bluuebunny/crossref_metadata_2025_split huggingface dataset:
SULT1A1 concordance between whole blood and breast cancer tissue
Authors: Grabinski J. L. , Arno E. , Smith L. S. 
Published: March 2020

14090 Background: The human sulfotransferase (SULT1A1) enzyme is involved in the conjugation of tamoxifen. Studies have demonstrated the significance of polymorphisms within the SULT1A1 gene in relation to breast cancer survival and tamoxifen metabolism (Nowell et al, J Natl Cancer Inst 2002). DNA for genotyping in previous studies was obtained from a number of different biological specimens including whole blood or paraffin-embedded formalin-fixed tissue. The purpose of this study was to evaluate the genotypic concordance of SULT1A1 polymorphisms in whole blood and breast cancer tissue. Methods: Breast cancer patients receiving tamoxifen and previously genotyped for the SULT1A1 gene were consented for enrollment. Samples representing each of the three possible genotypes (*1/*1, *1/*2,*2/*2) were selected for the collection of archived tissue. DNA was extracted from whole blood using the QIAamp Blood Midi Kit (Qiagen Inc., Valencia, CA, USA) and from formalin-fixed paraffin-embedded breast cancer tissue using the QIAamp DNA Mini Kit (Qiagen Inc., Valencia, CA, USA) as per protocol. Genotyping of the SULT1A1 gene was conducted using a validated Pyrosequencing assay. Results: Tissue samples representing each of the three different SULT1A1 genotypes were compared to the whole blood genotypes. Each of the clinical samples demonstrated 100% concordance between the two different specimens. Conclusion: Our data provides evidence to support the genotyping of clinical samples for the SULT1A1 gene utilizing either whole blood or tumor tissue from breast cancer patients. No significant financial relationships to disclose.
Functional imaging by DCE-US as a surrogate for response in phase I/II of different targeted therapies by DCE-US: Which quantitative parameter and which timing
Authors: Lassau N. , Koscielny S. , Chami L. , Roche A. , Soria J. , le Cesne A. , Boige V. , Armand J. 
Published: March 2020

14093 Background: The early evaluation of targeted treatments is a major challenge in oncology. Functional approaches based on the measure of tumoral vascularization have been developed using different modalities of imaging (CT, MRI, US). We analyzed the response of tumors in three studies using different targeted treatments with dynamic contrast enhanced-ultrasonography (DCE-US). Seven parameters characterizing tumor perfusion were estimated. The objective of the study was to determine which parameter is the most appropriate and when to use it to confirm earlier the efficacy of treatment. Methods: A total of 157 DCE-US were performed in 30 responding patients (PFS>3 months) selected from 3 following studies (multikinase inhibitor targeting angiogenic-receptor with a cytotoxic, thyrosine-kinase inhibitor targeted angiogenic-receptor and C-kit, VEGF monoclonal antibody). Each DCE-US was performed using contrast agent (Sonovue,Bracco) with perfusion and quantification softwares (Toshiba) from raw linear data. Seven quantitative parameters of perfusion were estimated: peak intensity (PI) and area under the curve (AUC), area under the wash-in (AUWI), area under the wash-out (AUWO), time to PI, mean transit time (MTT), wash-in slope. DCE-US were performed before treatment and after during 5 periods (P) : 1–12 days(P1), 13–22 days(P2), 23–43 days(P3), 44–110 days (P4), > 111 days(P5). Results: 1099 parameters have benefited a statistical analysis. Significant modifications (P<0.05) of 4 parameters (PI, AUC, AUWI, AUWO) were observed for the 3 treatments. The earliest significant modifications were observed during the 3rd period for the first 2 studies and during the 4th period for the 3rd study. Conclusions: DCE-US is a sensitive tool to evaluate early tumor response to targeted drugs. Four functional parameters were significantly modified patients responding to treatment: PI, AUC, AUWI, AUWO. Those modifications appear earlier for the multikinase inhibitor targeting angiogenic receptor and the thyrosine-kinase inhibitor targeted angiogenic receptor and C-kit ( (23–43 d) compared to VEGF monoclonal antibody (44 -110 d). DCE- US represent a key add value to early evaluation of targeted therapies. No significant financial relationships to disclose.
A pilot trial of topotecan administered orally in patients with advanced solid tumors expressing hypoxia inducible factor (HIF)- 1α
Authors: Melillo G. , Gutierrez M. , Holkova B. , Rapisarda A. , Raffeld M. , Horneffer Y. , Chang R. , Murgo A. J. , Doroshow J. H. , Kummar S. 
Published: March 2020

