bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel therapeutic strategy for ER-negative human breast cancers, targeting AP-1 activity
Authors: Sakaguchi K. , Nakajima H. , Fujiwara I. , Mizuta N. , Magae J. 
Published: March 2020

14129 Background: While agents targeting estrogen receptors are the most effective in adjuvant therapy for human breast cancers expressing estrogen receptor(ER), breast cancers lacking ER are clinically serious, because they are highly malignant and exhibit resistance to the usual anti-cancer drugs, including estrogen receptor-antagonists and DNA breaking agents. Although a transcription factor, AP-1, is known to be related to tumor malignancy including metastasis, invasion and drug-resistance, it remains to be elucidated how AP-1 plays in development and expression of malignant characters of human breast cancers. Methods and Results: Here, we used MX-1, a human breast cancer cell line lacking ER and several ER positive cell lines, to clarify the roles of AP-1 and the therapeutic efficacy of ascochlorin, a newly developed prenylphenol antibiotic on ER-negative breast cancer. We found that MX-1 exhibited higher AP-1 activity and expressed higher levels of c-Jun, c-Fos and Fra-1 when compared with conventional ER-positive human breast cancer cell lines. Consistent with this study in vitro, histological study on human breast cancer tissues suggests that ER-negative cancers express high Fra-1 protein, and that paclitaxel- sensitive cancers express low Fra-1 protein. The ascochlorin, which inhibits AP-1 through the Erk signaling pathway, suppressed the AP-1 activity of MX-1 cells, and selectively killed MX-1 cells, partly due to induction of apoptosis. Moreover, administration of ascochlorin elongated life span of mice intraperitoneally implanted with murine mammary carcinoma cells. Conclusions: Our results suggest that AP-1 is an effective clinical target molecule for the treatment of ER-negative human breast cancer, and that ascochlorin is promising therapeutic agent for these refractory breast cancers. No significant financial relationships to disclose.
A phase I two arm trial of AS703569 (R763), an orally available aurora kinase inhibitor, in subjects with solid tumors: preliminary results
Authors: Renshaw J. S. , Patnaik A. , Gordon M. , Beeram M. , Fischer D. , Gianella-Borradori A. , Lin C. , Mendelson D. 
Published: March 2020

14130 Background: Aurora kinases are a family of kinases that play a crucial role in regulating segregation of chromosomes from parent to daughter cell and have been linked to tumorigenesis. Aurora kinase A is commonly amplified in solid tumors and has been established as an oncogene. Aurora B is often overexpressed and leads to defects in mitosis and increased tumor invasiveness. AS703569 is an orally available, highly potent inhibitor of aurora kinases A and B and several other kinases. AS703569 has been shown in vitro and in tumor xenograft models to inhibit proliferation and to trigger apoptosis of several tumor types. We report on the initial results of a phase I study of AS703569 in patients with solid tumors. The study objectives are to determine for each of 2 different dosing regimens the MTD and to evaluate safety, PK and pharmacodynamic effects. Methods: This is a phase I, two arm, dose-escalation study. Cohorts of 3 patients ≥18 years old with advanced solid tumors are being assigned to one of 2 dosing regimens. The dose escalation follows a modified Fibonacci scheme. The starting dose level is 6 mg/m2 p.o. per 21-day cycle divided in 2 or 3 doses (regimen 1: dosing on days 1, 8 or regimen 2: dosing on days 1, 2, 3). Patients with stable disease or response will be offered additional cycles. Results: A total of 15 patients have been included to date. The tumor types represent a typical widespread in phase I trials, including 3 cases of uterine/cervical cancer and 2 cases of breast cancer. The first 2 cohorts of 3 patients on dose level 1 (regimen 1 and 2) have been treated with no dose-limiting toxicities (DLTs) or serious adverse events (SAEs). Dose-escalation is proceeding for both regimens with 9 patients treated on dose level 2, 6 in regimen 1 where due to a DLT (likely disease-related and unlikely related to AS703569) the cohort was expanded, and 3 in regimen 2. Thus far, only two patients were withdrawn from the study due to disease progression and one patient withdrew consent. Two patients are ongoing at 4+ cycles and one at 3+. Conclusions: Treatment of patients in this phase I study of the aurora kinase inhibitor AS703569 at dose level 1 and 2 has been well tolerated over several cycles. Dose escalation is ongoing and analysis of PK and pharmacodynamics will be reported. No significant financial relationships to disclose.
Increased detection and contrast enhancement of small malignant lung nodules in mice by a tumor-targeting nanoimmunocomplexed contrast agent
Authors: Freedman M. T. , Pirollo K. F. , Chang E. H. 
Published: March 2020

