1 gene were identified by the presence of a 273 bp DNA fragment. Results: The study comprised 30 patients and 30 controls. The frequency of GSTM1-null genotype was found to be (n = 14) 46.7% in lung cancer patients and (n = 5) 16.6% in controls. The difference was statistically significant (Fisher’s chi square test: 4.80, P: 0.0251). Conclusion: We found an increased incidence of GSTM1-null genotype among lung cancer patients, indicating that the GSTM1 absence is associated with a slightly increased lung cancer risk in people from the Lake District in Turkey. No significant financial relationships to disclose.
Identification of potential cancer targets from diagnostic and prognostic gene signatures
Authors: Vansant G. , Oades K. , Pickering M. , Monforte J. 
Published: March 2020

20096 Background: The purpose of this study was to determine the potential of gene signature development to also identify leads among different tumor types compared to normal cells. The theory is that cancer cells will express unique markers that are related to their growth and metastatic potential and therefore be potential targets for therapeutics. Methods: Multiplex PCR Approximately 100 genes were chosen to produce 3 multiplexes for RT-PCR analysis. These genes were identified from gene signatures found in peer reviewed manuscripts. RT and PCR primer pairs designed for each gene to be monitored are chimeric, with a gene specific sequence and a universal sequence common to all forward and reverse primers, respectively. A pair of universal primers that recognize the universal sequences in the chimeric primers are included in the reaction in great excess, with one fluorescently labeled. After reverse transcription and a few rounds of PCR, these universal primers drive the reactions, so all the PCR products are essentially amplified by the universal primer set. The chimeric primers are designed to produce PCR products that all have a difference in length of approximately 5 base pairs, resulting in a stratified set of labeled PCR products. 25ng of total RNA from each tumor derived cell line was used as template for the reverse transcription reactions. Half of these reactions were carried over as templates for the PCR reactions. The PCR products were fluorescently labeled during the PCR reaction and analyzed on a capillary electrophoresis system. Results: Many genes were expressed at high levels across all cancer cell types compared to control cells including an A kinase anchoring protein, cyclin-E2, JPO1, mucin 1, and the transferrin receptor CD 71. Conclusions: Analysis of the expression of genes that are part of diagnostic and prognostic gene signatures in tumor related cell lines revealed many genes whose expression were altered in tumor derived cells that are potentially related to the ability of the carcinogenic cells to proliferate and metastasize. Subsequently, a secondary benefit of the development of prognostic or diagnostic gene signatures with statistical analysis, may be the elucidation of potential therapeutic targets for the treatment of cancer. No significant financial relationships to disclose.
Epidermal growth factor receptor (EGFR) mutations in breast and cervical cancer
Authors: Park M. S. , Puttaswamy K. , Gombos Z. , Geza A. , Brose M. S. 
Published: March 2020

20101 Background: EGFR is a tyrosine kinase receptor in the HER family which is widely expressed in a number of epithelial tumors and is believed to play a key role in cell proliferation. Molecular analysis of the EGFR gene in patients with non-small-cell lung cancer have identified a distinct subset of tumors that possess specific point mutations in the tyrosine kinase region of the EGFR gene, which correlate to response to tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Clinical trials involving TKIs are currently under way for patients with breast and cervical cancer. While responses thus far may have been modest it is unclear whether specific EGFR mutations are present in breast and cervical cancers which identify patients with improved prognosis and better response to therapy in these cancers. Using clinical samples with 5 years of follow-up clinical data, we have set out to determine whether EGFR mutations exist in breast and cervical cancers, and how these mutations, if any, correlate with the clinical data. Methods: We plan to perform sequence analysis of the tyrosine kinase domain of the EGFR gene (exons 18–24) in 50 archival breast and 44 cervical cancer specimens using PCR amplification and sequencing of genomic DNA. Clinical information has been extracted from patient charts on samples and will be correlated with the presence of any EGFR mutations identified. Results: To date we have collected 50 breast and 44 cervical tumor blocks and have isolated genomic DNA from the specimens. Sequencing for point mutations in exons 18–24 is underway. Clinical data on the cervical cancer specimens revealed a mean age at diagnosis of 48.2 years, tumor grades that were mostly intermediate (50%) and high (45%), and all FICO stages at diagnosis (43% stage I, 30% stage II, 5% stage III, 5% stage IV). In addition the rate of recurrence was 32%, and survival rate was 82% with an average time of follow-up for the set of 4.9 years. Conclusions: Our data will further elucidate the role of point mutations in EGFR gene in breast and cervical cancer prognosis and response to therapy, and will complement data currently being collected in clinical trials using TKIs. No significant financial relationships to disclose.
Prognostic implications of YKL-40 overexpression in breast cancer
Authors: Kim S. H. , Das K. , Noreen S. , Coffman F. , Hameed M. 
Published: March 2020

20115 Background: YKL-40 has been implicated as a connective tissue growth factor and a migratory factor for endothelial cells. Elevated serum levels of YKL-40 have been found to correlate with worse survival in a variety of malignancies including breast cancer. We wished to determine if tumor overexpression of this protein also had prognostic implications in breast cancer. Methods: A prospectively collected database of breast cancer patients treated at the University Hospital of Newark was used for analysis. Immunohistochemical analysis was performed on 115 patients for whom full clinical information and follow up was available. Specimens were categorized as lacking immunoreactivity (0), having focal sparse immunoreactivity (1), or strong more diffuse immunoreactivity (2). Results: YKL-40 expression was noted in 38 patients (33%). Of these, 24 demonstrated strong (2) immunoreactivity (21%). Strong (2) YKL-40 immunoreactivity significantly correlated with larger tumor size (p < .05). Tumors expressing any level of YKL-40 were also significantly more likely to be estrogen and/or progesterone receptor negative (p < .01). No significant correlation was demonstrated between YKL-40 status and nodal stage. At a mean follow up of 2.3 years, disease-free survival was significantly worse in the subset of patients whose tumors overexpressed any level of YKL-40 compared to the non-expressors (p < .01). In multivariate analysis, YKL-40 status was independent of T-stage and N-stage in predicting disease recurrence. Conclusions: Immunoreactivity for YKL-40 was a significant predictor of breast cancer relapse in this subset of patients. This was independent of T or N-stage and suggests that tumor immunohistochemistry for this protein may be a valuable prognostic marker in breast cancer. No significant financial relationships to disclose.