bluuebunny/crossref_metadata_2025_split huggingface dataset:
Additive/synergistic efficacy of zoledronic acid and LBH589 in the spheroid-based cellular angiogenesis assay
Authors: Soltau J. , Weber H. , Schächtele C. , Drevs J. 
Published: August 2020

e14627 Background: The compounds Zoledronic acid (ZA) and LBH589 (histon deactetylase (HDAC) inhibitor) have shown in previous experiments antitumoral and antiangiogenic effects. Aim of this study was to determine their ability to inhibit VEGF-A induced endothelial cell (EC) sprouting and to observe potential additive/synergistic effects of the combination ZA and LBH589 in the spheroid-based cellular 3D angiogenesis assay. Methods: HUVEC spheroids were embedded in a 3D collagen gel, stimulated with VEGF-A [25 ng/ml] and treated for 24h with different concentrations of ZA alone or in combination with LBH589. Sprouting intensity of EC spheroids was quantitated by an image analysis system determining the cumulative sprout length per spheroid using an inverted microscope and digital imaging software. The mean of the cumulative sprout length of 10 randomly selected spheroids was analyzed as an individual data point. Results: Before testing the compounds in combination the single IC50 values for ZA (42 μM) and LBH589 (2.9 μM) were determined. The IC50 of ZA has to be considered with caution because of the low inhibitory effect which did not reach basal sprouting levels. In the first combination experiment a dilution series of ZA was tested in combination with a constant LBH589 concentration [2.9 μM, IC50 value as determined previously]. The combination of ZA with LBH589 was ∼330 fold more effective in the inhibition of EC sprouting than ZA alone [0.58 μM compared to 190 μM]. However, the sprouting intensity in the combination of LBH589 and ZA was very low. Therefore the experiment was repeated with a dilution series of ZA in combination with a constant LBH589 concentration that showed no inhibition of EC sprouting previously (1 μM). The second combination experiment revealed IC50 values of 1300 μM for ZA alone and 1.5 μM in combination with LBH589 [1 μM]. The combination LBH589 and ZA is again ∼870 fold more effective in the inhibition of EC sprouting than ZA alone. Conclusions: Our results indicate a very strong synergistic effect of the combination ZA and LBH589 in the spheroid-based angiogenesis assay. No significant financial relationships to disclose.
Phase I study of sunitinib (SU) in combination with pemetrexed (Pem) in patients (pts) with advanced solid tumors (ST)
Authors: Nakagawa K. , Okamoto I. , Shimizu T. , Miyazaki M. , Tsurutani J. , Ichikawa Y. , Terashima M. , Takeda M. , Fumita S. , Kiriyama T. 
Published: August 2020

e14630 Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, FLT3, and CSR-1, and shows antitumor activities in several types of solid malignancies. Non-small-cell lung cancer (NSCLC) xenograft data indicate SU enhanced the antitumor activity of Pem. This phase I study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of combination therapy with the oral SU and Pem for Japanese patients with advanced ST. Methods: Pts with ST refractory to standard therapy were randomly assigned to receive either oral SU 50 mg/day for 2 weeks followed by 1 week rest (Schedule 2/1, S-2/1) or SU 37.5 mg continuous daily dose (CDD). Fixed-dose Pem (500mg/m2 IV) was administered on day1 every 21 days. A standard “3+3” design was employed in both treatment schedules and treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed. Results: A total of 12 pts (med. age 63 years, range 49–69; 10 Male/ 2 Female) have been enrolled (6 pts in the S-2/1 arm and 6 pts in the CDD arm). The most common cancer is NSCLC (9 pts, 75%). All patients completed their first cycle for DLT evaluation, and no DLTs were observed in either treatment arm. The most common toxicities were fatigue (n=8), anorexia (n=6), and thrombocytopenia (n=12). Treatment-related ≥ grade 3 adverse events (AEs) included fatigue (n=1), hypertension (n=1), neutropenia (n=4), leucopenia (n=3), thrombocytopenia (n=2), lymphopenia (n=2), and increased ALT (n=1). Three pts (S-2/1: 2, CDD: 1) required dose reduction of SU due to G3 toxicities. All toxicities were clinically manageable and reversible. One pt with NSCLC had a documented PR with cavity formation inside the tumor. Conclusions: SU 37.5 mg/day (CDD schedule) plus Pem 500mg/m2 every 21 days, and SU 50 mg/day (S-2/1 schedule) plus Pem 500mg/m2 every 21 days were well tolerated and associated with encouraging antitumor activity. [Table: see text]
Detection of methylation in the CpG islands of the RASSF1A and RAR2b gene promoters in breast cancer (BC)
Authors: Desiris K. , Voyatzi S. , Stravoravdi P. , Boukovinas I. , Kiziridou A. , Paikos D. , Stergiou E. , Sibilidis G. 
Published: August 2020