14131 Background: Lung cancer screening with CT results in the detection of many small lung nodules, few of which are cancerous. As a result many patients are followed to assess nodule growth. Contrast enhanced MRI and CT are used to determine whether small nodules are hypervascular or hypovascular, differentiating between nodules that are more/less likely to be malignant. For nodules 7 mm and larger, contrast enhancement has few false negatives, but a moderate number of false positives leading to unnecessary biopsies. Reported here is a new method of delivering contrast agent that transfers it directly into the cancer cells. This delivery system is a nano size immunoliposome complex containing gadopentetate dimeglumine which is targeted to the transferrin receptor on the cell. Methods: Syngeneic mouse model of lung metastases is used. Mouse renal carcinoma cells are tail vein injected into female BALB/c mice. For small lung nodules (1–4 pixels), the animals are imaged 7–9 days post inoculation. Images are obtained with a 7T MRI using RARE sequences. Results: Comparisons of pixel intensity were made between the pre- and post contrast images and between the novel and standard contrast agents. Using the complex, nodules as small as 2 pixels (200 μm) in size can be visualized and have greater pixel intensity. Conclusions: A novel carcinoma specific nanocomplexed MR contrast agent shows improved enhancement when compared to standard MR contrast. This agent is on the path towards clinical testing. It could help determine which small nodules identified on screening CT have a high or low probability of malignancy. Specific targeting to carcinoma cells should result in fewer false positives. This novel imaging contrast agent should enable detection, and earlier confirmation of malignancy, in nodules substantially smaller than currently possible. No significant financial relationships to disclose.
Implication of human epidermal growth factor receptor-2 (HER-2) over expression in treatment of breast cancer in developing countries—report on 250 cases from Bangladesh
Authors: Hossain M. , Rahman S. , Alam A. , Qamruzzaman C. , Hossen M. , Hai M. , Reza M. 
Published: March 2020

14139 Background: Carcinoma breast is the second most common malignancy in Bangladeshi women. Though HER-2 over expression has profound effect on prognosis of breast cancer, no published data is available about this among Bangladeshi patients. Our aim in this study was to see HER-2 status in Bangladeshi patients, and their relation with other prognostic parameters. Implication of this molecular marker in management of breast cancer in poor country like ours remains controversial, keeping in mind the exorbitantly high cost of Trastuzumab. Methods: This prospective study was conducted in the department of Oncology at Bangladesh Medical College Hospital, National Institute of Cancer Research and Hospital and Ahsania Mission Cancer Hospital Bangladesh, from January 2003 to December 2006. Total 250 women with breast carcinoma were enrolled; biopsy specimens were tested by immunohistochemistry to detect HER-2 status. For recommending treatment with Trastuzumab, patients with 3+ immunohistochemistry results were considered HER-2 positive. Fluorescent In Situ Hybridization (FISH) testing facility was not available. These findings were correlated with age, ER/PR and nodal status. The practical application of marker in terms of use of Trastuzumab was analyzed. Results: Age of patients ranged from 19.75 years to 72 years, mean age was 49.75 years. HER-2 was over expressed in 38.4 % (96) cases and their mean age was 42.92 years compared to 47.61 years in HER-2 negative cases. HER-2 positive cases tended to have higher rates of lymph node metastases (44 out of 96) compared to HER-2 negative (46 out of 154) cases (45.8 % vs 29.87 %). ER/PR was positive in 64 % cases. HER-2 over expression was inversely related to ER / PR expression. Of the HER-2 positive cases, 11.45 % (11 out of 96) afforded treatment with Trastuzumab. Conclusions: HER-2 is over expressed in almost 38 % of breast carcinoma patients in Bangladesh. This expression is associated with relatively young age, lymph node metastasis and lack of ER / PR expression. Only 11.45 % of patients with HER-2 over expression afforded Trastuzumab though 38 % of cases over expressed HER-2. No significant financial relationships to disclose.
Changes in the kinase expression panel of K562 human leukemia after Avemar treatment
Authors: Telekes A. , Rásó E. 
Published: March 2020

