bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reversal of the Warburg effect in breast cancer cells by a novel agent.
Authors: Arora Ritu , Schmitt David , McClellan Steven , Tan Ming , Reed Eddie , Owen Laurie , Dean-Colomb Windy Marie 
Published: March 2020

e13566 Background: It is well known that most cancer cells display a Warburg effect, a state of active glycolysis with lactate production under aerobic conditions. NF-κB has been shown to play a role in modulating cancer metabolism and control the balance between glycolysis and mitochondrial respiration. We have previously shown that panepoxydone (PP), a compound isolated from an edible mushroom, interferes with NF-κB mediated signal transduction. Additionally, we have shown that PP decreases cell viability and proliferation in breast cancer cells. To further characterize the antitumor effect of PP, here we have evaluated it ability to modulate cancer metabolism. Methods: The metabolic action of PP was evaluated in estrogen receptor positive (MCF-7) and triple negative (MDAMB-231) breast cancer cell lines. Cytotoxicity was determined by the cell titer glow assay and expressed as IC50. Metabolic activity, expressed as basal oxygen consumption rate (OCR, an indicator of oxidative phosphorylation) and extracellular acidification rate (ECAR, an indicator of lactate acid production), was measured in real-time using the XF24 Extracellular Flux Analyzer. Mitochondrial membrane potential (MMP) alteration was determined through flow cytometry and LDH-A expression was analyzed via western blot. Results: Significant antitumor activity with PP was seen in both MCF-7 (IC50 5 µM) and MDAMB-231 cells (IC50 15 µM). This correlated to a significant dose-dependent reduction in OCAR in MCF-7 (2-fold, p<0.05) and MDAMB-231 cells (3.5-fold, p<0.01). However, while a decrease in ECAR (1.5-fold, p<0.05), along with decreased LDHA expression was noted in the 231 cells (3.5-fold, p<0.01), this was not seen with the MCF-7 cells. A similar trend was noted with increased damaged mitochondria noted in 231-cells, but again no significant difference in MCF-7 cells. Conclusions: Taken together, these results indicate that PP has the potential to modulate metabolism in breast cancer cells, especially triple negative cells, as noted by its ability to inhibit glycolysis. The inhibition of glycolysis has become an important strategy in treating cancer and development of novel glycolytic inhibitors, such as PP, warrants its further investigation in breast cancer treatment.
Association of drug exposure with clinical response and toxicities in metastatic renal cell carcinoma patients (mRCC) receiving an alternative dosing (AD) regimen of sunitinib.
Authors: Teo Yi Ling , Chue Xiu Ping , Chau Noan-Minh , Tan Min-Han , Kanesvaran Ravindran , Wee Hwee Lin , Ho Han Kiat , Chan Alexandre 
Published: March 2020

e13582 Background: An AD regimen of 37.5mg daily in repeated 4-weeks on, 2-weeks off cycle has been proposed to ameliorate frequent dose modifications due to toxicities as observed with the approved dosing regimen of sunitinib for mRCC. This study aims to determine the effect of drug exposure (sunitinib and active metabolite, SU12662) on clinical response and toxicities in patients receiving this AD regimen. Methods: All mRCC patients starting on sunitinib were invited to participate in this study. In week 4 of each cycle, toxicities were assessed and graded according to CTCAE and plasma AUCss was quantified using high-performance liquid chromatography. Clinical response was assessed after 2 treatment cycles; and was used with drug exposure and toxicities data for dose adjustments. Statistical tests such as Mann-Whitney U were used to compare the levels between groups. Results: 24 patients with a mean age of 58.8 ± 11.2 years were recruited. Majority were males (75%) and Chinese (87.5%). Among the 17 and 14 analyzable cases for cycle 1 and 2, median total AUCsswere 2.2 and 2.1 µg•h/ml respectively. Fourteen patients completed 2 treatment cycles; 7 (50%) partial response, 4 (28.6%)stable disease and 3 (21.4%) progressive disease. A dose increment to 50mg daily was performed for a patient with disease progression. Common grade 2 and above toxicities were hypertension, hand foot syndrome (HFS) and mucositis. Higher drug exposures were observed among patients who achieved clinical responseand among those who experienced at least grade 2 toxicities. Conclusions: Drug exposure could likely be associated with clinical response and toxicities in this AD regimen. [Table: see text]
Predictive value of VEGF gene polymorphisms in metastatic colorectal cancer patients treated with a bevacizumab-based chemotherapy.
