bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of a proton pump inhibitor (lansoprazole) and food on the bioavailability of enzastaurin administered as single oral doses to healthy subjects
Authors: Welch P. , Musib L. , Darstein C. , Baldwin J. , Ayan-Oshodi M. 
Published: March 2020

14076 Background: Enzastaurin (ENZ) targets the PKCβ and PI3K/AKT pathways to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. In vitro studies show ENZ solubility is highest at pH 2.0 and decreases with increasing pH. This study examined the effect of increased gastric pH by a proton pump inhibitor (lansoprazole) and the effect of food on the bioavailability of a single oral dose of ENZ in healthy subjects. Methods: In this open-label, three-period, fixed sequence, crossover study, healthy subjects received an oral, 500-mg single dose of ENZ in the fed state, alone (A) and with lansoprazole (B), and in the fasted state alone (C). Lansoprazole was dosed for 5 days, with ENZ administered 2 hours after the 5th dose. A two-week washout occurred between each period. Plasma samples were collected at predose and scheduled timepoints for up to 168 hours post-ENZ dose for pharmacokinetic (PK) characterization of ENZ and its active metabolites. Results: 22 subjects were enrolled in the study with 19 subjects completing all treatment periods. The table summarizes the PK results for enzastaurin and total analytes (enzastaurin + metabolites). ENZ Cmax and AUC(0–8) were unaffected by the administration of lansoprazole, when ENZ was then given in the fed state. Enzastaurin Cmax and AUC(0–8) increased significantly, respectively by 6.8 and 2.8 fold, when ENZ was administered after a standardized breakfast, compared to the fasted state. Median tmax increased from approximately 3 hours in the fed state to 6 hours in the fasted state, indicating slower absorption when ENZ was administered in the fasted state. Conclusions: No significant alterations in ENZ exposures were seen in the presence of lansoprazole, indicating that increased gastric pH did not decrease exposures of ENZ, when ENZ is administered in the fed state. Exposures of ENZ and its active metabolites were significantly enhanced by administration of ENZ after a meal. [Table: see text] No significant financial relationships to disclose.
MAP4/OP18 mRNA expression predicts progression in patients treated with vinorelbine plus carbolpatin in advanced lung cancer patients in a Multicenter trial
Authors: Galan J. , del Barco S. , Mendez M. , Esquerdo G. , Huarriz M. G. , Bandres E. , Gil M. C. , Paules A. B. , Gayo J. , Garcia- Foncillas J. 
Published: March 2020

14088 Background: Non-small-cell lung cancer patients with locally advanced or metastatic disease at the time of diagnosis show marginal response to chemotherapy in terms of tumor shrinkage, time to progression and median survival. MAP4 and stahmin have been previously reported as potential markers of resistance to treatment based on microtubule-destabilizing agents. Methods: In this multicenter study, we have used quantitative PCR to analyse expression of MAP4, stathmin, beta-tubulin III, BRCA1 and ERCC1 in mRNA isolated from peripheral blood samples of 51 non-small-cell lung cancer patients treated with vinorelbine/carboplatin. Results: In a preliminary set, 29 patients with stage IIIB and IV were analyzed. Lower levels of MAP4/OP18 mRNA expression are statistically related with response to vinorelbine-based treatment (p=0,029). This significant relationship is maintained in a second analysis after third cycle of treatment (p=0,032). Higher levels of MAP4/op18 were associated with a lower TTP (p=0,05). Conclusions: Our preliminary results suggest that the ratio MAP4/OP18 may be a good predictor of response for patients with non-small-cell lung cancer treated with vinorelbine-based chemotherapy. No significant financial relationships to disclose.
Phase I/II trial of OncoVEXGM-CSF combined with radical chemoradiation (CRT) in patients with newly diagnosed node-positive stage III/IV head and neck cancer (HNC)
Authors: Coffin R. S. , Hingorani M. , McNeish I. , Sibtain A. , Hamilton B. , Love C. , Nutting C. , Harrington K. 
Published: March 2020