14143 Background: The positive effect of the wheat germ extract Avemar has already been proved in cancer. Compared to the control group significantly longer survival times were achieved in both in vivo experiments and clinical studies. Inhibition of cell growth was also detected in K562 human leukaemia cell line in vitro. Avemar given p.o.(3 g/kg) resulted in significant increase of the survival time compared to the control group (p<0.005 Mann-Whitney) in i.v. implanted K562 xenograft model, which was practically the same as the effect of Gleevec treatment. Since, the mechanism(s) of action of Avemar is still not properly characterized a kinase expression panel in K562 in vitro model was examined. Methods: K562 cells (8x105 cell/ml), were treated with Avemar (500 μg/ml) and mRNS from 3–3 parallel samples and their appropriate controls were isolated 24, 48 hours after the treatment and 24 hours after washing the cells previously treated with Avemar for 48 hours. To determine the kinase expression pattern Kinase OpenArray™ plates were used, having over 500 kinase genes with controls in quadruplicates in each plate. Changes in expression was declared if the average value was over 1 (2-fold change in mRNA copy number) and the standard deviation was relatively small (2xSTDEV = AVERAGE). Results: We have found 16 kinases which expression has temporary or durative (maintained for 24 hour after washing) decreased (e.g.: CCL2, ABR, FLT1, EphB6, TGFa) and 30 which expression has increased (e.g.: CPT1B, IRE1, ITK, RON, LTK, EphB2, FASTK). Conclusions: Our result demonstrated that many of the kinases which expression was altered by Avemar treatment is known to participate in cell cycle, cell migration, apoptosis and signal transduction. Thus, our results might shed light on the main mechanism(s) of action of Avemar and raise the possibility to identify the active substance(es) of this natural extract. No significant financial relationships to disclose.
Manifestations of cardiovascular toxicity associated with the approved tyrosine kinase inhibitors
Authors: Verbois S. L. , Saber H. , Benson K. A. , Morse D. E. , Justice R. 
Published: March 2020

14152 Background: Since 2001, 5 tyrosine kinase inhibitors (TKi’s; imatinib, erlotinib, sorafenib, sunitinib and dasatinib) have been approved for hematologic and solid tumor indications including, CML, ALL, GIST, RCC, pancreatic and NSCLC. While individual agents are designed to inhibit the TK activity of specific targets, “cross-talk” with non-target TKs (e.g., ABL, EGFR, VEGFRs, KIT, KDR, CSF1R, PDGFRs, RET, the SRC family, EPHA2, RAF, and FLT3) is extensive. The relationship between inhibition of individual kinases and the toxicity profile of each drug is unclear. Methods: Following from the observation of cardiovascular (CV) toxicity in clinical settings (pre- and post- marketing) and from the original non-clinical toxicologic evaluations, a new “class-related” review of non-clinical toxicological findings was conducted. To compare the non-clinical and clinical CV findings, the Adverse Event Reporting System (AERS) was searched for all events, excluding those of non-CV nature and those unlikely to be drug-related (e.g. hemorrhagic events were excluded from the initial analyses). Individual patient reports were not reviewed in full, therefore definitive attribution of disease related events can not be made. Results: While variable in expression, the non-clinical signs of toxicity included cardiac and vascular inflammation, cardiac degeneration and hypertrophy, decreased cardiac function (e.g. LVEF decreases), alterations in blood pressure, and QT prolongation. Clinical reports for the TKi’s have included hypo- and hypertension, conduction abnormalities and arrhythmias, cardiac hypertrophy and changes in cardiac function (LVEF and CHF). Conclusions: It is not possible at this time to relate the CV toxicities associated with the TKi’s to a specific pattern of TK inhibition. CV toxicity has been observed both clinically and non-clinically and warrants further investigation. No significant financial relationships to disclose.
Combined therapy for rectal cancer in the elderly
Authors: Bohac G. C. , Hartshorn K. , Cheng D. 
Published: March 2020