e14632 Background: Aberrant methylation of CpG islands of cancer-related genes has emerged as an important epigenetic mechanism during carcinogenesis. We examined the methylation of RASSF1A (Ras-association domain family 1, isoform A) and RAR2b (Retinoic Acid Receptor 2b) genes in BC. The knowledge of their role in BC is limited and confused to date. Methods: Promoter methylation was measured in 37 pts, 26 with BC and 11 with benign lesions. The specimens were obtained from archive formalin-fixed paraffin-embedded tumors. After DNA extraction, the methylation was determined by chemical modification of DNA with sodium bisulfite and subsequent double “hot start” Methylation-Specific PCR (MSP), followed by detection on agarose gel. Results: Methylation of at least one of the genes was observed in 18/26 pts (p<0.05). Methylation of RASSF1A gene was observed in 15/26 and RAR2b in 11/26 pts. Both genes were methylated in 8/26 pts. Correlation between methylation and clinicopathological features revealed an association of the RASSF1A gene with T2 tumors (12/15 pts, p<0.05) and ER (+) status (12/15 pts, p<0.05). T2 tumors and ER (+) status presented together in 9/15 pts. The methylation of RAR2b gene was not associated with any known clinicopathological features. In benign lesions methylation of at least one of the genes was observed in 8/11 pts (p<0.05). Methylation of RASSF1A gene was observed in 5/11 pts and RAR2b in 7/11 pts. Both genes were methylated in 4/11 pts. Conclusions: Both genes are frequently methylated in both benign and malignant breast lesions. The association of methylation of RASSF1A gene with tumor size and ER status is noteworthy. The small number of pts does not allow us to confirm the exact role of gene methylation in BC yet. Larger studies are required in order to assess if these epigenetic alterations point out new BC markers, which could be helpful for BC control. No significant financial relationships to disclose.
Effect of a synthetic peroxisome proliferator-activated receptor-gamma (PPARγ) ligand on breast cancer cells
Authors: Youn H. , Lee B. , Jung S. 
Published: August 2020

e14638 Background: Peroxisome proliferator-activated receptor-gamma (PPARγ) ligands have been identified as a potential source of therapy for human cancers. And, it is reported that PPAR-γ ligands could serve as negative regulators of breast cancer development and progression, but their mechanism is still unknown. The purpose of this study was to determine whether the PPAR- γ ligand induces cell cycle arrest and apoptosis of MDA-MB-231(ERα-negative) and MCF-7(ERα-positive) breast cancer cell. Methods: The effect of PPAR-γ ligands on the cell viability of breast cancer cells was determined using mitochondrial tetrazolium(MTT) assay. The cell cycle distribution and apoptosis induction were evaluated by using the flow cytometry. The expression of apoptosis-related proteins were measured with Western blot analysis. Results: The treatment of MDA-MB- 231 cell with PPAR-γ ligand, troglitazone was shown to induce cell cycle G1 arrest and induction of apoptosis. Moreover, troglitazone treatment, applied in a dose-dependent manner, caused a marked decrease in phosphorylated retinoblastoma(pRb), cyclin D1, D2, D3, cyclin dependent kinase(Cdk) 2, 4, and 6 expression as well as a significant increase in Cdk inhibitor, p21 and p27. Troglitazone showed antiproliferative effect on MCF-7 cell with tamoxifen, respectively and synergically. Troglitazone and tamoxifen could induce G1 arrest and apoptosis of MCF-7 cell, through upregulation of Bax and downregulation of Bcl-2 and cyclin D1. Conclusions: PPAR-γ ligand, troglitazone induces cell cycle arrest and apoptosis of MDA-MB-231 cell and increases the sensitivity of anti-hormonal therapy in MCF-7 cell. These results suggest that troglitazone has anticancer effect on both ERα-negative and positive breast cancer cells. No significant financial relationships to disclose.
Colorectal cancer risk prediction tool for men and women without known susceptibility
Authors: Freedman A. N. , Slattery M. L. , Ballard-Barbash R. , Willis G. , Cann B. J. , Pee D. , Gail M. H. , Pfeiffer R. M. 
Published: August 2020

