bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of gemcitabine pathway genotypes in ethnic Asians and their relationship with outcome in non-small cell lung cancer (NSCLC) patients
Authors: Soo R. A. , Lee S. C. , Ng S. S. , Chong P. Y. , Tham L. S. , Wang L. Z. , Lee H. S. , Soong R. , Goh B. C. 
Published: March 2020

2008 Background: Genotypic variation for drug metabolising enzymes, targets and transporters is associated with inter-patient and inter-ethnic variability in toxicity and efficacy. Gemcitabine is a nucleoside anti-metabolite used in a range of solid tumors. Aims: 1) to determine genotype distribution of genes involved in gemcitabine pharmacology pathway in ethnic groups; 2) to evaluate the association between genotypes and treatment related outcomes in patients with chemo-naive, advanced NSCLC receiving gemcitabine based chemotherapy on a prospective study. Methods: Candidate genes involved in gemcitabine pharmacology were identified from a comprehensive search of public databases (NCBI, PharmGKB), and publications. 25 variants of 9 candidate genes (RRM-1, SLC28A1, SLC28A2, SLC28A3, SLC29A2, POLA2, DCTD, CDA, TS) were genotyped from blood in 94 healthy donors and 76 cancer patients (breast 22, NSCLC 54) with pyrosequencing. Chi-squared, Kruskall-Wallis, and Kaplan-Meier analysis were used to evaluate associations between genotypes and ethnic groups and clinical end points. Results: Significant differences in genotype distribution between Chinese, Malay and Indian were seen in 5/25 loci (see table ). In NSCLC patients, POLA2 2089 (G > A) was associated with neutropenia (p = 0.022), SLC28A1-1576 (C > T) with neutropenia nadir (p = 0.030) and thrombocytopenia nadir (p = 0.037), RRM-1 -524 (T > C) with neutropenia (p = 0.024) and SLC28A2–283 (CA 18.3 vs CC 8.5 months, p = 0.004), and SLC28A2–22 (CC 8.0 vs CT 18.3 months, p = 0.002) with survival. Conclusions: Our results suggest there is significant genotypic variability among ethnic groups. Variants in gemcitabine transporters and targets may be useful indicators of gemcitabine related toxicity and survival. Further studies should be performed to confirm these preliminary findings. [Table: see text] No significant financial relationships to disclose.
Retrospective analysis of cutaneous T-cell lymphoma (CTCL) biopsy samples for interleukin-2 receptor (IL2-R) subunit expression by immunohistochemistry (IHC) and real-time quantitative PCR (RT-PCR): Correlation to response to denileukin diftitox
Authors: Alexander V. J. , Bissonnette R. P. , Rosen J. I. , Cooke T. , Foss F. M. 
Published: March 2020

20080 Background: Denileukin diftitox, a chimeric diphtheria toxin-IL2 protein, exerts its cytotoxic effect on cells expressing high or intermediate affinity IL2-R. IL2-R is a complex of 3 distinct polypeptide chains: IL2-Rα (CD25), IL2-Rβ (CD122), and IL2-Rγ (CD132). IL2-R α/β/γ heterotrimer binds with high affinity, IL2-R β/γ with intermediate affinity, and IL2-R α/γ with low affinity. Denileukin diftitox is indicated for patients with persistent or recurrent CTCL whose malignant cells express IL2-Rα protein. There is no currently available methodology to measure expression of the high affinity receptor in patient samples. This study was initiated to discover a correlation between expression of IL2-R components (at the mRNA and protein levels) and clinical response to denileukin diftitox. Methods: Of 33 available frozen clinical CTCL biopsy samples, 27 (10 responders) were sufficient for IHC. IL2-Rβ staining intensity was assigned a value of 0 (no staining relative to background), 1+ (weak), 2+ (moderate), or 3+ (strong). 22 samples (8 responders) were sufficient for RT-PCR. mRNA levels of the 3 IL2-R chains were normalized to 36B4 mRNA or 18S rRNA. Correlation between clinical response and IL2-R chain expression was assessed using Spotfire Decision Site. Results: The population of samples tested was representative of the study population. 26 of 27 samples exhibited 2+, all exhibited 1+, and none 3+ IL2-Rβ staining. The percentage of cells stained varied from 20%–90% for 1+ and 10%–80% for 2+ with no correlation to response. Correlation of levels of individual IL2-R subunit mRNA expression with response could not be established. Conclusions: Neither the IL2-Rβ IHC nor the RT-PCR assay, at current sensitivity levels, appear to identify denileukin diftitox responders. Larger sample datasets from current studies, and further assay refinement, are ongoing to define the merits of these approaches. [Table: see text]
Neuroendocrine cancer of the kidney: Clinical implications of expression microarray analysis
Authors: Harris W. B. , Assikis V. , Yin-Goen Q. , Lewis M. M. , Lawson D. , Amin M. B. , Young A. N. , Petros J. A. 
Published: March 2020