Authors: Ulivi Paola , Marisi Giorgia , Scarpi Emanuela , Passardi Alessandro , Ragazzini Angela , Frassineti Giovanni Luca , Zoli Wainer , Valgiusti Martina , Nanni Oriana , Calistri Daniele , Casacci Fabio , Amadori Dino 
Published: March 2020

e14512 Background: Bevacizumab (B) + chemotherapy (CT) is a common choice for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of B efficacy have still not been identified. In this study we verified the role of specific VEGF polymorphisms as predictive markers of the efficacy of B in mCRC patients. Methods: One hundred and forty-nine patients enrolled onto the phase III prospective multicentric randomized “Italian Trial in Advanced Colorectal Cancer (ITACa)” trial were considered for this study. Seventy-four patients received FOLFIRI or FOLFOX plus B and 75 patients received only CT. A peripheral blood sample was collected from each patients and submitted to genomic DNA extraction. Five single nucleotide polymorphisms (SNPs) were analyzed by direct sequencing: VEGF -2578 C/A, -1498 C/T, -1154 G/A, -634 G/C, +936 C/T. All candidate genotypes were evaluated for a potential correlation with objective response rate (ORR) (Chi-square test). Results: In the B-treated group, the presence of VEGF -2578 AA, -634 GG or -1498 CC polymorphisms was associated with a better ORR compared to the other genotypes. In particular, of the 17 patients carrying the VEGF -2578 AA genotype, 14 (82.4%) showed a response, whereas only 30 (54.6%) of the 55 patients carrying -2578 CC or CA responded to therapy (p=0.05). Similarly, of 30 patients with VEGF -634 GG, 23 (76.7%) responded to therapy, whereas only 21 (50%) of the 42 patients with VEGF -634 GC or CC were responders (p=0.03). Moreover, 13 (81.3%) of the 16 patients carrying VEGF -1498 CC were responders, whereas of the 56 patients with VEGF -1498 CT or TT, only 31 (55.4%) showed a response (p=0.07). No differences in terms of ORR were observed in patients receiving only chemotherapy. However, as a result of the low power of the interaction test, the relation between ORR and treatment was very close to statistical significance for VEGF -2578 only (p=0.07). Conclusions: VEGF -2578 C/A seems to be a potential predictive marker for B-based CT in mCRC patients. Further studies on larger case series are now needed to confirm this finding.
Phase I/II trial of intraperitoneal implantation of agarose-agarose macrobeads (MB) containing mouse renal adenocarcinoma cells (RENCA) in patients (pts) with advanced colorectal cancer (CRC).
Authors: Ocean Allyson J. , Parikh Tapan , Berman Nathaniel , Escalon Juliet , Shah Manish A. , Andrada Zoe , Akahoho Eugene , Pogoda Janice M. , Stoms George B. , Escobia Verula B , Ruggiero Joseph T. , Fahey Thomas J. , Smith Barry H. 