14504 Background: Neoadjuvant or Adjuvant Chemoradiotherapy (CRT) plus surgery is the standard of care for treatment of Stage II/Stage III rectal cancer. Previous studies of practice patterns have evaluated SEER data using single dose chemotherapy as a surrogate for having ever been treated. No study to date has evaluated the use of CRT along with surgery to determine the ability of elderly patients with rectal cancer to complete prescribed therapy. Methods: A retrospective study of all patients treated for Stage II/III rectal cancer identified by Tumor Registrar from January 1, 1987 to June 1, 2006 at the Boston VAMC and Boston Medical Center were analyzed. Data was extracted from computerized records and paper charts. Statistical analysis was performed with SAS software. The primary endpoint was to determine if younger (<70 yr) and older (>=70yr) patients were equally likely to complete CRT and surgery without having a dose of chemotherapy or radiation reduced, held, or delayed. Secondary endpoints were to determine if older and younger age groups were equally likely to receive CRT and a multivariate analysis of factors (age, having received neoadjuvant therapy, number of comorbidities, stage of tumor) had an effect on these outcomes. Results: A total of 266 patients were identified and included in the study. The likelihood of completing CRT and surgery without a dose being held, delayed or reduced was statistically similar among patients age 70 and older (16.1%) as among younger patients (23.9%) (Chi-square 2.16 p=0.1414). However, older patients were far less likely (58.24%) than younger patients (76%) to receive CRT (Chi-square 8.79 p=0.003). A multivariate analysis of factors associated with completion of CRT without a dose being held, delayed or reduced identified only the number of comorbidities (one or more) OR=0.383 (95% CI 0.186–0.790) as statistically significant. In addition, multivariate analysis of factors associated with receiving CRT identified having received neoadjuvant therapy OR=5.397 (95% CI 2.303–12.60) and age >=70 OR=0.424 ( 95% CI 0.201–0.898) as statistically signficant. Conclusion: Elderly patients with rectal cancer are less likely to be prescribed CRT than younger patients. However, elderly patients who are prescribed to receive CRT appear to be able to tolerate the therapy as well as younger patients. No significant financial relationships to disclose.
A systematic review on the efficacy of repeat hepatectomy for recurrent liver metastases from colorectal carcinoma
Authors: Sim J. , Yan T. D. , Black D. , Morris D. L. 
Published: March 2020

14506 Background: Liver recurrence after hepatectomy for colorectal liver metastases (CRLM) is common and associated with a reduced survival if not treated aggressively. The objectives of this systematic were to critically appraise the quantity and quality of current clinical evidence and demonstrate the efficacy of repeat hepatectomy for CRLM. Methods: Electronic searches for relevant studies published in peer-reviewed medical journals on repeat hepatectomy for recurrent CRLM prior to September 2006 were performed on six databases. The reference lists of all retrieved articles were manually searched for further identification of potentially relevant studies. All relevant articles identified were assessed with application of selection criteria. The quality of each included study was assessed. Clinical effectiveness was synthesized through a narrative review with full tabulation of results of all included studies. Results: Seventeen studies with more than 20 patients were included for quality appraisal and data extraction. These 17 studies consisted of two multi- institutional, one bi-institutional and 14 single-center observational studies. The overall perioperative morbidity rate ranged from 7–30% and mortality rate varied from 0–5%. The rates of intra-abdominal abscess, wound infection, bile leak, hepatic failure and pleural effusion ranged from 2.4–23%, 2.4–11%, 0.8–10%, 0–4.5% and 2.4–9.5%, respectively. The overall median survival since initial hepatectomy was 26 to 73 months. The overall median survival since the repeat hepatectomy ranged from 23 to 56 months, with 3- and 5-year survival of 24–68% and 21–49%, respectively. The median disease-free survival ranged from 9 to 52 months, with 3- and 5-year disease-free survival of 16–68% and 16–48%, respectively. After repeat hepatectomy the rates of disease recurrence in the liver and at an extra-hepatic site were 15–67% and 27–64%, respectively. Conclusions: The current literature suggests that repeat hepatectomy is associated with a prolonged survival for recurrent CRLM. Although all studies were observational case series, repeat hepatectomy is justified in selected patients, as there is a lack of evidence for alternative treatment. No significant financial relationships to disclose.
Trans-arterial chemoembolization (TACE) of liver metastases (LM) from colorectal cancer (CRC) adopting irinotecan-eluting beads: Results of a phase II clinical study
Authors: Fiorentini G. , Aliberti C. , Giovanis P. , Tilli M. , Rossi S. , Benea G. 
Published: March 2020