20093 Background: Conventional clinical trial strategies cannot be used to develop new therapies for rare malignancies. Neuroendocrine neoplasms of the kidney are extremely rare. Here we compare the gene expression profiles of a neuroendocrine tumor from a 32 year old male with a horseshoe kidney, a large renal primary and metastatic thyroid lesions to the profiles of other cancers. Response to systemic therapy is also reported. The ultimate objective of this project is to identify new therapeutic targets for patient-specific cancer therapy. Methods: After informed consent, tissue from the patient was analyzed by cytology and immunohistochemistry. Total RNA was isolated from formalin-fixed paraffin-embedded archival reference tissues with Arcturus Paradise Reagents. Gene expression was analyzed with Affymetrix X3P arrays of the entire expressed genome. A supervised significance analysis of microarrays (SAM) procedure, using 400 data permutations, was performed to identify gene products that were differentially expressed. Clinical outcomes were documented in the patient’s medical record on the basis of standard medical imaging. Results: Cytology, immunohistochemistry and microarray studies revealed similar patterns for the primary and metastatic lesions. Gene expression profiles of the patient’s kidney and thyroid lesions, as well as other kidney and neuroendocrine tumors, identified 11 genes overexpressed significantly in the neuroendocrine tumors. Each was associated with neuroendocrine biology. The patient had a mixed response to chemotherapy with gemcitabine and cisplatin and progressive disease after 3 monthly treatments with sandostatin. He awaits assessment of response to metaiodobenzylguanidine (MIBG). Conclusions: Gene expression profiling was effective in characterizing an unusual case of renal cancer with metastasis to thyroid, though no new therapeutic target has yet been identified. Comparing response or resistance to therapy with microarray analysis may prove to be an effective strategy for developing patient-specific cancer therapy. This work was supported, in part, by a VA Merit Review Award. No significant financial relationships to disclose.
Effects of polymorphism (plm) in interleukin (IL) 1 and IL10 genes on surgery outcome in ovarian cancer (OC)
Authors: Braicu E. I. , Mustea A. , Koensgen D. , Pirvulescu C. , Sun P. , Chekerov R. , Nuernberg P. , Toliat M. R. , Lichtenegger W. , Sehouli J. 
Published: March 2020

20094 Background: IL1 and IL10 are overexpressed in 55% to 98% of advanced epithelial OC. Different studies demonstrated IL1 and IL10 as independent prognostic factors for OC. This study was performed to investigate the influence of plms of IL-1A, IL-1B and IL-10 gene on the occurrence tumor biology of OC. Methods: In a prospective, monocentric, case-control study 147 pts with OC (71 pts with primary OC and 77 pts with recurrent OC) and 129 pts with no history of malignancies were genotyped for plms of the IL-1 gene (IL-1A -889 T/C and IL-1B -511 C/T promoter) and IL-10 gene (IL-10 -1082 G/A, -819 C/T and -592 C/A). All pts were collected within Tumor bank Ovarian Cancer Project. Genomic DNA fragments were amplified by PCR and the allele sequences were obtained by pyrosequencing. We analyzed significance using the Chi-Square by Pearson and Fisher’s exact test. Statistical significance was determined by Mann-Whitney test. A two-tailed p value <0.05 was considered statistically significant. Overall survival (OS) was estimated using the Kaplan-Meier product limited method. Results: The median age of the pts with OC was 55.5 years (range 19–81 y). Median follow-up period was: 31.5 months (range: 1–225 mo). There were no significant associations between allelic frequencies for IL-1A and IL-1B in OC. The IL-10 plm in -819 and -592 positions significantly correlates with the postoperative residual tumor (p = 0.036 and p = 0.035 respectively). For pts without any postoperative tumor residuals the most encountered genotype was C/C at −819 and −592. The same genotype was associated in univariate analysis with a better OS (95% CI = 37.5–94.5 and 40.8–91.2, respectively). In the multivariate models there was no correlation between any plms and disease-free and OS. Postoperative residual tumor (OR =0.202, 95% CI = 0.088–0.462, p = 0.0001) and ascites volume (OR = 0.106, 95% CI = 0.046–0.248, p = 0.026) were independent prognostic factors for reduced OS. Conclusions: Plm of IL1A, IL1B, IL10 showed no association with occurrence of OC. IL-10 promoter plm may influence the tumor biology and could potentially predict results of radical surgery. No significant financial relationships to disclose.
Swedish ovarian cancer patients are found with a high frequency of human leucocyte antigen (HLA) A2, -B7, -B12, -B15 -B44 and -DRB1–4 haplotypes
Authors: Bergfeldt K. , Gamzatova Z. , Tholander B. , Bergdahl M. , Nordström B. , Hjerpe E. , Masucci G. 
Published: March 2020