Published: March 2020

e14517 Background: RENCA tumor cells encapsulated in two concentric agarose layers which release signals to treat advanced cancers is a novel concept that has been substantiated in in vitro and in vivo models as reported in Cancer Research 71(3), 716-735, 2011.We report results of a phase I/II study in advanced CRC pts. Methods: Previously-treated advanced CRC pts (ECOG PS 0-2) were enrolled with informed consent obtained. Pts had intraperitoneal implantation up to 4 times via laparoscopy with 8 (37/40 pts- established dose) or 16 (3/40 pts) RENCA MB/kg. Serial exams, lab profiles, and imaging were done pre- and 3 months (mo.) post-implant to assess efficacy. Endpoints of safety, tumor marker decrease, response, and overall survival (OS) were evaluated. Results: 40 pts were implanted with RENCA MB (12 pts phase I; 28 pts phase II); 17M: 23F. Mean age 58.3. 14/40 pts had >1 implant (≥2: 14 pts; ≥3: 2 pts; =4: 2 pts). Response to MB is marked by a prominent initial rise in CRP, ESR, and IL-6, indicating a systemic inflammatory response (SIR) (100% of pts) and a parallel decrease in CEA and/or CA 19-9 in approximately 70%. SIR including its accompanying fatigue and anorexia lasts days to 3 wks. Overall, there was a statistically significant difference (p=0.009) in OS between the 70% of pts showing a decrease in tumor markers by at least 20% during the first 30 days post-implant (OS; 9.7 mo., C.I. 6.5-13.5) and those who did not (OS; 4.4 mo., C.I. 1.1-7.6). On PET-CT imaging, a striking feature of response, most often seen in pts with the longest OS, is tumor necrosis. MB were well-tolerated and no Grade ≥3 adverse events were treatment-related. Conclusions: For advanced, treatment-resistant CRC pts, early response to MB implantation characterized by tumor marker decrease in association with SIR correlates with a statistically significant increase in OS. RENCA MB represent a possible new therapeutic option for late-stage CRC. Clinical trial information: NCT01053013.
Reasons for delay in time to initiation of adjuvant chemotherapy (AC) for colon cancer (CC).
Authors: Wasserman David Warren , Boulos Majdi , Booth Christopher M. , Hopman Wilma , Goodwin Rachel Anne , Biagi James Joseph 
Published: March 2020

e14553 Background: AC improves survival among patients with colon cancer. Two meta-analyses have demonstrated a decrease in survival with increasing time to AC (TTAC). Here, we examine the predominant factors leading to delay in TTAC. Methods: Individual medical records of 565 patients with CC who initiated AC Aug 2005-Nov 2010 in Eastern Ontario were reviewed to capture patient and treatment characteristics including: medical comorbidities, post-operative complications, the reason if AC was not ordered after initial medical oncology (MO) consultation, dates of surgery, referral to MO, MO consult, central venous catheter (CVC) insertion, and first cycle of AC. Patients were then categorized into two groups: (i) medical/surgical reason for delay (MSRD), defined as post-operative complications or intercurrent illness, and (ii) No MSRD. No MSRD patients were further subcategorized as post-MO delay (PMOD), defined as AC deferred at time of consultation due to patient preference or further investigations required, vs. No PMOD. A multivariate logistic regression model was used to determine factors associated with TTAC > 8 weeks (w). Results: In the No MSRD group (n= 423), 25% (n=107) were subdivided into the PMOD subgroup. On multivariate analysis, TTAC >8w was significantly associated with the presence of a MSRD [OR = 2.4 (1.6-3.9), p = <0.001] or PMOD [OR = 3.3 (1.9-5.6), p = <0.001]. No other significant associations were found, including oral vs. IV AC. Proportion of cases with TTAC >8w in the subgroups were: MSRD 76.1% (n = 108); PMOD 80.4% (n = 86); No PMOD 57.6% (n = 182). Conclusions: MSRD and PMOD are strong predictors of increased TTAC; however, the majority of patients have no MSRD or PMOD. TTAC in this group is 9 weeks. This suggests that TTAC is modifiable, and likely reflects delays in referral, consultation, and chemotherapy booking. [Table: see text]
The "real life" impact of adding bevacizumab to first-line treatment of metastatic colorectal cancer: A retrospective large database study.
