bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimal combination therapy for advanced colorectal cancer: An examination of synergy and antagonism with EGFR inhibition.
Authors: Vora Nilesh , Evans Steven , Bernard Paula J , Francisco Federico , Nagourney Robert Alan 
Published: March 2020

e14075 Background: While FOLFOX +/- Bevacizumab is the most widely used combination in colorectal cancer (CRC), the EGFr antagonists Cetuximab & Panitumumab have not further enhanced activity. On the contrary, the addition of EGFR inhibitors to Irinotecan-based regimens at 1st & 2nd line has improved response and both progression freel & overall survival (Van Cutsem. 2010; Peeters. 2010.) Methods: We applied the ex vivo analysis of programmed cell death (EVA-PCD) (Nagourney, Curr Treat Opt Onc 2006) to examine interactions between EGFr antagonists and Irinotecan or FOLFOX in 534 human tumor primary culture microspheroids isolated from CRC surgical specimens or cytologically (+) fluids. Gefitinib was used as a surrogate for Cetuxima/Panitumumab activity. Tissue samples exposed to Oxaliplatin, 5FU, Irinotecan, and Oxaliplatin & 5FU (FOLFOX) provided dose response curves with and without Gefitinib for formal synergy analysis by median effect (Chou & Talalay). Results: Shown in table below. Conclusions: Results indicate superiority for Irinotecan combination with the EGFr antagonist Gefitinib. The percentage of synergistic interactions for Irinotecan & Gefitinib (41%) is demonstrably higher than that associated with FOLFOX & Gefitinib (4%). This suggests distinct modes of interaction between these classes of agents favoring Irinotecan and could have an impact upon future clinical trial designs. Recognizing the importance of Kras mutation, additional studies are underway to examine the impact of Kras mutation upon synergy. However, as wild-type and mutant samples would be expected to be equally distributed, subset analyses may reveal quantitative (higher % synergy) rather than qualitative differences (relative activity of Irinotecan vs FOLFOX). Results of these analyses will be reported. Supported in part by the Vanguard Cancer Foundation. [Table: see text]
inSIRT trial: Single-center phase II study of yttrium-90 radioactive resin microspheres in the treatment of liver-predominant metastatic colorectal adenocarcinoma after failure of first-line combination chemotherapy.
Authors: Reid Tony R. , Roeland Eric , Dad Shakeela , Shimabukuro Kelly Anne , Fanta Paul Timothy 
Published: March 2020

e14079 Background: Liver metastases develop in half of colorectal cancer (CRC) cases and once metastatic, ~90% die due to their consequences. We are evaluating the aggressive management of liver metastases through the incorporation of selective internal radiation therapy (SIRT) using Yttrium-90 (Y-90) radioactive microspheres after evidence of progressive disease following 1st-line FOLFOX ± bevacizumab. Optimal timing for microsphere treatment relative to chemotherapy is not clearly established. Methods: Subjects with predominant hepatic metastatic CRC despite 1st-line FOLFOX based therapy ± bevacizumab are eligible. Interventional radiology and nuclear medicine assess the liver lesions and the subject receives SIRT followed by 2nd-line FOLFIRI 4-6 weeks after the final SIRT. Results: To date, 9 metastatic CRC subjects have been treated and 10 subjects enrolled (goal 30 subjects). One subject was withdrawn due to progressive lung metastases. 4 of 9 subjects (45%) achieved PFS at 6 mos and average TTP is 7 months(0.7-21.3 mos). Overall treatment has been well tolerated, except one possible study related SAE of liver failure. The OS endpoint has not been achieved. Conclusions: Historically, 2nd-line FOLFIRI has achieved a 2.5 mos median PFS. Our preliminary results of 9 subjects with metastatic CRC show a PFS up to 21.3 monthsand 45% PFS at 6 mos. These encouraging results demonstrate the utility of an innovative direct approach to metastatic CRC after failure of 1st-line combination chemotherapy. Based on our promising preliminary results, our aim is to enroll 30-35 metastatic CRC patients. [Table: see text]
Treatment with bevacizumab in patients with metastatic colorectal cancer (mCRC).
Authors: Ocvirk Janja , Rebersek Martina , Boc Marko , Ebert Motara Maja , Mesti Tanja 
Published: March 2020