14095 Background: OncoVEXGM-CSF is a second generation oncolytic herpes virus expressing GM-CSF which has previously completed a Phase I study with evidence of anti-tumor activity. Combination of OncoVEXGM-CSF with CRT has additionally demonstrated significant pre-clinical anti-tumor activity. Methods: Patients (pts) with newly-diagnosed node-positive stage III/IV HNC were enrolled in cohorts of 4. Patients received radiotherapy (70 Gy/35 fractions to gross disease, 50 Gy/25 fractions to elective areas) with concomitant cisplatin (100mg/m2 days 1, 22, 43). Four doses of intranodal virus were given on days 1, 22, 43 and 64 as follows: Cohort 1 - 106, 106, 106, 106; Cohort 2 -106, 107, 107, 107; Cohort 3 - 106, 108, 108, 108 pfu/ml. Patients underwent neck dissection 4–6 weeks after the last dose. Endpoints were safety, viral replication and anti-tumor activity. Results: Eight pts have completed the protocol. Nodal stages were N2a (2 pts), N2b (3), N2c (2), N3 (1). Compliance with the CRT schedule was 100%. In Cohort 1, 1 pt received only 3 doses of virus because of early complete response (CR). In Cohort 2, 1 pt received 3 doses and 1 pt 2 received doses because of early CR. Neck dissection was undertaken as planned in all but 1 pt. CRT-related toxicities were not exacerbated by OncoVEXGM-CSF. Non-CRT-related toxicities were mild (grade 1–2 fever and injection site pain). No dose-limiting toxicities were seen. In pts in whom nodal biopsy was possible during treatment, evidence of viral replication was seen. Clinical responses in the primary site (7 pts) and nodal disease (8 pts) were impressive which anecdotally appeared to be greater than would be expected with chemoradiation alone. Pathological CR was confirmed at the primary tumour site in 6 pts and in the neck in 3 pts after neck dissection. Extensive tumour necrosis was seen in all injected nodes. Extensive staining for OncoVEX was also seen including in adjacent uninjected nodes demonstrating considerable intratumoral virus spread. Conclusions: Combination of OncoVEXGM-CSF and CRT is well tolerated with promising anti- tumor activity. Recruitment to the final dose-escalation cohort has now been completed. No significant financial relationships to disclose.
Phase I study of the safety and pharmacokinetics (PK) of paclitaxel or paclitaxel with carboplatin administered in combination with pazopanib (GW786034)
Authors: Suttle B. , Jones S. , Dowlati A. , Tan A. , Mauser C. , Taber K. , Gibson D. , Arumugham T. , Lager J. J. , Burris H. A. 
Published: March 2020

14118 Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit. Pazopanib also is a moderate inhibitor of CYP2C8 and CYP3A4 in vitro. Paclitaxel (T), a substrate for CYP2C8 and CYP3A4, administered alone and in combination with carboplatin (Cb) is highly active in breast, NSCLC, and ovarian cancers. The additive benefit of the anti-VEGF agent bevacizumab with T or T-Cb in breast and NSCLC provides strong rationale for use of a multi-targeted TKI with T or T-Cb. Methods: Pts with advanced cancer (ECOG PS 0–1) were eligible. Dose escalation was split into Part 1 [T (15–80 mg/m2) days 1, 8, 15 q 28 days plus pazopanib (400–800 mg) QD starting on day 2 of cycle 1] and Part 2 [T (80- 225 mg/m2) plus Cb AUC 6 q 21 days plus pazopanib 800 mg QD starting on day 2 of cycle 1]. Safety, PK, and clinical response were evaluated. Dose escalation occurred in cohorts of 3–6 pts based on dose-limiting toxicities (DLTs) and PK. Results: 12 pts in Part 1 received the following pazopanib/T doses (n = pts): 400 mg/15 mg/m2 (3), 800 mg/15 mg/m2 (3), 800mg /50 mg/m2 (3), 800mg /80 mg/m2 (3). Preliminary data were available from 9 pts in Part 1. Selected mean PK results for T are shown. 4 pts in Part 2 received 800mg /175 mg/m2/AUC 6 of pazopanib/T/Cb (data not yet available). Most common AEs (>20%) in Part 1 were Gr 1/2 and consisted of fatigue, diarrhea, anorexia, nausea, vomiting, dysgeusia, AST elevation, rash, hypertension, and cough; Gr 3 diarrhea was reported in 1 pt. The 800mg pazopanib/80 mg/m2 T cohort in Part 1 is being expanded to 6 pts due to a DLT (dose delay of > 2 wks due to an abscess). Best response (n=6 pts) in Part 1 was SD (83%) (range 1–5 cycles). Conclusions: Concomitant administration of pazopanib increased paclitaxel mean Cmax and AUC(0–8) approximately 20–35%. Determination of the MTR in Parts 1 and 2 is ongoing. These findings warrant further studies at therapeutic doses of pazopanib, paclitaxel, and carboplatin. [Table: see text] No significant financial relationships to disclose.
Phase I study of ECO-4601, a novel Ras pathway inhibitor
Authors: Kavan P. , Melnychuk D. , Langleben A. , Baker S. D. , Bangash A. , Gauthier C. , Ranger M. , Gourdeau H. , Harvey M. D. , Falardeau P. , Batist G. 
Published: March 2020