14103 Background: HIF-1 is a transcription factor frequently over-expressed in common human cancers that mediates a transcriptional program leading to tumor angiogenesis, survival and metastases. Previous studies have demonstrated that daily administration of topotecan (TPT), a topoisomerase I poison, inhibits HIF-1a expression, angiogenesis and tumor growth in human xenograft models. The primary aim of this study is to investigate whether TPT inhibits HIF-1a expression in human cancers. Methods: TPT was administered orally at 1.6 mg/m2 daily x 5 for 2 weeks, on a 28-day cycle, to adult patients with advanced solid tumors expressing HIF-1a in at least 10% of tumor cells, as assessed by IHC. Tumor biopsies are obtained before and at the end of treatment in cycle 2 and tested for HIF-1a protein expression by IHC and mRNA expression of HIF-1 target genes by real-time PCR. 18FDG-PET, to assess tumor metabolism, and DCE-MRI, to assess blood flow and permeability, were obtained at baseline, at the end of 2 weeks of therapy and then at the end of treatment on cycle 2. CT scans were performed before and after 2 cycles of therapy. Serial blood samples are obtained for PK analysis. Results: Seven patients, median age 54 (range 35–70), have been treated so far, with 6 patients being evaluable for the primary endpoint with paired tumor biopsies for analyses: melanoma (1), colorectal cancer (2), bladder (1), breast (1), ovarian (1). First two patients received the planned dose of 1.6 mg/m2; patient # 2 developed grade 3 neutropenia and grade 4 thrombocytopenia. As the objective was to develop a regimen for chronic dosing that was well tolerated and not directly cytotoxic, the protocol was amended to reduce the dose. Four patients have received a median of 2 cycles at 1.2 mg/m2, which has been well tolerated. A decrease of VEGF mRNA expression by more than 70% was observed in the 2 patients treated at 1.6 mg/m2 after 2 cycles of treatment. However, no consistent decrease of HIF-1a protein levels was detected in the corresponding tumor tissue. Enrollment continues. Conclusion: This is the first study aimed to validate inhibition of the HIF-1 signaling pathway in cancer patients. Funded in part by NCI Contract N01- CO-12400. No significant financial relationships to disclose.
Association of a novel polymorphism G-133C of thymidylate synthase (TYMS) gene with 5-FU-related severe diarrhea in Japanese patients with colorectal cancer
Authors: Matsumura Y. , Muto M. , Doi T. , Ohtsu A. , Hamaguchi T. , Shimada Y. , Yamada Y. , Shirao K. , Kaniwa N. , Sawada J. 
Published: March 2020

