bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of novel small molecule drugs in human explants across the disease sequence in colorectal cancer.
Authors: Murphy Adrian Gerard , Casey Rory , Fennelly David William , Reynolds Alison , Tosetto Miriam , Hyland John , Sheahan Kieran , O'Donoghue Diarmuid , Mulcahy Hugh , Kennedy Breandan , O'Sullivan Jacintha 
Published: March 2020

e13570 Background: The treatment of metastatic colorectal cancer has been improved by combining cytotoxic chemotherapy with bevacizumab. Newer anti-angiogenic agents are required to improve survival rates as response rates with the current therapies are modest. The preclinical development of such drugs is time-consuming and new methods are required to test the efficacy of lead drugs which represent the entire tumor micro-environment. Methods: Chemical screens were performed in zebrafish larvae to identify hits that affected intersegmental angiogenesis. Five lead drugs were then tested for cytotoxicity using the crystal violet assay. These drugs were tested using ex vivo colorectal tumor explants to determine their effect on secretion of IL-1β, TNF, IL-6 and VEGF. Human explants from 20 patients (Dukes A-D) were cultured for 72 hours and the levels of the above factors measured by ELISA. Comparisons were made between early (Dukes A&B) and late stages (Dukes C&D). Results: One thousand drugs were screened and 5 were found to reduce intersegmental angiogenesis in zebrafish larvae: AM1, AM2, AM3, AM4 and AM5. The drugs did not affect cell growth levels at 10 µM concentration. From the explant studies: AM1 decreased secretion of VEGF in late stages (p=0.005) and IL-6 in early stages (p=0.009). AM2 decreased VEGF in early (p=0.004) and late stages (p=0.02). AM3 decreased TNF secretion in late stages (p=0.02) and IL-6 secretion in early (p=0.009) and late stages (p<0.0001). AM4 decreased VEGF secretion in early stages (p=0.001), IL-6 in early stages (p<0.001) and late stages (p=0.03) and IL-1β in early stages (p=0.002). AM5 decreased IL-6 secretion in the early stages (p=0.03) and IL-1β in the early stages (p=0.001).Overall, IL-1β secretion was reduced by AM4, AM3 and AM5 (p<0.05). IL-6 secretion was reduced by AM1, AM3 and AM4 (p=0.001). TNF secretion was reduced by AM3 (p=0.02) and VEGF secretion was reduced by AM1, AM2 and AM4 (p<0.005). Conclusions: These studies show these drugs have stage-specific effects in colorectal tumor explants and may have the potential as new anti-angiogenic agents in colorectal cancer.
Development of a quantitative immunofluorescent method for analysis of nuclear and cytoplasmic p53 and p21 in circulating tumor cells (CTC) as biomarkers of response to p53-targeted therapy.
Authors: Woo Jacky , Wu Weiguo , Melnikova Vladislava O. , Anderes Kenna Lynn , Davis Darren W. 
Published: March 2020

e13575 Background: The tumor suppressor p53 is involved in many aspects of cell cycle control and p53 mutations are the most common genetic abnormality in solid tumors. Several diverse approaches targeting p53 signaling including activators of p53, cell cycle checkpoint inhibitors and MdM2 inhibitors are under development and will require determination of p53 status to demonstrate proof of concept and ultimately drive patient selection. Measurement of p53 status in tumor biopsies is often hindered by limited availability of tissues. Detection of p53 status in CTCs offers an alternative to biopsy. Methods: A multiplex immunofluorescent (IF) method for identification of CTCs was developed using cytokeratin, CD45 and DAPI. DO7, a p53 specific antibody, and total and phospho-p21 antibodies were optimized for multiplex detection. Bleomycin (50 mU/mL) was used to activate p53 in A549 p53 wt cells, HT29 and SkBr3 p53 mutant cells. Single cell-based IF analysis was performed pre and post treatment by quantitative Laser Scanning Cytometry (LSC). Results: Wild type A549 cells expressed lower baseline levels of nuclear p53 compared to mutant p53 cell lines HT29 and SKBr3. Total and phosphorylated p21 was also lower in A549 cells compared to HT29 and SKBr3 cells. Bleomycin treatment of wt A549 cells led to a transient increase in p53 expression by 30% while mutant HT29 and SKBr3 cells did not show any change in p53. Treatment of A549 cells with bleomycin led to a 100% increase in total p21and a 70% increase in phosphorylated p21. No change in p21 was observed in p53 mutant HT29 and SKBr3 cell lines. Conclusions: We developed a sensitive, quantitative method for detection of nuclear and cytoplasmic p53 and p21 protein in cell lines that functionally discriminates between p53 wt and p53 mutant status. The method is transferable to circulating tumor cells (CTCs) and may have utility in selecting patients based on functional p53 status and predicting responses to p53 pathway targeted agents.
Preclinical efficacy of the combination of olaparib plus carboplatin with vandetanib in triple-negative breast cancer.
Authors: Dey Nandini , Wu Hui , Sun Yuliang , De Pradip , Leyland-Jones Brian 
Published: March 2020