14128 Background: ECO-4601 is a structurally novel farnesylated dibenzodiazepinone with broad μM in vitro cytotoxic activity, and in vivo antitumor efficacy in rat glioma, hormone-independent human prostate, breast tumor xenograft tumor models. Preclinical data suggest ECO-4601 is a targeted anticancer drug with dual activity: selective binding to the peripheral benzodiazepine receptor (PBR), resulting in apoptosis, and inhibition of the Ras-MAPK pathway. Greatest efficacy was observed with continuous exposure, and a target plasma ECO-4601 efficacy concentration was determined. Preclinical toxicity studies did not demonstrate significant or dangerous side-effects. ECO-4601 is currently in phase I clinical trial testing to determine toxicity, pharmacologic profile and antitumor efficacy. Methods: ECO-4601 is administered as a 2-week continuous i.v. infusion (CIV), followed by 1 week off in repeated 21 day cycles. The trial includes dose- escalation and dose-extension portions, with comprehensive pharmacokinetics (PK) during the first cycle. Dose-escalation consists of increased doses in single pts until grade 3 toxicity is observed during cycle 1 of treatment, with up to five additional pts dosed to confirm dose-limiting toxicity (2/6 pts with grade 3 toxicities). The extension portion includes up to 15 pts at the dose determined in the first portion. Patients with a variety of cancers have been treated, including colorectal (10), ovarian (2), duodenal (1), and glioma (1). Results: ECO-4601 doses of 30, 60, 120, 180, 270, 360, and 480 mg/m2/day were evaluated in 14 patients. The number of cycles ranged from 1 to 8 with 7 pts completing at least 3 cycles of treatment. ECO-4601 is well tolerated and a maximum tolerated dose (MTD) has not been reached. Stable disease was observed in 6 of 7 evaluable pts; 4 colorectal, 1 ovarian, 1 duodenal. Preliminary PK shows steady state concentrations following 24 h CIV, dose proportionality, plasma concentrations above the preclinical efficacy threshold, rapid elimination post-infusion. Conclusions: ECO-4601 is a bifunctional targeting agent, against a novel combination of targets, that is well tolerated and demonstrates evidence of biological activity in an early phase clinical trial. The extension portion is currently ongoing. [Table: see text]
The use of gene array analysis to determine down-stream molecular expression patterns of trastuzumab (T) treatment
Authors: Welle S. , Welt S. , Shay T. , Lanning C. , Horton K. , Kostyal D. 
Published: March 2020

14135 Background: Breast cancers expressing the HER/2 amplicon are more aggressive and are associated with a poorer prognosis. HER/2 over-expression has been correlated with expression of proteins responsible for invasion, metastases, rapid growth, angiogenesis and apoptosis. However, it is unknown if T treatment of HER/2 over-expressing tumors reverses these phenotypes. Methods: BT 474 and SK-BR3 breast cancer cell lines contain the HER/2 amplicon. Under growth conditions demonstrating inhibitory effects of T by MTT and 3H-Thymidine incorporation, (0.25–50 micrograms/ml for up to 9 days), RNA extracts from treated and un- treated cells were analyzed and compared by whole human genome, gene array analysis. Results: Specific gene products reported to be up-regulated in HER/2 over-expressed breast cancer lines or responsible for aggressive behavior were assessed for down regulation by T treatment including: topoisomerase II, heregulin, egfr-1,2,3 and 4, p27, ki67, mapKinase, akt, caspase-3, caspase-7, caspase-9, bcl-2, veg-f, veg-f receptor, p38, sapk/jnk, erk1/2, LGALS1 galectin-1, LGALS3 galectin-3, proline-4-hydrolase P4HA2, FN1 fibronectin -1, CDH3 p-cadherin, laminin receptor protein -1, pro2605 and insulin like growth factor binding protein-3. No significant change in these mRNA levels were observed due to T treatment. In contrast, over 1000 other gene were found to be specifically and significantly up or down regulated including the down regulation of S100 Calcium binding protein associated with increase metastatic potential. Conclusions T treatment does not reverse the expression of a large array of proteins conferring poor prognostic features on HER/2+ tumor. The use of gene array analysis to study T induced gene expression is a robust method to assess downstream protein expression patterns mediated by antibody binding to receptor. No significant financial relationships to disclose.
Spontaneous tumor apoptosis, caspase 3 and the survival outcome in medulloblastoma patients treated by postoperative radiotherapy and chemotherapy
Authors: Santek F. , Markulin-Grgic L. , Kusec R. 
Published: March 2020