14108 Background: 5-FU remains a key drug for the treatment of several cancers, including cancers of the colorectum, stomach, and breast. Increasing evidence suggests that genetic polymorphism results in increased toxicity. This prospective study intended to elucidate the relations between 5-FU-related toxicity and polymorphisms of several genes. Methods: Blood for genotyping was obtained before treatment. Blood samples were drawn at 2-week intervals for 8 weeks to assess hematologic toxicity. Adverse events were assessed according to NCI CTC, v2.0. The genes encoding TYMS and thymidine phosphorylase (ECGF1) were analyzed with leukocyte DNA obtained from patients with colorectal cancer who received 5-FU (500 or 600 mg/m2) and leucovorin (LV) (250 mg/m2) weekly for 6 weeks every 8 weeks. Results: Seventy-eight patients with colorectal cancer were enrolled and genotyped. Toxicity was evaluated in all patients. No genetic polymorphisms detected were significantly associated with 5-FU-related hematological toxicity. Only G- 133C located in the 5’-UTR region of the TYMS gene was significantly associated with 5-FU-related grade 3 diarrhea. Conclusions: The TYMS G-133C SNP may be a critical determinant of severe diarrhea in patients treated with 5-FU/LV. [Table: see text] No significant financial relationships to disclose.
Effect of enzastaurin on cell signaling, proliferation and apoptosis in breast cancer cell lines
Authors: Spankuch B. , Kurunci-Csacsko E. , Bauknecht T. , Strebhardt K. 
Published: March 2020

14121 Background: Enzastaurin, an acyclic bisindolylmaleimide, is a potent selective serine/threonine kinase inhibitor that inhibits PKCβ, targets the PI3K/AKT pathway, and inhibits GSK3β phosphorylation. Enzastaurin induced apoptosis and decreased proliferation of various cancer lines, and decreased VEGF expression and microvessel density in human tumor xenografts. In animal models, enzastaurin had antitumor/antiangiogenic activity in non-small-cell lung, colon, renal cell, hepatocellular, and other cancers. Therefore, we sought to determine enzastaurin’s impact on cellular PKCβ-mediated signaling in breast cancer cells. Secondarily, we sought to determine the induction of the apoptotic cascade by enzastaurin. Methods: Breast cancer cell lines MCF-7, BT-474, MDA-MB-435 and SK-BR-3 were treated with differing enzastaurin concentrations. Western-Blot analyses were performed to examine PKCβ, phospho-GSK3β and caspase 9 expressions. The phenotype and proliferation of enzastaurin-treated cells were also monitored by fluorescence microscopy. Results: Treating all 4 cancer cell lines with ascending enzastaurin doses (0.1–10 μM) led to a significant downregulation of GSK3β phosphorylation (2–17%) compared to control cells. A 48–72 hr incubation with increasing enzastaurin doses also reduced the PKCβ expression significantly (5–50%). Moreover, a dose- dependent reduction of cell proliferation to levels of 15–40% compared to control cells with the highest enzastaurin concentration was detectable. We also saw a marked pro-caspase 9 reduction (0–30%) after enzastaurin compared to control cells. The microscopic inspection of treated cells phenotypically confirmed increasing apoptosis-induced cell death. Conclusions: Enzastaurin has a significant antiproliferative effect in different breast cancer cells. Moreover, enzastaurin suppresses GSK3β phosphorylation, suggesting that it may be a reliable pharmacodynamic marker for enzastaurin activity in breast cancer cells; however, more preclinical analysis is needed. Our study provides evidence for enzastaurin’s potential to directly suppress breast cancer cell proliferation and to induce tumor cell death by apoptotic induction. No significant financial relationships to disclose.
An open-label phase II clinical trial of PTK787 in patients with progressive neuroendocrine cancer
Authors: Anthony L. B. , McCall J. , Nunez J. , O’Dorisio T. , O’Dorisio S. 
Published: March 2020