e13579 Background: BRCA1-deficiency confers sensitivity to PARP1 inhibition (alone or in combination with platinum compounds) in triple-negative breast cancer (TNBC). Recent understanding of the biology of TNBC tumor cells has recognized molecular targets suitable for treatment with targeted therapeutics including cell surface RTK(s), such as EGFR. Methods: We studied the effect of combination of PARP inhibitor, (olaparib) plus carboplatin with a dual EGFR/VEGFR inhibitor, vandetanib in a TNBC model in both in vitro and in vivo settings. We tested the effects of drug combinations on (a) cell signaling marker(s) of survival/proliferation/apoptosis, (b) adhesion-dependent and clonogenic survival, and (c) different phenotypes (migration, invasion, vascular mimicry, and cord formation) using TNBC cell and HUVEC cells. The combination of PARP1 inhibition and EGFR/VEGFR inhibition was evaluated in tumor-bearing athymic mice treated with olaparib plus carboplatin and vandetanib. Results: Data showed that, (1) EC50s for vandetanib ranged from 5-15 µM, (2) vandetanib (10 µM) inhibited phosphorylation of AKT (S473 & T308), S6RP, 4EBP1 and ERK, (3) effect of olaparib on TNBC cell survival can be effectively studied in vitro by clonogenic assay, (4) TNBC cell lines exhibited higher sensitivity to vandetanib in clonogenic assay when combined with 10 µM fixed dose of olaparib, and (5) a combination of vandetanib with olaparib plus carboplatin time dependently increased caspase-3 and PARP cleavage, inhibited vascular mimicry, blocked fibronectin-directed migration, and suppressed clonogenic growth in TNBC cells.Vandetanib blocked (a) cord formation, (b) vitronectin-directed migration, and (c) HIF-1alpha accumulation and phosphorylation of proliferation markers (AKT, 4EBP1, and ERK) in HUVEC cells. Conclusions: Anti-proliferative/pro-apoptotic, and anti-migratory/invasive effects of vandetanib (alone or in combination with carboplatin plus olaparib) were observed both in tumor cells and in endothelial cells. We are currently studying in vivo the effect of combining olaparib plus carboplatin with vandetanib, in xenograft model the results of which will be presented in the meeting.
Association of baseline plasma biomarker signature with survival in advanced NSCLC patients on linifanib.
Authors: McKeegan Evelyn Mary , Chakravartty Arunava , Ansell Peter J , Davis Gerard , Chen Gong , Chan Sabrina , Chandran Raj , DeGuzman Angel , Gawel Susan , Dowell Barry , Bhathena Anahita , McKee Mark D. , Ricker Justin L. , Carlson Dawn M. , Devanarayan Viswanath 
Published: March 2020

e13583 Background: Linifanib is a potent and selective VEGF and PDGF receptor inhibitor that has activity in unselected, advanced NSCLC patients (pts) both as monotherapy in the relapsed setting and with carboplatin (C) and paclitaxel (P) in the first-line setting. A baseline plasma biomarker signature identifying NSCLC pts most sensitive to linifanib is needed. Methods: An exploratory retrospective analysis of four randomized clinical trials including linifanib or other treatments in relapsed NSCLC was conducted. Evaluable baseline plasma samples were obtained from 116 pts who received linifanib and 71 pts on other treatments. A signature combining established tumor markers (carcinoembryonic antigen [CEA] and fragments of cytokeratin 19 [CYFRA 21-1]) was derived using a sequential BATTing approach. The signature was then tested across a randomized trial of CP + placebo, linifanib 7.5 mg, or linifanib 12.5 mg in first-line advanced, non-squamous NSCLC. Results: In 2/3L NSCLC, the signature was associated with improvement in survival on linifanib monotherapy (HR=0.51 vs. signature negative; P=0.0017), but no improvement in survival on other treatments (P=0.87). In the first-line setting with CP, the signature was associated with significant PFS improvement with linifanib and a trend towards significant overall survival improvement at high dose (Table). Conclusions: A baseline plasma biomarker signature is associated with improved survival in advanced NSCLC patients on linifanib. Incorporation of this signature should be considered in any further investigation of linifanib in NSCLC. [Table: see text]
FOLFIRI-3/bevacizumab induction, then capecitabine/bevacizumab maintenance as front-line strategy for metastatic colorectal cancer: A phase II trial.
Authors: Kim Stefano Chong Hun 
Published: March 2020