Authors: Hammerman Ariel , Greenberg-Dotan Sari , Battat Erez , Bitterman Haim , Brenner Baruch 
Published: March 2020

e14571 Background: Bevacizumab is included in the Israeli National List of Reimbursed Drugs (NLRD) for 1st line treatment of all metastatic colorectal cancer (mCRC) patients since 7/2006. This study evaluates the "real life" impact of adding bevacizumab to 1st line treatment of mCRC by comparing patients' outcomes before and after the drug's availability in the NLRD. Methods: We conducted a retrospective database study ,using the computerized databases of Clalit Health Services' (CHS), Israel's largest health care provider, to compare two cohorts: (A) all CHS' patients diagnosed with mCRC between 1/2000-12/2004 that received 1st line irinotecan or oxaliplatin-based combination chemotherapy (before bevacizumab was introduced), and (B) all CHS's patients that started 1st line treatment with irinotecan or oxaliplatin-based combination chemotherapy and bevacizumab between 7/2006 and 8/2009 (allowing a minimum follow-up of 3 years). The primary endpoint was overall survival (OS) and the secondary endpoints were 1st line progression free survival (PFS) and metastatectomy rates. Since data on actual progression status was unavailable, PFS was defined as the duration of 1st line treatment. As CHS covers more than 50% of the Israeli population, our study may represent the general care received by Israeli patients with mCRC. Results: The study population included 1,739 patients: 1,052 in cohort A and 687 in cohort B. Patient demographics were similar between the cohorts. Median OS was 15.0 months for cohort A (95% CI: 13.4–16.6) and 23.0 months for cohort B (95% CI: 21.7–24.3), with an unadjusted hazard ratio (HR) of 0.71 (95% CI: 0.64-0.80, p<0.0001). Median PFS was 9.8 months (95% CI: 9.0–10.5) for cohort A and 14.0 months (95% CI: 13.0-15.0) for cohort B, with a HR of 0.80 (95% CI: 0.71-0.87, p<0.0001). The rate of metastatectomies was significantly higher in cohort B (8.1% vs. 3.9%; P = 0.001). Conclusions: In this retrospective database analysis, OS, PFS and metastatectomy rates of 1st line treatment of mCRC were significantly higher in the later period of the study. The addition of bevacizumab to standard treatment of mCRC may have had a major contribution to this improvement.
Survival outcome of ampullary and duodenal adenocarcinomas.
Authors: Shaib Walid Labib , Sharma Rahul , Kim Sungjin , Chen Zhengjia , Kauh John S. , Kooby David A. , Maithel Shishir K. , Landry Jerome Carl , El-Rayes Bassel F. 
Published: March 2020

e14579 Background: Adenocarcinomas of the duodenum are divided into two locations: ampullary (AMP) and duodenal (DA). AMP represents 2% of all gastrointestinal (GI) malignancies and commonly present with tumor related obstruction of the common bile duct. DA is rare, and constitutes 0.4% of GI but 45% of small bowel malignancies. The literature regarding treatment and outcome of DA and AMP is very limited. The objective of this project is to evaluate the outcome for these cancers. Methods: After IRB approval, AMP and DA patients were identified from Emory University database. A chart review from July 1995 to July 2012 was conducted. Data was collected for demographic characteristics, pathology, treatment and survival.Survival rates were estimated by Kaplan Meier method and compared with Log-rank test. A Cox proportional hazard model was fitted to estimate the adjusted effect of AMP versus DA on overall survival (OS). Results: A total of 162 patients with AMP (94) and DA (68) were identified. Median age at diagnosis for AMP was 62 and for DA was 63 years. Equal distribution of males and females was found in both locations. No difference was found comparing grade of the tumors. There was a difference in race. DA presented with larger primary tumor compared to AMP. DA presented with advanced stage. Treatment was driven by stage and included surgery, surgery followed by adjuvant chemotherapy (5-FU based) +/- radiation or chemotherapy alone. Median OS of 27.5 for AMP and 19.3 months for DA, not statistically significant difference. Adjusting for stage, no significant survival difference was observed (HR=0.88 95%CI=0.54 – 1.46, p=0.63). Conclusions: Race, size, stage and treatment were different comparing AMP to DA. Majority of AMP had early stage and were treated with surgery; DA tends to present at a late stage. When accounting for stage and location, the OS was not significantly different. [Table: see text]
Retrospective analysis of dose intensity, toxicity, and clinical outcomes in 5-fluorouracil based regimens in the treatment of metastatic colorectal cancer.