e15002 Background: Given the high incidence of colorectal cancer (CRC), and the availability of procedures that can detect disease and remove precancerous lesions, there is a need for a model that estimates the probability of developing CRC across various age intervals and risk factor profiles. Methods: The development of separate CRC absolute risk models for men and women included estimating relative risks and attributable risk parameters from population-based case-control data separately for proximal, distal, and rectal cancer and combining these estimates with baseline age-specific cancer hazard rates based on Surveillance, Epidemiology, and End Results (SEER) incidence rates and competing mortality risks. Results: For men, the model included a cancer- negative sigmoidoscopy/colonoscopy in the last 10 years, polyp history in the last 10 years, history of CRC in first-degree relatives, aspirin and nonsteroidal anti-inflammatory drug (NSAID) use, cigarette smoking, body mass index (BMI), current leisure-time vigorous activity, and vegetable consumption. For women, the model included sigmoidoscopy/colonoscopy, polyp history, history of CRC in first-degree relatives, aspirin and NSAID use, BMI, leisure-time vigorous activity, vegetable consumption, hormone-replacement therapy (HRT), and estrogen exposure on the basis of menopausal status. For men and women, relative risks differed slightly by tumor site. A validation study in independent data indicates that the models for men and women are well calibrated. Conclusions: We developed absolute risk prediction models for CRC from population-based data, and a simple questionnaire suitable for self-administration. This model is potentially useful for counseling, for designing research intervention studies, and for other applications. No significant financial relationships to disclose.
A prospective study of the interaction between p53 genotype and overall survival in patients with colorectal cancer liver metastases (CRCLM) with and without neoadjuvant therapy (oxaliplatin and capecitabine/5-FU): A p53 research group study
Authors: Kandioler D. , Pilat N. , Kappel S. , Gruenberger T. , Laengle F. , Mittlboeck M. , Herberger B. , Kuehrer I. , Jakesz R. , Muehlbacher F. 
Published: August 2020