e14007 Background: Bevacizumab with FOLFIRI or FOLFOX regimen is the standard of care in metastatic colorectal cancer (mCRC). As second line regimen after FOLFOX, FOLFIRI-3 has showed a significantly better PFS in comparison with other irinotecan-based regimen. We therefore evaluated the safety, efficacy and possible predictive factors for FOLFIRI-3 in combination with bevacizumab as initial treatment for mCRC. Secondarily, we evaluated the feasibility of Capecitabine-Bevacizumab maintenance. Methods: We conducted a phase II, multicentric trial of FOLFIRI-3 regimen (irinotecan 100mg/m2 day 1, LV 200mg/m2 day 1, 5-FU bolus 400 mg/m2 day 1 followed by a 36-h 5-FU continuous infusion 2400 mg/m2, irinotecan 100mg/m2 day 3) with bevacizumab (5mg/kg day 1) repeated every 2 weeks, as first-line treatment in mCRC for 6 months, followed by maintenance treatment with bevacizumab (7.5 mg/kg day 1) and capecitabine (1000 mg/m2 day 1 to 14), repeated every 3 weeks. The primary endpoint was objective response rate (ORR). Secondary endpoints were PFS, overall survival (OS), and biologic analysis of potential predictive factors of response to treatment. Results: From October 2007 to July 2009, 61 patients were enrolled for treatment. The ORR was 66.7% (8.3% of complete response and 58.3% of partial response). Stable disease was observed in 25% of patients (disease control rate of 91.7%). PFS was 12 months, and OS was 33 months. Forty patients entered to maintenance phase. Favorable tolerance profile was observed. Median PFS was 14 months, and OS was 36 months. Its efficacy was maintained in patients recently exposed to oxaliplatin. Conclusions: As front-line regimen in mCRC, FOLFIRI3-bevacizumab is maybe the best among irinotecan-5FU-bevacizumab based regimens to obtain objective response rate. PFS and OS are high but it can be secondary to high complete resection rate in our trial. In recently oxaliplatin-exposed patients, FOLFIRI3-bevacizumab regimen should be considered as first line treatment. Capecitabine-bevacizumab maintenance is clearly feasible and its encouraging result should be validated in a large phase III trial.
Different clinical outcome of metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx) according to KRAS genotype and disease extension.
Authors: Bruera Gemma , Cannita Katia , Di Giacomo Daniela , Lamy Aude , Troncone Giancarlo , Dal Mas Antonella , Coletti Gino , Frébourg Thierry , Sabourin Jean-Christophe , Tosi Mario , Ficorella Corrado , Ricevuto Enrico 
Published: March 2020

e14010 Background: Bevacizumab (BEV) plus triplet chemotherapy can increase efficacy of first-line treatment of MCRC, particularly if integrated with secondary liver surgery in liver-limited (L-L) patients (pts). Clinical outcome of FIr-B/FOx regimen was evaluated according to KRAS genotype in L-L and other MCRC pts. Methods: Tumoral and metastatic samples were screened for KRAS codon 12 and 13, and BRAF mutations by SNaPshot and/or direct sequencing. MCRC pts were classified as L-L and other or multiple metastatic (O/MM). Activity and efficacy were evaluated and compared using log-rank test. Results: Fifty-nine pts were evaluated: 31 KRAS wild-type, 53%; 28 KRAS mutant, 47%. At 21.5 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. PFS and OS were, respectively: overall in 25 L-L compared to 32 O/MM evaluable pts, 17 and 12 months, 47 and 21 months, significantly different; in KRAS wild-type, 12 L-L compared to 18 O/MM, 21 and 12 months, 47 and 28 months, significantly different; in KRAS mutant, 13 L-L compared to 14 O/MMS, 11 months equivalently, 39 and 19 months, not significantly different. Conclusions: First line FIr-B/FOx regimen can increase activity and efficacy of KRAS wild-type and mutant MCRC pts; integration with secondary liver surgery significantly discriminates increased clinical outcome in KRAS wild-type L-L compared to O/MM pts while not in KRAS mutant pts.
Safety and efficacy of percutaneous endoscopic gastrostomy tube placement in patients with malignant peritoneal carcinomatosis induced bowel obstruction.
Authors: Vashi Pankaj G , Braun Donald Peter , Popiel Brenten , Gupta Digant 
Published: March 2020