Authors: Mulder Karen E. , Loree Jonathan , Ghosh Sunita , Spratlin Jennifer L. 
Published: March 2020

e14595 Background: Metastatic colorectal cancer (mCRC) chemotherapy utilizes either sequential monotherapy followed by combination therapy or early combination therapies. Patients receive therapy consisting of oxaliplatin with 5-FU as an intravenous formulation (FOLFOX6) or capecitabine (CAPOX). A retrospective analysis was performed comparing average relative dose intensity (ARDI), overall survival (OS), progression free survival (PFS), and toxicity profiles of these 2 regimens in mCRC patients. Methods: 122 mCRC patients identified between January 1, 2006 and December 31, 2011 received either FOLFOX6 (n= 46) or CAPOX (n=76) in Edmonton, Alberta. ARDI was compared by calculating a percent of target dose achieved in the average cycle for each patient. Data on OS, PFS, baseline demographics, and toxicities was gathered. Survival data was plotted using the Kaplan-Meier method and compared using the log-rank test. Variable comparisons were performed with the Student’s t-test or the Fisher’s Exact test. Follow up was complete until November 1, 2012. Results: Oxaliplatin ARDI trended towards being lower in those treated with CAPOX compared to FOLFOX6 (84.01 vs 89.52 p=0.0553), and 5-FU component was significantly lower (81.28 vs 95.76, p<0.0001). More patients treated with CAPOX had dose limiting toxicities (DLTs), although not statistically significant (68.42% vs 54.35%, p=0.1268), while toxicities of grade 2 and higher were increased with CAPOX (38.16% of patients vs 15.22%, p=0.0079). Neuropathy rates were similar between regimens as were cycle numbers were completed between CAPOX and FOLFOX6 (5.329 vs 6.174, p=0.2796). Survival analysis demonstrated trends towards improved median OS (300 vs 227 days, p=0.1183) and median PFS (132 vs 101.5 days, p=0.1674) with CAPOX. The groups had similar age, gender, and ECOG at diagnosis. Conclusions: Patients treated with CAPOX had significantly more DLTs resulting in lower doses of oxaliplatin and capecitabine compared to FOLFOX6. This does not seem to impact clinical outcomes as mCRC patients on CAPOX showed a trend toward improved outcomes compared to FOLFOX6.
Methylated miR-124, -137, and -34b/c as predictive biomarkers for ulcerative colitis-associated colorectal neoplasia.