20100 Background: There is an increased interest on the association between HLA markers and prognostic outcome in several cancer forms. We have previously reported that the high prevalence of the A2 allele in Scandinavia, which decreases with latitude in Europe, correlates to a similar decrease in ovarian cancer mortality among European countries. We have also published the association of this allele with severe prognosis in serous adenocarcinoma of the Ovary in stage III-IV. We now present a complete distribution of the HLA- A, -B -C and DRB1 alleles and haplotypes in relation to histology and clinical stage. Methods: An unbiased selection of epithelial ovarian cancer patients (n = 56) recorded by age, histology, stage and treatment were analyzed for HLA-A, -B, -C and -DRB1 genotypes by PCR/sequence-specific oligonucleotide hybridization procedure (PCR/SSOP). HLA frequencies from healthy Swedish bone marrow donors were used as comparison. Results: HLA-A2, -B7, -B15, -B44 as well as the A2, -B15, -DR4 haplotypes frequency are significantly higher than in the healthy Swedish population. We noticed a high concentration of this haplotypes among the serous adenocarcinomas. Seven patients were homozygotes for A2 allele (23%), two times the healthy Swedish population (12%), and 3 times the median frequency in Europe (8%). Six of these had the haplotype -A2, -B7. Conclusions: HLA-A2 homozygotes and some HLA-A2 -B and -DRb1 haplotypes are higher expressed than in healthy individuals. These observations corroborate the relevance of HLA in association with ovarian cancer, previously partially investigated. Ongoing studies consider the relationship of HLA-A2 and its haplotypes to possible oncogenes and prognosis in ovarian cancer. No significant financial relationships to disclose.
Multicentric descriptive study of the lung cancer treatment
Authors: Quintana M. , Pallares C. , Martinez I. , Gich I. , Bonfill X. 
Published: March 2020

20109 Background: Given the insufficient available information on the clinical characteristics and the results of the lung cancer treatment at a population level, we performed a large multicentric descriptive study in the main hospitals in our city. Methods: We analyzed the patients diagnosed and treated for lung cancer during 1999 in five University Hospitals in Barcelona (Spain). We performed a retrospective analysis of the individual data obtained from the clinical records using a specifically validated questionnaire. A descriptive analysis was performed, stratifying for type of tumor, stage, and institution. The follow-up for the complete population was 5 years. Results: We included 836 patients (94.6% male, 5.4% female) with an average age of 64 years. Karnofsky was ≥ 70% in 85% of patients. Histologic distribution was non-small cell (NSCLC) 85.5%, small-cell (SCLC) 14.5%. 42% of cases were stage IV (38% NSCLC, 67.8% SCLC). First treatment was performed in 82% of cases with therapeutic intention (52% was chemotherapy). Pulmonary resection with lobectomy and platinum-based chemotherapy were the more frequent treatments. Complete remission was obtained in 25% of cases. Survival was 42.0, 17.9 and 12.6% at 1, 3 and 5 years respectively (NSCLC: 43.8, 19.4, 13.1%; SCLC: 31.9, 9.5, 9.5%). The mean interval first visit - treatment start was 2 months. The mean of direct costs per patient was 9000 €. The cost per life-year gained was 5200 € for NSCLC and 7600 € for SCLC patients. Conclusions: The obtained results allow to describe the clinical characteristics of a wide cohort of patients diagnosed of lung cancer and their survival to 5 years. Globally, these results are similar to those who have been published in our country and others, and constitute a very thorough referent for assessing the impact of future therapeutic advances. The comparison among hospitals can also be the matter of further analysis for identifying the causes of the observed differences. Equally, specific strategies for some patients’ subgroups could be designed in order to improve the cost-effectiveness of their treatment. No significant financial relationships to disclose.
Development of a clinically feasible molecular assay to predict recurrence of Dukes’ B colon cancer
Authors: Jiang Y. , Zhang Y. , Briggs T. , Talantov D. , Mazumder A. , Atkins D. , Wang Y. , Deleany C. , Brown M. , Casey G. 
Published: March 2020