e15003 Background: Mutations in the p53 gene have been suggested as both a marker of tumour aggressiveness and a means of predicting response to chemotherapy. Unfortunately, there remains no clear evidence that p53 gene mutation affects cancer survival rates. Methods: We sought to evaluate whether mutation in the p53 gene is a marker of more aggressive tumours or of chemotherapeutic failure. Between 2001 and 2003 we collected data prospectively on 76 patients with CRCLM at a single institution. Patients considered to be technically operable were included. 51 patients received preoperative therapy with oxaliplatin plus 5-FU or capetcitabine and 25 were treated with surgery only. Treatment decision was based on the preference of the surgeon or the patient. The groups did not differ in age, chronicity of CRCLM, staging and grading of the primary colorectal cancer. The p53 gene was assessed in all tumours through complete direct gene sequencing (Exon 2–11 including splice sites). Results: For entire cohort the p53 gene mutation rate was 55%, and the median survival was 44.2 months. The overall death rate was 51%. There were 14 (41%) deaths in patients with a normal p53 gene compared to 25 (60%) deaths in patients with mutations in this gene (Logrank P=0.079). For patients that received only surgical treatment the overall death rate was 48% and was unaffected by the presence of p53 gene mutation (Logrank P=0.54). For patients who received neoadjuvant chemotherapy, median survival was 44 months if they had a normal p53 gene compared to only 20 months in patients with p53 gene mutations. The unadjusted hazard ratio for death was 3.24 in the p53 mutation group compared those with a normal p53 gene (95 percent confidence interval 1.5 to 7.0; P=0.045). The adjusted hazard ratio for death in patients with a p53 gene mutation receiving neoadjuvant chemotherapy was 5.5 (95% CI 2.3 to 13.2; P=0.0042). Conclusions: In CRCLM patients receiving neoadjuvant chemotherapy, the p53 gene mutation predicts overall survival. Our data suggests an interaction between the p53 gene and chemotherapy in patients with colorectal liver metastasis. No significant financial relationships to disclose.
Receipt of chemotherapy among Medicaid-enrolled patients diagnosed with regional colon cancer
Authors: Foley K. L. , Tooze J. A. , Song E. Y. , Klepin H. D. , Geiger A. M. 
Published: August 2020

e15016 Background: Although overall improvements in colon cancer mortality have been observed, persistent disparities marked by socioeconomic inequality remain. Inadequate treatment received by the poor leads to disparities in overall and disease-free survival. This paper evaluates the patient, health services, and community characteristics associated with receipt of chemotherapy among poor Medicaid beneficiaries diagnosed with SEER-staged regional colon cancer. Methods: A dataset was constructed from Medicaid-enrolled patients diagnosed with colon cancer from 1999 to 2002 (n=692). Using claims data, North Carolina Central Cancer Registry data, and U.S. Census data, multivariable models were constructed to evaluate the association between patient, health services, and community characteristics and adjuvant chemotherapy. Results: Characteristics of the study population include: 66% female; 25% ages 65–74 and 46% ages 75+; and 42% African American. 1 in 4 of individuals with regional stage colon cancer had a Medicaid or Medicare claim for chemotherapy within 12 months of diagnosis. Individuals under age 65 (OR 6.4, CI 3.6–11.1) and ages 65- 74 (OR 4.4, CI 2.6–7.7) were significantly more likely to receive chemotherapy than individuals 75 and older in the multivariable model. Although non-cancer related comorbidity, class of case, and poverty were significantly associated with received chemotherapy in unadjusted models, their effects were no longer significant after controlling for age. Conclusions: A substantial percentage of Medicaid enrollees do not receive recommended adjuvant chemotherapy. The poor elderly may be especially at risk for under treatment. No significant financial relationships to disclose.
Extended TME- and MRI-assisted pathology show high incidence of pt4 after neoadjuvant treatment
Authors: Aamdal S. , Larsen S. G. , Hole K. H. , Grøholt K. K. , Dueland S. , Aamdal S. , Giercksky K. 
Published: August 2020

e15033 Background: The clinical ability of pre- and post neoadjuvant MRI to predict the necessary extension of TME (ETME) in evaluation of the areas at risk in locally advanced rectal cancer (LARC). Evaluation of treatment response to chemo/ radiation in T4 tumours is difficult. MRI cannot discriminate between different tissue components within a voxel. Increasing rate of late local relapses are reported from different studies. Methods: Prospective registration of 92 MRI evaluated T4a cancers undergoing multimodal treatment for rectal cancer between 2002 and 2007 in a tertiary referral cancer centre. MRI was found to predict T- downstaging in 10% after neoadjuvant treatment. In 35% both MRI and histopathological examination staged the patients as T4 after treatment. 55% (n=51) of the patients were downstaged after the routine postoperative pathology work-up. A new technique with MRI- based sampling of areas of infiltration was introduced and dedicated histopathological evaluation of these threatened areas was performed. Results: ETME was performed in 95% of the patients, mostly as en-bloc resections. After MRI focused pathology 50% were reclassified and up scaled to have pT4. Accordingly, at least 2/3 of the MRI staged T4 tumours before treatment still were pT4 after multimodal treatment. Conclusions: The tumours were downsized, but to lesser amount downstaged. If cure is the goal of the treatment, extended TME as en-bloc resections has to be performed. It is necessary to remove tumour as shown in pre-treatment MRI, as well as tumour, fibrosis and mucus as shown in MRI after post neoadjuvant treatment. MRI assisted pathology is an important option for right T-stage classification and for planning the extent of surgical resection. No significant financial relationships to disclose.
Final safety results from the post-marketing survey (PMS) of bevacizumab (BV) in Japanese colorectal cancer patients
Authors: Doi T. , Shirao K. , Uetake H. , Hatake K. , Takahashi Y. , Nihira S. 
Published: August 2020