e14083 Background: This study was designed to prospectively evaluate the safety and toxicity of bevacizumab in mCRC patients (pts) with mCRC pts in routine clinical practice as well as selection of pts. Methods: Baseline characteristics, pre-specified bevacizumab-related adverse events, and efficacy data were collected from 273 mCRC pts who started bevacizumab-containing therapy between January 2008 and August 2010. Results: The data from 273 pts (median age 62) were included in the evaluation. The ECOG performance status (PS) at baseline was 0 in 60%, 1 in 37% and 2 in 3% of pts. Eighty pts (29%) received adjuvant chemotherapy, and 84 (31%) received chemotherapy ± bevacizumab or cetuximab for prior treatment of metastatic disease. Majority of the 273 pts received irinotecan-based chemotherapy (65%). Complete response (CR) was reported in 7%, partial response (PR) in 31% and stable disease (SD) in 36% of the first-line treated pts. In pts previously treated for metastatic disease CR, PR and SD were 6%, 24% and 45%, respectively. In the first-line pts median progression-free survival (PFS) was 10.9 months (95% confidence interval [CI], 9.8 - 12.0), while median overall survival (OS) was 24.3 months (95% CI, 21.4 – 30.3). PFS was 10, 9 and 8.7 months and OS was 16.7, 13.5 and 12.8 months in pts previously treated for metastatic disease with chemotherapy, chemotherapy + cetuximab or chemotherapy + bevacizumab, respectively. Two-year survival rate was 51% in the first-line pts and 32%, 14% and 38% in pts previously treated for metastatic disease with chemotherapy, chemotherapy + cetuximab and chemotherapy + bevacizumab, respectively. Metastasectomy was performed in 39 (15.5%) of the pts. One hundred and nine pts received bevacizumab with subsequent chemotherapy and CR, PR and SD were 1%, 9% and 30%. Overall rates of bevacizumab-related grade 1-2/3-4 adverse events were: proteinuria 38/9 %, hypertension 16/3 %, thromboembolic events 1/5 %, infection 2/3 %, bleeding 2/1 % and fistula 0/1 %. Conclusions: The authors concluded that bevacizumab-containing therapy and use of bevacizumab for long period of time demonstrated efficacy and good tolerability when used as a first-, second- and third-line treatment in routine clinical practice.
Phosphorylated Akt and MAPK expression in primary tumors and in corresponding metastases and clinical outcome in colorectal cancer patients receiving irinotecan-cetuximab.
Authors: Giampieri Riccardo , Scartozzi Mario , Maccaroni Elena , Mandolesi Alessandra , Biagetti Simona , Alfonsi Simona , Giustini Lucio , Loretelli Cristian , Faloppi Luca , Bianconi Maristella , Bittoni Alessandro , Del Prete Michela , Cascinu Stefano , Giorgi Francesca 
Published: March 2020

e14086 Background: Other than the well-known EGFR pathway activation via the Ras-Raf-MAP-kinase, a possible role of other potential biomarkers could be relevant in determining resistance to anti-EGFR treatment, such as the protein-serine/threonine kinase Akt. We tried to assess the role of Akt and MAPK expression in metastatic colorectal cancer patients and their relationship with outcome for patients receiving Irinotecan-Cetuximab. Methods: Eligible patients were metastatic colorectal cancer patients treated in 2nd or 3rd line setting with a irinotecan-cetuximab based regimen. Patients were tested for K-ras status and subsequently assessed by immunoistochemistry for pAkt and MAPK expression, both in primary tumours and metastases whenever sufficient tissue was available. The role of pAkt and MAPK expression was evaluated for K-ras wild type patients for different likelihood of response, overall survival and progression free survival. Response was evaluated by RECIST criteria. Survival analysis was performed via Kaplan-Meier method. Results: In metastases pAkt correlated with RR (9% vs. 58%, p=0.004), PFS (2.3 months vs.9.2 months p < 0.0001) and OS (6.1 months vs.26.7 months p < 0.0001) and pMAPK correlated with RR (10% vs, 47%, p = 0.002), PFS (2.3 months vs.8.6 months p < 0.0001) and OS (7.8 months vs.26 months p=0.0004). At multivariate analysis pAkt and pMAPK in metastases were able to independently predict PFS. pAkt in metastases independently correlated with RR as well. Conclusions: pAkt and pMAPK expression in metastases may modulate the activity of EGFR-targeted antibodies. We could speculate that in patients with pAkt and pMAPK metastases expression targeting these factors may be crucial.
Preclinical activity of BC2059, a novel compound that degrades beta-catenin, in colon cancer models.
Authors: Sharma Sunil , Soldi Raffaella , Gilcrease Glynn Weldon , Horrigan Stephen 
Published: March 2020