Authors: Toiyama Yuji , Hur Keun , Tanaka Koji , Inoue Yasuhiro , Tabata Tsutomu , Kusunoki Masato , Boland C. Richard , Goel Ajay 
Published: March 2020

e14631 Background: Accumulating evidence suggests that microRNAs (miRNAs) can be targets of methylation-induced silencing in colorectal cancer, which can occur in an age-dependent manner, and constitutes an epigenetic “field defect”. We hypothesized whether methylation of miR-124, -137 and -34b/c can predict colorectal neoplasia in patients with ulcerative colitis (UC). Methods: We examined 185 samples from 70 UC patients (45 patients without neoplasia, 12 with dysplasia and 13 with cancers) for the methylation status of miR-124, -137 and -34b/c by quantitative bisulfite pyrosequencing analysis. In addition, expression levels of these 3 miRNAs in dysplastic (n=12), cancerous (n=13) and non-neoplastic UC mucosa (n=20) were quantified by TaqMan qRT-PCR. Results: MiR-124 and -137 methylation levels were significantly higher in rectal tissues than in proximal mucosa from non-neoplastic UC tissues, and were significantly associated with age and disease duration in rectal tissues. Methylation levels of all 3 miRNAs were significantly higher in dysplasia and cancer compared to mucosa without neoplasia, and showed a “field defect” in the non-neoplastic rectal tissues from patients with cancer . Receiver operating characteristic (ROC) analysis revealed that methylation levels of all 3 miRNAs in non-neoplastic rectal tissues could discriminate patients with cancer from those without (miR-124 AUC value = 0.74; miR-137 AUC = 0.79; miR-34b/c AUC=0.72). Furthermore, methylated miR-137 in non-neoplastic rectal tissues allowed discrimination of UC patients with neoplasia from those without (AUC = 0.76), and independently predicted neoplasia (OR= 5.55; 95% CI: 1.40–22.05; P = 0.0148). Expression levels of all 3 miRNAs were significantly downregulated in dysplasia or cancer compared to non-neoplastic UC mucosa, and the expression and methylation were negatively correlated. Conclusions: Methylation of miR-124, -137 and -34b/c in rectal biopsies, particularly miR-137, may serve as novel predictive biomarkers for neoplasia in UC patients. Restoration of expression by reversing their methylation status could be an attractive strategy to slow or reverse age-related UC-associated neoplasia.
Heterogeneity of colorectal cancer (CRC) in reference to KRAS proto-oncogene utilizing wave technology.
Authors: Perez Kimberly , Walsh Robert , Brilliant Kate E. , Nobel Leila , Yakirevich Evgeny , Breese Virginia , Jackson Cynthia , Chatterjee Devasis , Pricolo Victor , Roth Leslie , Shah Nishit , Cataldo Thomas , Safran Howard , Hixson Douglas , Quesenberry Peter J. 
Published: March 2020

e14637 Background: The use of Epidermal growth factor receptor (EGFR) inhibitor monotherapy in patients that have KRAS wild type has produced response rates of only 10-20%. We propose two possible explanations to explain these low response rates; 1) levels of resistant CRC cells carrying mutated KRAS are below the sensitivity of standard direct sequencing modalities (<5%) or 2) the standard practice of analyzing a single area within a heterogeneous tumor is a practice that can overlook areas with mutated KRAS. Methods: In a collaborative effort with Lifespan Pathology Department and the Molecular Pathology Core of the COBRE for Cancer Research Development, 3 FFPE tissue blocks of human CRC were obtained. The three specimens previously demonstrated KRAS mutations detected by the Applied Biosystems Kit. The Wave system 4500 (High performance ion-pairing liquid chromatography (IP-HPLC)) was utilized to evaluate tissue for presence of KRAS proto-oncogene mutations at codon 12 and 13. Results: Initially, sensitivity of WAVE technology was compared with direct sequencing by evaluating a dilutional series. WAVE detected mutant alleles at levels of 2.5% compared to 20% performed with standard direct sequencing. Samples from 3 patients were evaluated by WAVE technology. 8 samples from patient 1 were analyzed. In 2 of 8 samples, no mutations were detected at concentrations as low as 5%. In one sample a mutation was noted by WAVE and not by direct sequencing. All 4 samples from patient 2 tested positive for Exon 12/13 mutations. Of the 7 samples from patient 3, 5 were positive for Exon 12/13 mutations and 2 were negative for Exon 12/13 mutations. Conclusions: Results demonstrated a greater degree of sensitivity in mutation detection when compared to standard sequencing. These studies also demonstrated heterogeneity of expression of KRAS mutations between areas of the tissue samples at a genomic level. The low clinical response rates to EGFR inhibition might be explained by the variation in mutation presence, which was dependent upon the region examined. The heterogeneity demonstrated in these studies provides another phenotypic variant that will impact clinical care.