14525 Background: Patients with LM from CRC have a poor prognosis with survival rates of 31% at 1 year and 2.6% at 3 years. Surgery is feasible in a minority of patients and most them received systemic chemotherapy. Irinotecan (IRI) is an active drug in the treatment of advanced CRC. The advantage of delivering chemotherapy by hepatic arterial infusion is the achievement of high-dose of the drug in the target . TACE is a combination of local drug infusion with selective embolization of the feeding arteries of the liver metastases. DC bead is a new embolic microsphere product that can be loaded with IRI before administration in TACE. The purpose of this study is to assess the safety and efficacy of this new embolic microspheres IRI loaded and administered as TACE in patients with LM from CRC. Methods: 35 patients with LM from CRC Stage II-III Pettavel Classification pretreated were observed from Nov 2005 to Dec 2006. 25 gave their written consent to be treated with one o more cycles of TACE. Imaging was performed before, immediately and 4 weeks after TACE to determine response and the need for further treatment. Each patient received i.v hydration, antibiotics, analgesics and medications against nausea before TACE. Survival was calculated with Kaplan-Meier method. Results: 60 cycles were administered. We observed a Response Rate of 80% by RECIST criteria. A month after TACE we had a reduction of +50% of CEA in 60% of patients. A reduction of the lesional contrast enhancement of the metastases was observed in 80% of patients. 22 patients are alive, with a median survival of 9.5 months (range 6–13). Median duration response was 16 weeks (range 12–25). 14 cases experienced WHO Grade 2 right upper quadrant pain (RUQP) and 11 cases Grade 3 lasting 12 hours (range 3–30). All patients had 2 days Grade 2 fever (range 1–7), ten had 3 days Grade 3. 20 have had Grade 2 nausea and vomiting for 6 hours (range 4–29). No alopecia or marrow toxicity was reported. Conclusions: DC bead -TACE was feasible and effective in patients with LM from CRC. RUQP seems the most significant toxic event and needs analgesic therapy. No survival data are conclusive because the follow up is short. DC bead of IRI 100 mgr-TACE myght be an appropriate palliative therapy for these patients. No significant financial relationships to disclose.
Preoperative oxaliplatin (O), capecitabine (X), and external beam radiotherapy (RT) in patients (pts) with newly diagnosed, primary operable, locally advanced rectal cancer (LARC)
Authors: Öfner D. , de Vries A. , Thaler J. , Eisterer W. , Greil R. , Lukas P. , Rabl H. , Samonigg H. , Kapp K. , Gnant M. 
Published: March 2020

14527 Background: Local recurrence after surgery is a cause of treatment failure and relapse in pts with LARC. Preoperative RT decreases local recurrence but not distant spread. X and O are both highly active chemotherapies for advanced colorectal cancer, particularly in combination, and both are radiosensitizers. Therefore, the addition of X and O to preoperative RT should improve efficacy in terms of local control and prevention of metastases. Methods: This study investigated the efficacy (rate of downstaging) and safety of preoperative chemoradiation in pts with LARC (of lower and middle rectum), T3NxM0 staged by MRT. RT was administered for 5 weeks, 5 days/week, 1.8 Gy/fraction, total dose 45 Gy, 3D conformation technique, in combination with O 50 mg/m2 intravenously on days 1, 8, 15, and 22, and oral X 825 mg/m2 twice a day on RT-days during weeks 1–4. Surgery was performed 14–28 days after completion of RT. Results: 59 pts were enrolled (19 female, 40 male); median age 61 years (range 34–76), 100% of pts are evaluable for efficacy and toxicity. 41 patients had comorbidities: 16 cardiac, 3 hepatic, 6 diabetes, 1 neurological/psychological, 49 others. Tumor downstaging was observed in 53% of pts (23 T2, 2 T1, 6 T0). 5 pts withdrew because of adverse events. 28 pts (47%) experienced grade 1 neurotoxicity and 5 pts (8%) had grade 2 neurotoxicity. The most frequent grade 3/4 NCI-CTC adverse event was diarrhea: 5/59 pts (8%). Total O and X doses received were 90% and 93% of the planned doses, respectively. The main reason for chemotherapy dose reduction was diarrhea occurring during the 3rd-4th week of treatment. Per-protocol therapy was terminated for 8 pts due to interruption of RT for more than 3 days or adverse events such as diarrhea and nausea (total dose received 25.2–34.2 Gy). Conclusions: These results demonstrate that preoperative O and X in combination with RT is feasible in pts with LARC, and comparable with 5-FU. As expected, the only clinically relevant toxicity was diarrhea, and dose intensity of both chemotherapeutic agents and RT was high. [Table: see text]