14127 Background: PTK787 is an orally active angiogenesis inhibitor blocking all known vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptor (PDGFR)-tyrosine kinases . The majority of metastatic neuroendocrine malignancies express VEGF and PDGF receptors. Since both growth factors have been implicated in tumor-induced angiogenesis, PTK787 offers a novel approach for inhibiting tumor growth. Methods: In a phase II trial, we investigated the safety and antitumor activity of PTK787 in patients who had biopsy-proven metastatic neuroendocrine cancer, such as carcinoid, and had shown evidence of progression on somatostatin analog therapy. Eligible patients had measurable lesions other than bone, a Karnofsky performance status > 60% and normal hematologic, renal and hepatic functions. Patients on octreotide therapy were required to be on a stable dose not exceeding 30 mg monthly of the LAR formulation. Initial dosing of PTK787 was 1,250 mg daily. Results: Eight patients (5 males) were enrolled between 5/20/05 to 9/09/06. Median age was 61 years (range, 48 to 65). There was 1 withdrawal of consent. The median time on study was 6.2 ± 2.1 mos with 1 patient continuing on treatment as of January 2007. Three patients required a 10–28 day discontinuation for rising SGOT/SGPT, alkaline phosphatase and Grade2 proteinuria. Resumption of PTK787 at 1,000 mg daily was well tolerated in 1 patient. One patient developed carcinoid crises with fever, flushing, rising 5-HIAA accompanied by Grade 2 proteinuria. A partial (>50% decrease in 5-HIAA) biochemical response was observed in 25% of the patients. The observed radiographic (CT scans) and scintigraphic (OctreoScan) responses in 6 patients has been stable disease at 3 and 6 mos. Recruitment to this trial continues. Conclusions: PTK787 results in a 25% biochemical partial response rate in neuroendocrine tumor patients with progressive disease following somatostatin analog therapy. Alternative dosing schedules are planned to improve tolerability. [Table: see text]
Clinical outcome of patients with thymic epithelial tumors
Authors: Palmieri G. , Montella L. , Merola G. , Merola C. , Matano E. , Petillo L. , Evoli A. 
Published: March 2020

14148 Advanced chemorefractory thymic epithelial tumors still represent a challenge in clinical oncology. Neoplastic thymoma cells express EGFR. We evaluated the clinical activity of Cetuximab, a chimeric human-mouse monoclonal IgG1 antibody blocking ligand binding to EGFR, in five cases of advanced chemorefractory thymic epithelial tumor. Materials and Methods: Patient Characteristics and response evaluation. Patients’ characteristics and responses to treatment are represented in the table . The patients were assessed for EGFR expression in the primitive tumor, being considered this data as a basis for an anti EGFR treatment. Moreover they were evaluated as concerns clinical status and biochemistry and imaged by a combined PET-CT. Treatment schedule: The patients received intravenous cetuximab (C225, Erbitux, Merck KgaA, Darmstadt, Germany) over 1 hour at 400 mg/m2 loading dose followed by the weekly administration of 250 mg/m2. The first dose of 400 mg/m2 was given during the course of 2 hours. Subsequent weekly treatments were given at a dose of 250 mg/m2 during the course of 1 hour. This preliminary evaluation suggests for the first time that cetuximab may be a useful therapeutic choice in advanced pretreated thymic tumors. Despite the need for prolonged follow-up of the patients and further confirmatory studies, the EGF/EGFR pathway seems to play a pivotal role in thymic tumor. [Table: see text] No significant financial relationships to disclose.
Circulating tumor cells (CTC) in newly diagnosed breast or colorectal cancers
Authors: Groot M. D. , Croonen M. , Mastboom W. , Vermes I. , Tibbe A. , Tissing H. , Terstappen L. 
Published: March 2020

14512 Background: The presence of CTCs is associated with poor prognosis in patients with metastatic carcinomas. The significance of CTCs at the time of diagnosis and after therapy is not known. A prospective clinical trial is conducted to determine if monitoring CTC levels in pts diagnosed with breast and colorectal cancer identify pts at risk for recurrence. CTCs are correlated with pathological stage as follow-up is too short to assess recurrence risk. Methods: Currently 213 pts with newly diagnosed breast and 119 pts with colorectal cancer before surgery with curative intend have been enrolled as well as a control group of 120 patients in whom diagnosis of breast or colorectal cancer was excluded. Thirty ml of blood was screened for the presence of CTCs at baseline before surgery and every following year using the CellSearch™ System. Results: Presence of CTCs in 30mL of blood in breast, colorectal cancer and the control group is provided in the table . In colorectal cancer the average number of CTCs /30 mL at baseline for Dukes A, B and C was 0.2, 0.7 and 1.1 respectively, for stage 0, I, II, III breast cancer 0.3, 0.5, 0.6 and 1.8 respectively and for the control group 0.24 CTCs /30 mL. Conclusions: CTC can be detected in a substantial proportion of pts before and after definitive surgery for breast and colorectal cancer. The number of CTCs before surgery correlated with the stage of the disease. Specificity of the CellSearch™ System is being increased to improve the discrimination of patients with benign and malignant disease. Follow-up must clarify whether the presence CTCs is an identifier for the risk of recurrence. [Table: see text] No significant financial relationships to disclose.
A multicenter phase 2 clinical trial testing a combination of oxaliplatin, bolus 5-fluorouracil, leucovorin and capecitabine in patients with metastatic colorectal cancer (MCRC)
Authors: LoConte N. K. , Holen K. D. , Eickhoff J. , Dzelak T. , Richie K. , Teeter K. , Warren D. , Jumonville A. J. , Kwong R. W. , Mulkerin D. L. 
Published: March 2020