e14090 Background: BC2059 (BetaCat Pharmaceuticals) is a novel small molecule that degrades ß-catenin in a proteosomally dependent manner in cancer cells. Methods: We tested the activity of BC2059 in vitro, in patient derived colon cancers in 3-dimensional cultures and in vivo using HT-29 xenografts. We also used a novel doxycycline driven siRNA model that downregulates ß-catenin to test activity of BC2059. Results: BC2059 was highly active with IC90s in MTS assays (μM): SW480 (0.44), Colo205 (0.66), Colo201 (0.03), HT29 (0.92) and relatively inactive in SW48 (9.83) or L cells (normal) (4). In a 3-Dimensional culture system where we grew patient-derived colon cancer cells in a matrigel system and measured cell death by ethidium bromide exclusion, surprisingly, the average EC50 was 200 picomolar indicating that the compound was much more effective in patient derived samples. In matrigel tumor invasion assays, BC2059 demonstrated potent inhibition of tumor invasion. In HT-29 mouse xenografts, BC2059 series demonstrated tumor growth inhibition with no weight loss with depletion of ß-catenin. We also used chromatin immunoprecipitation (CHIP) assays to demonstrate depletion of ß-catenin on myc and axin promoters. In combination experiments, BC2059 displayed synergy in vitro with 5-fluorouracil in vitro. We used a doxycycline driven siRNA system in colon cancer cell lines and show that the compound activity is synergistic with depletion of ß-catenin. We also conducted combination of BC2059 series of compounds using a proteasome inhibitor MG132 and demonstrate reversal of activity with proteasome inhibition. Conclusions: In conclusion, BC2059 demonstrates potent activity in vitro and in vivo against colon cancer models singly or in combination. Further, it is surprisingly potent in patient derived colon cancer models. It appears to degrade ß-catenin in a proteosomally dependent manner on important effectors like myc and axin. It merits further evaluation in this tumor type.
Is systemic inflammation the result of insufficient cortisol production in patients with colorectal cancer?
Authors: Ramanathan Michelle Leana , Roxburgh Campbell SD , Horgan Paul G , Mcmillan Donald C. 
Published: March 2020

e14092 Background: Patients with colorectal cancer who have a raised systemic inflammatory response have been shown to have poorer outcomes, independent of their tumour stage. In particular, the combination of C-reactive protein (CRP) and albumin, the modified Glasgow Prognostic Score (mGPS) has been shown to have consistent and superior prognostic value. However, the basis of a systemic inflammatory response in these patients is not clear. One hypothesis is that the presence of a systemic inflammatory response in patients with colorectal cancer may be due to impaired cortisol production, a potent anti-inflammatory agent. Therefore, the aim of the present study was to examine the relationship between preoperative systemic inflammatory response and endogenous cortisol production. Methods: A prospective study was performed to incorporate the assessment of adrenocortical function using synthetic ACTH, a short Synacthen test, as part of the preoperative assessment of patients undergoing potentially curative resection for colorectal cancer. Preoperative systemic inflammatory response was assessed using mGPS. Results: A total of 80 patients underwent short Synacthen testing. The majority of patients were under 75 years old (79%), were male (59%), had colon cancer (75%) and had TNM stage I/II disease (54%). Approximately 50% received adjuvant treatment. Using standard criteria (peak cortisol <450 nmol/L = inadequate) impaired cortisol response was seen in 3 (4%) patients. There were no significant associations between the baseline, 30 minute, or change in cortisol (both relative and absolute) and age (p=0.814, p=0.443, p=0.730, p=0.929), sex (p=0.714, p=0.440, p=0.324, p=0.953), site (p=0.519, p=0.255, p=0.145, p=0.222), TNM stage (p=0.115, p=0.591, p=0.492, p=0.289), mGPS (p=0.280, p=0.202, p=0.800, p=0.818), or white cell count (p=0.787, p=0.316, p=0.462, p=0.567). Conclusions: The results of the present study show that impaired cortisol production, as evidenced by the short Synacthen test, was uncommon in patients with potentially curable colorectal cancer. Moreover, they indicate that the presence of a systemic inflammatory response is not associated with impaired cortisol production.
Comparison of magnetic resonance imaging and histopathological response to neoadjuvant chemotherapy in locally advanced rectal cancer: The GEMCAD 0801 trial.
Authors: Brown Gina , Patel Uday Bharat , Santos Cores Jesus , Isabel Gil Garcia Maria , Ayuso Juan Ramón , Puchades Roman Iciar , Mas Estelles Fernando , Risueno Noelia , Salud Antonieta , Maurel Juan , Aparicio Jorge , Pericay Pijaume Carles , Alonso Vicente , Safont M. José , Gallén Manuel , Vera Ruth , Feliu Jaime , Martin-Richard Marta , Fernandez-Martos Carlos 
Published: March 2020