14136 Background: The role of apoptosis in neurooncology is still an unexplored area. Only a small number of studies which have combined clinically relevant data and treatment modalities, with the apoptotic activity have been published. Methods: The influence of spontaneous tumor apoptosis and its potential regulators caspase 3, BAX, p53 and bcl-2 was analyzed in 30 medulloblastoma patients with a long follow-up period, after the treatment at the Clinic of Oncology and Radiotherapy by postoperative radiotherapy with or without postirradiational chemotherapy. The mean apoptotic and mitotic index ratio (AI/MI) was measured in all tumor samples obtained by the initial neurosurgical procedure. Results: Significantly different survival groups of adequately treated patients were found only if the apoptotic indexes measured by the morphometrical analyzes (AIM) had been correlated with the TUNEL-essay results (AIT) in the same tumor sample, (log rank test=2.0287, p=0.04). The mean apoptotic index measured in the described combined way had slightly higher values AIM+T=38.2±20.3 (median=32.0), than when measured only by morphometrical analysis AM=23.9±24.9 (median=15.0). In the multivariate analysis according, the most relevant variables were the disease free interval (p<0.001) and the number of CT cycles (0.005<p<0.01). Further parameters of significance were the modality of postoperative radiotherapy, and the general condition of patients measured according to the WHO grading system at the end of treatment (p<0.001) as well as on the late controls, ater completion of the treatment (p<0.001) Conclusions: Our expirience in evaluating the metodology of apoptotic index measurement has confirmed the advantage of combined method of detection of the apoptotic index AIM+T over the use of each of the described methods alone. The apoptotic index has shown a significant influence on survival of the medulloblastoma patients only when divided with the mitotic index MI. Using clinical data of our medulloblastoma patients, the index of apoptosis alone as a prognostic factor has not appeared to be of significant relevance. No significant financial relationships to disclose.
An open, pharmacokinetic (PK) and mass balance study of 14C-AZD2171, incorporating DCE-CT evaluations
Authors: Reid A. H. , Tang A. , Spicer J. , Gallerani E. , Mears D. , Settatree S. , Yap T. A. , Puchalski T. , Harrison M. , De-Bono J. S. 
Published: March 2020