e14012 Background: Percutaneous Endoscopic Gastrostomy (PEG) tube placement in advanced peritoneal carcinomatosis with bowel obstruction is a feasible palliative procedure to help patients with obstructive symptoms. We describe the safety and efficacy of using PEG tube for decompression in patients with large peritoneal masses. Methods: A consecutive case series of 62 patients (Apr-08 to Jun-11) with advanced abdominal carcinomatosis induced bowel obstruction. All patients were extensively treated for their cancer. None of them were surgical candidates due to extensive peritoneal involvement. All patients had symptoms of nausea, vomiting and pain at the time of PEG tube placement. All patients had a 28F (Bard) PEG tube placed for drainage. The primary outcomes of interest were complications and symptom resolution due to PEG tube placement. Frequency of nausea, vomiting and severity of pain was recorded daily in patient charts. Results: 16 were males and 46 females. The mean age was 50.5 years. Most common cancers were ovary, pancreas, colon and stomach. Of 62 patients, 57 patients had expired at the time of this analysis. Of those 57 expired, 49 had PEG tube at the time of death, while 8 had complete resolution of symptoms with PEG tube removed before death. The 5 out of 62 patients who are alive still have the PEG tube for drainage (average 70.4 days). The average duration of PEG tube placement for all patients combined was 70.9 days (range 6-312 days). Relief of nausea, vomiting and pain was observed in 53 (85.5%), 55 (88.7%) and 35 (56.5%) patients respectively. Of a total of 43 patients who had PEG tube placed for >= 30 days, 24 (56%) could continue with their chemotherapy cycles because of symptom resolution. Non life threatening complications of PEG tube placement were observed in 9 (14.5%) patients. 3 had infection at the insertion site, 2 had bleeding and 3 had leaking at the PEG tube site while 1 had aspiration. 6 (9.7%) patients required replacement of the PEG tube due to occlusion. Conclusions: Placement of PEG tube in presence of advanced peritoneal carcinomatosis is safe and effective in relieving obstructive symptoms as well as extending the period of active cancer therapy.
Effect of major liver resection on colon cancer metastasis in the lung and liver.
Authors: Hoffman Robert M. , Momiyama Masashi , Suetsugu Atsushi , Kishimoto Hiroyuki , Chishima Takashi , Bouvet Michael , Endo Itaru 
Published: March 2020

e14014 Background: Liver resection is a common procedure in liver-metastatic colon cancer. However, recurrence is common and distant liver metastasis may be appear after liver resection. Methods: Experimental liver metastases were established by spleen injection of the Colon 26 murine colon cancer cell line expressing green fluorescent protein (GFP) into transgenic nude mice expressing red fluorescent protein (RFP). Experimental liver metastases was established by splenic injection of Colon-26-GFP. Experimental lung metastases were established by tail vein injection with Colon 26-GFP. Three days after cell injection into the spleen or tail vein, groups of mice underwent liver resection (35%+35% [repeated minor resection] vs. 70% [major resection]). Metastatic tumor growth was measured by color-coded fluorescence imaging of the GFP-expressing cancer cells and RFP-expressing stroma. Results: Although major and repeated minor resection removed the same volume of liver parenchyma, the two procedures had very different effects on metastatic tumor growth. Major resection, stimulated liver and lung metastatic growth as well as recruitment of host-derived stroma into the metastases compared to repeated minor resection. Repeated minor resection did not stimulate metastasis or stromal recruitment. There was no significant difference in liver regeneration between the two groups. TGF-β was also preferentially stimulated by major resection. Conclusions: Host-derived stroma density, which is stimulated by major resection compared to repeated minor resection, may stimulate metastatic growth. Stromal growth may be stimulated by TGF-β. The results of this study indicate that caution should be taken when planning a major liver resection for metastatic colorectal cancer. Conservative resections that spare liver parenchyma should be considered whenever possible.
The kinetics of the excision repair cross-complementing group-1 (ERCC1) gene in patients with colorectal cancer.
Authors: Merla Amartej , Mallick Atrayee Basu , Augustine Titto A , Chaudhary Imran , Gajavelli Srikanth , Maitra Radhashree , Daroqui Cecilia , Aparo Santiago , Seetharam Raviraja , Rajdev Lakshmi , Kaubisch Andreas , Madajewicz Stephan , Negassa Abdissa , Mariadason John , Ghalib Mohammad Haroon , Goel Sanjay 
Published: March 2020