e15035 Background: BV was approved in Apr. 2007 in Japan in patients (pts) with advanced colorectal cancer. The number of pts in Japanese clinical trials were extremely limited. Therefore, the Japanese MHLW (Ministry of Health Labor and Welfare) required Chugai to initiate a PMS in all pts after the launch as a post-approval commitment to evaluate the incidence of adverse drug reactions (ADRs) in Japanese pts. This is the first safety well controlled large cohort PMS in Asian pts. Objectives: To assess the use of BV in clinical practice and to evaluate the incidence of ADRs in Japanese pts. Methods: All pts who were treated by BV were registered before initial administration since the launch of BV in Jun. 2007. Follow-up period was 6 months. Results: Between Jun. and Nov. 2007, 2712 pts were registered from 574 institutions, and 2699 pts were eligible for the safety analysis. Pts characteristics were colon/rectum/colon and rectum cancer; 1580/1105/14, M/F; 1632/1067, median age; 61 (15–86), ECOG P.S.0/1/2/3; 2192/477/28/2, combination chemotherapy regimens with BV (FOLFOX / FOLFIRI /5-FU LV /IFL/Other); 1716/778/141/54/10, treatment lines (1st, 2nd, 3rd and more); 1238/1418/43. Of 2699 pts, ADRs were reported in 1589 pts (58.9%) with serious ADRs in 381 pts (14.1%). The common BV ADRs of interest were hypertension; 13.0%, hemorrhage; 11.3% (epitaxis;7.3%), proteinuria; 4.1%. Other ADRs were wound healing complications 1.2%, GI Perforation 0.9%, and thromboembolism (arterial/venous); 0.4 /1.3%. No Japanese-specific ADRs were observed. Conclusions: These safety results are consistent with those reported in International observational studies (BRiTE, Hedrick et al. JCO 2006;24(Jun 20 Suppl.):abstr 3536; First BEAT, Berry et al. JCO 2008;26(May 20 Suppl):abstr 4025). [Table: see text]
Correlation of bone marrow micrometastasis to TNM stage of colorectal tumors
Authors: Soni M. , Saha S. , Korant A. , Chakravarty B. , Arora S. , Iddings D. , Sirop S. , Bisnoi R. , Wiese D. , Singh T. 
Published: August 2020