14140 Background: AZD2171 is an oral, highly potent and selective VEGF signaling inhibitor in clinical development. Methods: Patients with solid metastatic tumors received a single radiolabeled oral dose of 14C- AZD2171 45 mg; blood samples and all excretions were collected for evaluating the PK and metabolic profiles. After sufficient radioactivity recovery, patients started once-daily oral dosing with AZD2171 30 mg. The primary objective of the study was to determine the rates and routes of excretion of AZD2171 using 14C-AZD2171. Efficacy (RECIST), safety and tolerability were secondary objectives. The potential effects of AZD2171 on DCE-CT vascular parameters were also explored. Results: Six patients received treatment and remained on study for 64–171 days. In 5/6 patients, the amount of radioactivity recovered in the urine and feces samples within 168-hours post- dosing ranged from 84.8–93.0%; the analogous amount in the remaining patient was only 34.1%. In all patients, mean radioactivity recovered was 58.8% in feces and 20.8% in urine. Radioactivity appeared to be confined to plasma. Three patients (2 renal cell carcinoma; 1 mesothelioma) had a best RECIST response of stable disease (SD); 1 patient had a confirmed reduction in max tumor diameter of 10% to <30%. Two patients had progressive disease and 1 patient was non-evaluable. The most common adverse events (AEs) were diarrhea (n=5) and hypertension (n=3); no grade 3 or 4 AEs occurred more than once. There was evidence of reductions in DCE-CT parameters post treatment, particularly perfusion, permeability surface product (PSP) and positive enhancement integral. For each of these parameters, a decrease from baseline outside the baseline reference range was recorded for 3 patients (including 2 with SD) at 1 month after the start of daily dosing of AZD2171. Overall, within-patient variability (W-PV) was generally low for all DCE-CT parameters measured and was consistently lower than between-patient variability. The W-PV was largest for PSP (18%) and lowest for mean transit time (7%). Conclusions: The primary route of AZD2171 elimination appears to be hepatic. AZD2171 was well tolerated and clinically meaningful disease stabilization was seen. Changes in tumor vascular parameters were detected by DCE-CT. [Table: see text]
Tolerance of avastin in metastatic colorectal cancer—a single institute Kuwait Cancer Control Centre experience
Authors: Vyas V. , Awadi S. A. , Khodary A. E. , Nemec J. , Muralidharan K. C. , Delvadiya M. D. 
Published: March 2020

14156 Background: Bevacizumab is being used in combination with five fluorouracil(5-FU) based chemotherapy like FOLFIRI, FOLFOX, and capecitabine, since its inception in the treatment of metastatic colorectal cancer one year ago. Methods: a retrospective analysis was carried out to assess the toxicity profile of bevacizumab. Results: total 36 patients received bevacizumab in combination with various 5-FU based regimens .Twenty one were males 15 were females. A total of 288 cycles have been administered. Toxicities included change in medication for uncontrolled hypertension and mild epistaxis in 3 cases. One patient with intact primary in sigmoid colon developed perforation, peritonitis and she died subsequently. Conclusions: Conclusion- this preliminary results indicate that bevacizumab in combination with 5-FU based chemotherapy was tolerated. Extra precaution is required in cases of intact primary tumours. No significant financial relationships to disclose.
The study of the relationship between Notch signal transduction pathway and polycomb protein Bmi1 in colorectal caner cells
Authors: Zhang H. , Ye Y. , Xu F. , Zhou J. , Wang S. 
Published: March 2020

14501 Background: As is known the polycomb group protein BMI1 has been shown to support normal stem cell proliferation via its putative stem cell factor function. However, the potential molecular mechanism of BMI1 act as a cancer stem cell factor may also promote cancer development is unclear. In this study we demonstrated for the first time that Notch signal transduction pathway regulating expression of Bmi1 in colorecta caner cells and investigate the Notch1 mRNA and Bmi1 mRNA level in human colorectal cancer samples and their correlation with clinicopathological parameters of colorectal cancer. Methods and Results: We assessed Notch1 and Bmi1 mRNA in 50 cases of colorectal cancer and adjacent normal tissue by RT-PCR. The immunohistochemistry was used to determine the expression of ICN and in the 50 tissues of colorectal cancer and normal mucosa. Bmi1 SW480 cells were treated with DAPT (g-secretase inhibitor) at different times. MTT assay and flow cytometry were used to measure the proliferation and apoptosis of SW480 cells. The expression of ICN, Bmi1 were measured by western blot. Notch1 and Bmi1 mRNA level were increased in colorectal cancer compared with adjacent normal mucosa (P<0.05), the median values were 1.97-fold, 1.88-fold, respectively. It was found that overexpression of Notch1 and Bmi1 was related to differentiation and lymph nodes metastasis in colorectal cancer (P<0.05). The correlation between Notch1 and Bmi1 mRNA level, ICN and Bmi1 protein level are significant at the 0.01 level. Treating SW480 with DAPT, resulted in significant growth inhibition, apoptosis induction and downregulation of ICN and Bmi1. Conclusion: Our results show that overexpression of Notch1 and Bmi1 may play a critical role in the development of colorectal cancer. Notch1 signal transduction pathway regulating expression of Bmi1 in colorectal cancer cells.Blockade of Notch1 signal pathway can inhibit proliferation and accelerate apoptosis of colorectal cancer. [Key words] Colorectal cancer; BMI1; Signal transducers and activators of transcription3; Western blotting No significant financial relationships to disclose.