e14019 Background: Oxaliplatin is an integral drug in the management of patients with colorectal cancer (CRC); however, half the patients fail to benefit from it. We know that in vitro, the excision repair cross-complementing group-1 (ERCC1) gene is inducible and contributes to cellular resistance to oxaliplatin. Using peripheral blood mononuclear cells (PBMC) as a surrogate tissue, we sought to confirm in vivo, the inducibility of ERCC gene expression and its relationship to clinical outcomes. Methods: Patients with CRC who received oxaliplatin consented to blood (PBMC) sampling at 0, 2, 48 hours, and 14 days during any cycle of chemotherapy. Clinical benefit from oxaliplatin was determined using the parameters of response rate and progression free and overall survival (PFS and OS). ERCC1 gene expression was quantified by qPCR (quantitative real time polymerase chain reaction) and WB (western blotting). Results: A total of 52 patients have been enrolled of which 29 patients have sampling at all 4 time points. ERCC1 gene expression was induced in 48.5% and 66.7% by mRNA and WB, respectively. Down regulation was observed in 30.3% and 8.3% by mRNA and WB, respectively. No change was noted in rest of the patients. The median PFS in patients with ERCC1 induction by qPCR was 7.25 months and was numerically shorter than the 13 months noted in patients with stable or reduced ERCC. This may suggest that in patients with ERCC induction, there is compromised PFS, but our data is limited by the small sample size. The difference in induction noted between qPCR and WB remains unclear. We did not find any significant difference in PFS when taking baseline expression of ERCC into consideration. Conclusions: This study confirms the inducibility of ERCC gene expression in vivo, in a sub-population of patients with CRC when they are treated with oxaliplatin. This gene induction is a potential marker of resistance to chemotherapy. We failed to find an association between clinical benefit and baseline ERCC expression. The factors that influence the inducibility of this gene remain unknown requiring further studies.
Adjuvant chemotherapy containing oxaliplatin without radiotherapy to improve survival of local advanced low and middle rectal cancer.
Authors: Ding Ke-Feng , Li Jun , Song Yong-Mao , Wang Jian-Wei , Yuan Ying , Zhang Suzhan 
Published: March 2020

e14024 Background: In this study, the impact of oxaliplatin on survival of local advanced rectal cancer patients were analyzed by comparing the survival of patients accepted only radical surgery (group S) and patients accepted radical surgery following oxaliplatin-containing adjuvant chemotherapy (group SO). Methods: The data of patients, who accepted radical surgery in our center from Jan 2002 to Jun 2009, were reviewed. Inclusion criteria: carcinoma ≤12 cm from the anal verge; pathologically confirmed T3/4 or N1/2; without history of malignancy; neither transanal nor transsacral resection. Patients who accepted radiotherapy were excluded. The disease specific survival (DSS) and overall survival (OS) of patients in group S and SO were analyzed. Results: 236 patients were included in analysis (S 135 vs. SO 101), including 11 patients without survival information. The most of patients' basic characteristics were similar in two groups (P>0.05). However, the ratio of stage II patients in group S was higher than that in group SO (51.9% vs. 27.0%, P<0.001). The DSS of group SO were higher in patients with stage II, N1a or mucious adenocarcinoma than patients in group S (P<0.05). The OS of group SO were higher in patients with N1a, N2 or mucious adenocarcinoma than patients in group S (P<0.05). Conclusions: Adjuvant chemotherapy containing oxaliplatin improved survival of local advanced low and middle rectal cancer. Randomized perspective trials are needed to clarify the importance of oxaliplatin for rectal cancer. [Table: see text]