20110 Background: The 5-year survival rate of Dukes’ B colon cancer patients is approximately 75%. In our earlier genome-wide measurements of gene expression we have identified a 23-gene signature that sub-classifies Dukes’ B tumors and may provide better means of risk assessment on an individual basis for these colon cancer patients. The aim of this study is to validate this gene signature in an independent and more diverse group of patients, and further develop this prognostic signature into a clinical feasible test using formalin-fixed paraffin-embedded (FFPE) tissue samples. Methods: Using Affymetrix U133a GeneChip we analyzed the expression of the 23 genes in total RNA of frozen tumor samples from 123 Dukes’ B patients who did not receive adjuvant systemic treatment. Furthermore, we developed a quantitative RT-PCR assay for this gene signature in order to perform the test with standard clinical FFPE samples. Results: In the independent validation set of 123 patients, the gene signature proved to be informative in identifying patients who would develop distant metastasis (hazard ratio, HR 2.56; 95% confidence interval CI, 1.01–6.48), even when corrected for the traditional prognostic factors in multivariate analysis (HR, 2.73; 95% CI, 0.97–7.73). The RT-PCR assay developed for this gene signature was also validated in an independent set of 114 patients as a strong prognostic factor for the development of distant recurrence (HR, 6.38; 95% CI, 2.88–14.2) in univariate analysis and in multivariate analysis (HR, 13.3; 95% CI, 5.13–34.4). Conclusions: Our data provide not only a validation of the pre-defined prognostic gene signature for Dukes’ B colon cancer patients but also a clear feasibility of testing the gene signature using RT-PCR with standard FFPE specimens. The ability of such a test to identify patients that have an unfavorable outcome demonstrates potential clinical importance that could lead clinicians to choose a more aggressive therapeutic option for the high-risk patients. [Table: see text]
Effective detection of the epidermal growth factor receptor mutation in pathologic specimens of non-small cell lung cancer patients by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR Clamp
Authors: Hoshi S. , Aoyagi S. , Kono C. , Amano Y. , Yamada Y. , Yamaguchi T. , Ogawa C. , Suzuki N. , Sano Y. , Nukiwa T. 
Published: March 2020

20113 Background: EGFR mutations link to the responsiveness to gefitinib, so it is important to get result of EGFR mutations more rapidly and sensitively. Methods: We screened 14 trans-bronchial lung biopsy (TBLB) specimens of non-small cell lung cancer (NSCLC) patients; 10 patients responded to gefitinib and 4 patients did not respond to gefitinib. We examined exons 18 through 21 (the area of the EGFR gene coding for the tyrosine kinase domain) both by the PNA-LNA PCR clamp method and the conventional sequence method. Results: We found five different mutations in 9 patients of 10 who responded to gefitinib by the PNA-LNA PCR clamp method, but only in 7 patients by the conventional sequence method. Detected mutations were the point mutation of exon 18(719S) and exon 21(858R), deletions of exon 19 (E746-A750del (nt2235–2249), E746-A750del (nt2236–2250), L747-E749del A750P). All 4 patients who did not respond to gefitinib were not detected any EGFR mutations either by the PNA-LNA PCR clamp method or by the conventional sequence method. We could get result for 2 days by the PNA-LNA PCR method, but by 7 days by the conventional sequence method routinely. Conclusions: The PNA-LNA PCR clamp method is more sensitive and rapid than the conventional sequence method. The detected EGFR mutations have good relation to gefitinib response. No significant financial relationships to disclose.
An open-label study to evaluate dose and cycle dependence of the pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD)
Authors: Gabizon A. , Isacson R. , Rosengarten O. , Tzemach D. , Shmeeda H. , Sapir R. 
Published: March 2020