e15039 Background: Bone marrow (BM) micrometastasis(M) has been shown to be an important prognostic factor in Breast Cancer. However, there is paucity of data for BMM in Colorectal Cancer(CrCa). Hence a study was undertaken to find any correlation between TNM staging with BMM in CrCa patients(pts). Methods: A total of 155 consecutive patients(pts) from March 2004-October 2008 with CrCa were included in the study. Prior to resection of the primary tumor, pts underwent bilateral posterior-superior-iliac spine BM aspiration and samples were examined for presence of micrometastasis by Automated Cellular Imaging System using Chroma Vision Cytokeratin Detection Kit to detect cells expressing CK 8 as defined by CAM 5.2 monoclonal antibody. BMM and TNM staging were recorded and analyzed for correlations. Results: Of 155 CrCa pts, 11.6%(18/155) were found to have BMM. BMM was positive(+ve) in 50%(9/18) bilaterally and 50%(9/18) unilaterally. BMM was +ve in 11.5%(13/113) of colon pts and 12%(5/42) of rectal pts. When analyzed by T stage in colon pts, BMM was present in 10.5%(2/19) of T1 pts, 16.6%(2/12) of T2 pts, 14% (6/42) of T3 pts, 37.5%(3/8) of T4 pts, and 16%(5/31) of M1 pts. Upon analyzing rectal cancer pts data, BMM was found in 8.3%(1/12) of T1 pts, 16.6%(3/18) of T3 pts and 16.6% (3/18) of M1 pts. Of 113 total Colon pts, 27%(31/113) had nodal disease without distant metastasis(stage III); 13%(4/31) of these pts had BMM with 60% (3/5) unilaterally and 40%(2/5) bilaterally. In the Rectal group, 16%(7/42) had stage 3 disease; 14% (1/7) of stage 3 rectal pts had BMM. Conclusions: BMM did not correlate with tumor size, nodal status or distant metastasis. This discrepancy between tumor stage and BMM suggests BMM to operate independently of TNM staging. Further studies correlating prognosis and disease free survival in +ve BMM pts are needed to examine the significance of BMM in CrCa. [Table: see text] No significant financial relationships to disclose.
Analysis of pharmacogenetic biomarkers in rectal patients trated with chemoradiotherapy
Authors: Lamas M. J. , Balboa E. , Duran G. , Rana P. , Gomez A. , Bernardez B. , Lopez R. , Carracedo A. , Barros F. 
Published: August 2020

e15051 Background: 5FU-based chemoradiotherapy before total mesorectal excision (TME) is currently the gold standard treatment for stage II and III rectal cancer patients. Pathological complete response (pCR) is related with a longer survival. We have used known predictive pharmacogenetics biomarkers to identify in our series responders and non responders to preoperative RQ. Methods: 77 stage II/III rectal patients were genotyped using direct sequencing (TS VNTR) and SNAPshot (DPYD, EGFR) techniques. DNA was obtained from peripheral blood samples. We have studied Thymidylate synthetase (TS VNTR; high expression haplotypes: TSER 2R/3R, 3C/3G, 3G/3G and low expression: TSER 2R/2R, 2R/3C, 3C/3C; TS 1494del6: associated to a better efficay of 5Fu), dihydropyrimidine dehydrogenase (DPYD; DPYD*2 associated to worse toxicity), EGFR (CA repeats in intron 1: 16/16 associated to worse efficacy) polymorphisms. Median age of our study cohort was 65 years old (37–85). There were 24 female and 53 male patients. All of them were Caucasian. 21 patients (27.3%) had stage II and 56 (72.7%) stage III. They were staged by TC, colonoscopy and endorectal ultrasonography. The patients received 5fu 325 mg/m2/day continuous infusion along the hyperfractionated accelerated radiotherapy schedule (50,4 Gy). All were submitted to TME. Outcomes after surgery are measured by tumour regression grade (from TRG1= complete pathological response, to TRG5=no regression). Data were studied by univariate and multivariate analysis. Results: The sample was in Hardy-Weinberg equilibrium for all polymorphisms, irrespectively of the response status. 50 patients (64.9%) and 27 (35.1%) had low and high expression genotype for TS respectively. pCR (TRG1) was obtained in 24 patients (31,6%) and microscopic foci (TRG2) in 14 (18,2%), TRG 3–4 in 38 (49,3%), and 1 patient had no response (TRG5). We haven’t found a statistically significant relationship between TRG1 and TS status, or any other biomarker studied. There's no relationship also with initial clinical stage. Conclusions: Biomarkers EGFR (intron 1 CA repeats), TS (TS 1494del6, TS VNTR) and DPYD in blood samples, are not good enough to predict response to RQ in rectal cancer. No significant financial relationships to disclose.