14526 Introduction: The combination of oxaliplatin (OX) with bolus and infusional 5FU has shown high activity in MCRC. Substituting capecitabine (CAPE) for 5FU in a novel high-dose schedule designed to mimic FOLFOX-6 is a feasible and well tolerated treatment (Hegeman, ASCO, 2005, #2058). A multicenter phase 2 study of this combination was performed to evaluate efficacy in first-line treatment of MCRC. Methods: Eligible patients have ECOG PS 0–2, no grade 2 or higher neuropathy, and no prior systemic treatment for metastatic cancer. Patients are treated with OX 100 mg/m2, leucovorin (LV) 20 mg/m2 and 5FU 400 mg/m2 IV bolus followed by CAPE 1500 mg/m2 PO Q8H x 6 doses, repeated every two weeks. The primary endpoint was confirmed antitumoral response. Patients were allowed to come off study to pursue surgical resection, if feasible. Results: 36 out of a planned 45 patients have been enrolled since 6/04. Survival (OS) and time to progession (TTP) data are available for all 36 patients. Toxicity and efficacy data is available for 33 patients. The median age of enrolled patients is 65.5 years (range 42–78). 16 (44%) of patients are male. 94% of patients are ECOG PS 0 or 1. Toxicity data is presented in the table . 14/33 (42%) of patients had a grade 3/4 toxicity (see table ). The response rate was 33% (95% confidence interval [CI] 18–52%): 11 patients achieved a partial response (33%), 14 (42%) had stable disease, and 8 (24%) had progressive disease. Median overall survival was 17.1 months (M) (CI 0.7+-27.5+ M). The one-year survival rate was 67%. The median TTP/TTF was 4.1 M (CI 0.3–14.3 M). Four (11%) patients have come off of the study protocol to pursue metastatectomy. Conclusion: OX, infusional 5FU, LV and CAPE is active and well tolerated in MCRC. This regimen had fewer episodes of grade 3–4 hand-foot syndrome and mucositis than prior regimens including longer durations of capecitabine. Study supported by sanofi-aventis. [Table: see text] [Table: see text]
Capecitabine (X) compared to X + erlotinib (E) as first-line treatment in patients (pts) with metastatic colorectal cancer (MCRC): Interim efficacy results from a randomized phase II study
Authors: Vincent M. , Kerr I. , Dingle B. , MacKenzie M. J. , Sanatani M. 
Published: March 2020