2012 Background: There are no definitive data in humans on the dose dependency and/or cycle dependency of the pharmacokinetics of PLD. The skin toxicity of PLD tends to worsen after several treatment cycles. Therefore, it is important to characterize the PK of PLD after 2 or more cycles. Methods: Fifteen patients with various solid tumors were randomized to two arms of treatment in an open-label study. Arm A received PLD at doses of 60, 30, and 45 mg/m2 in 3 successive cycles every 4 weeks (q4w). Arm B received PLD at doses of 30, 60, and 45 mg/m2 in 3 successive cycles q4w. Twelve patients, 6 on each arm, completed all three cycles and were fully evaluable. Plasma levels of doxorubicin were analyzed by HPLC and fluorimetry following a previously published method (J Chromatogr B, 779:259–69, 2002) with minor modifications. PK analysis was done by non-compartmental method. The following parameters were obtained: Cmax, AUC∞, terminal half-life (T1/2), and Clearance (CL). The paired t test was used for statistical analysis. Results: There was no significant difference in the parameters examined when the dose was increased from 30 to 60 mg/m2. However, when we analyzed the effect of cycle number on the PK, we found a gradual and significant inhibition of CL when patients advance from the 1st through the 3rd cycle of PLD (p=0.0003), with a mean increase of 44% in AUC/mg dose (p=0.0011). Cmax and T1/2 mean values increased by 17% and 18% respectively between the 1st and 3rd cycles, but only the increase in T1/2 was statistically significant (p=0.0127). Conclusion: While the PK of PLD is not dose-dependent within the dose range of 30 to 60mg/m2, there is evidence of a cycle-dependent effect that results in inhibition of CL when patients receive successive cycles of PLD. This effect may account for the delayed skin toxicity of PLD. These results suggest the need for dose adjustments of PLD to minimize the risk of toxicity, such as an initial high loading dose followed by reduced maintenance doses from the 2nd or 3rd cycle onwards. [Table: see text] [Table: see text]
Phase I trial of CT-2106 (polyglutamated camptothecin) administered weekly in patients (pts) with advanced solid tumors
Authors: Daud A. , Garrett C. , Simon G. R. , Munster P. , Sullivan D. , Stromatt S. , Allevi C. , Bernareggi B. 
Published: March 2020

2015 Background: CT-2106, a camptothecin (CPT) conjugate, is a topoisomerase I inhibitor. Covalent binding through the hydroxyl group of CPT to polyglutamate, a biodegradable polymer of glutamic acid, enhances CPT aqueous solubility and prevents opening of the lactone ring and subsequent CPT binding to albumin. Responses were observed in a Q3 week dosing study in which the maximum tolerated dose (MTD) was 75 mg/m2. Objectives of this study are to determine the MTD and pharmacokinetics (PK) of CT-2106 given weekly to pts with advanced cancer. Methods: Pts received CT-2106 (10 min IV infusion) on days 1, 8, and 15 of each 28 day cycle. Toxicity (NCI CTC v3) and tumor response (RECIST) were assessed. Plasma was analyzed for conjugated and unconjugated CPT by liquid chromatography and tandem mass spectrometry. Results: Enrollment is complete with 21 evualuable pts. Dose limiting toxicities (DLT) are shown in the table . Median age = 60 years (range 36–83), median doses = 6 (1–9), median prior therapies = 3 (1–6). Most pts (12) had melanoma. In a Q3 week study assessments of conjugated and unconjugated CPT demonstrated that CT-2106 provides prolonged exposure to conjugated CPT and slow, progressive release of active CPT from the polymeric backbone. The PK of unconjugated CPT is dependent on the disposition profile of conjugated CPT; unconjugated CPT elimination is formation rate limited. The distribution of conjugated CPT appears to be restricted to extracellular body fluids. Total clearance includes renal excretion documented by substantial urinary excretion levels and CPT cleavage via metabolic pathways. Accumulation of conjugated or unconjugated CPT was not observed with repeated Q3 week dosing. PK in this weekly dosing study will be presented. Conclusions: CT-2106 is generally well tolerated without the toxicities normally associated with CPT, specifically hemorrhagic cystitis and severe diarrhea. The MTD is 25–35 mg/m2 in these heavily pretreated pts. [Table: see text] [Table: see text]