14560 Background: The oral fluoropyrimidine X (Xeloda®) has efficacy, safety and convenience benefits vs. 5-FU/LV in adjuvant / first-line CRC. E (Tarceva®) inhibits epidermal growth factor receptor (EGFR), which predicts poor prognosis. A randomized open-label phase II study was performed to establish activity of X alone vs. X + E (XE) in first-line. Methods: Pts (ECOG PS 0–2 and/or elevated LDH) with MCRC not eligible for immediate surgical metastatectomy and unwilling/unable to undergo combination chemotherapy were randomized to X (1000mg/m2/d bid d1–14 q3w) or XE (X 1000mg/m2/d bid d1–14 q3w + E 150mg/d). A third arm (E alone) was included but dropped after 13 pts, following safety committee review of progressions at first CT scan. Primary endpoint: time to progression (TTP). Results: 59 pts (median age 65y, range 46–84; 44 M, 15 F) have been accrued (X=21; XE=25; E=13). Mean time on study: 3.8 months (range 0.2–12). 9 pts are on active treatment, 21 pts on follow-up and 29 pts have died. Interim efficacy results are available for 50 pts (X n=15; XE n=22, E n=13). There were no significant differences in response rate, median TTP (4.9 vs. 9.2 months) and median overall survival (18.2 vs. 15.1 months) for X vs. XE. Grade 3 adverse events (AEs) with X were diarrhea, nausea, hand-foot syndrome (HFS), angina, dyspnea (all 5%). Corresponding rates of grade 3 AEs with XE were diarrhea (20%), fatigue (16%), stomatitis (12%), HFS (8%), vomiting (8%), dehydration (8%), thrombosis, weight loss, decreased appetite, dry eyes, headache, anxiety, abdominal pain, anorexia, hyponatremia (all 4%). The only grade 4 AEs were skin rash (4%) and subjective weakness (4%) - both XE. Conclusions: Interim results indicate that XE is at least as effective as X alone in first-line MCRC. Recruitment is continuing and further follow-up may help fully determine the potential benefits of adding E to X. [Table: see text] No significant financial relationships to disclose.
Five-year survival analysis of liver metastasis of colorectal cancer after hepatic resection
Authors: Xu J. , Zhong Y. , Fan J. , Zhou J. , Zhou J. , Qin L. , Niu W. , Wei Y. , Ren L. , Qin X. , Wu Z. 
Published: March 2020

14571 Background: To evaluate the relation between hepatic resecion and survival rate of liver metastasis of colorectal cancer ( LMCC). Methods: Use retrograde case analysis method, 133 cases of LMCC received hepatic resection from 1/1/2000 to 31/12/2005 were included,with attention to the relation between hepatic resection and survival rate. Results: There were 133 cases underwent curative hepatic resection in all 470 LMCC cases, of which 30 cases (30/196,15.3%) in synchronous liver metastasis (SLM) group and 103 cases (103/274,37.6%) in metachronous liver metastasis (MLM) group, P<0.01. Mortality rate related to operation was 3.3%(1/30) in SLM and 1.9%(2/103) in MLM(P<0.05). Until 31/6/2006, all 133 cases were followed-up, 1,3,5 years survival rate and median survival time of SLM (81.0%, 40.3%, 16.5%, 22 months) is similar to that of MLM (88.2%, 49.1%, 31.7%, 25 months, P > 0.05), but the recurrence rate is higher(36.7% vs 20.4%,P=0.03). Compared to 49 cases whose liver metastases focus can be resected but chosen non- operative therapy, 1, 3, 5 years survival rate of 133 resected cases is higher (55.6%, 11.0%, 0 vs 86.2%, 39.2%, 29.4%, P=0.0034). In SLM, 22 cases received I stage resection of the primary colorectal tumor and liver metastasis and 8 cases received liver metastasis resection after the primary surgery (II stage operation). 1, 2, 3 years survival are 90.0% vs 87.5%(P > 0.05),61.4% vs 55.3%(P > 0.05)and 35.4% vs 30.0%(P > 0.05) and the median survival time is 28 months vs 26months(P > 0.05).COX multivariate analysis was used to analyze the prognositic factors. Incision margin =1cm(β=-0.8351,P=0.0363)and reoperation after recurrence(β=- 0.9428,P=0.0411)were protective survival factors, and postoperation recurrence (β=0.6471,P=0.0226) was survival risk factor. Conclusions: Curative hepatic resection is the first choice of liver metastasis of colorectal cancer and can improve survival. No significant financial relationships to disclose.