e14097 Background: MRI methods for rectal cancer response assessment post chemoradiotherapy include post treatment T staging(ymrT), tumor regression grading(mrTRG) and length change/modified RECIST measurement. The usefulness of MRI in evaluating response to neoadjuvant chemotherapy has not been investigated. We assessed the reproducibility and agreement of these three parameters with histopathological T and TRG stage(ypT, pTRG). Methods: 28 eligible patients were enrolled in a prospective phase II trial to evaluate safety and efficacy of neoadjuvant CAPOX-B in patients with MRI defined T3 rectal adenocarcinoma. Patients received 4 cycles of Cap 2000 mg/m2(d1-14),Ox 130 mg/m2(d1) and B 7.5 mg/kg(d1) every 3 weeks(last cycle without B). Seven radiologists assessed MRIs using the following categories: ymrT (T0-T4 using T3 substaging), mrTRG (1-5), and length change(Stable disease, Complete response,Partial response). Agreement was assessed by kappa (central reviewer data verses each local centre reviewer).Agreement between central reviewer MRI results and both pathology endpoints was also assessed. Results: 24 patients had evaluable pre and post chemotherapy imaging and pathology (4 did not have post treatment MRI). Thirteen patients had good response (ypT0-3a) and 11 had poor response (>ypT3a). Sixteen patients had good pTRG(2-4) and 8 had poor pTRG(0&1). ymrTRG showed a moderate level of reproducibility;K=0.45-0.58. ymrT showed a fair to moderate level of agreement;K=0.2-0.53. Length assessment also showed a fair level of agreement; K=0.21-0.38. ymrTRG showed 75% agreement with ypT(16/22); K=0.49(0.13-0.84) and 79% agreement with pTRG(19/24); K=0.55(0.22-0.88). ymrT showed a fair level of agreement with ypT;K=0.21, pTRG;K=0.2, length assessment showed slight agreement with ypT;K=0.1, pTRG;K=0.1. Conclusions: This is the first study to show MRI can evaluate response of rectal cancer following neoadjuvant chemotherapy. As mrTRG showed best agreement with pathology, we recommend mrTRG as the preferred method of post treatment assessment in this setting.
A pilot study of the immunohistochemical pattern of neuropilin-2 (NRP2) labeling and correlation with tumor stage in colon cancer.
Authors: Sun Hongliu , Kussman Ashleigh M. , Freeman Carol , Meredith Judy , Hensley Kenneth , Gato-Weis Cara , Skeel Roland T. , Nawras Ali , De Las Casas Luis 
Published: March 2020

e14098 Background: Neuropilin 2 (NRP2) is a transmembrane glycoprotein, non-associated with kinase domains, implicated in neovascularization and metastasis of colon cancer. NRP2 has been proposed as a molecular marker for targeted cancer therapy based on its multiple functions in cancer promotion. NRP2 signaling pathway and its expression have been demonstrated in many carcinomas. To the best of our knowledge, no description of the immunohistochemical staining pattern of NRP2 in colon cancer has been published in the English medical literature. The aim of this study is to investigate the NRP2 labelilng pattern in colon cancer and correlate it with tumor stage. Methods: Tumor sections from 35 randomly selected colectomy specimens with colorectal cancer collected during the last three years were retrieved from the University of Toledo Medical Center Department of Pathology archival material. Formalin fixed, paraffin embedded, 4 μm tissue sections containing invasive tumor were immunolabeled with a commercial antibody against NRP2, using a Ventana Benchmark LT automated instrument. Randomized, immunolabeled colon cancer tissue sections were blindly reviewed by two pathologists. Cytoplasmic and nuclear expression of NRP2 by tumor cells was graded as negative (no staining), focal (staining in <50% of cells), and diffuse (staining in ≥ 50% of cells). Adjacent benign colonic mucosa was used as an internal control. Results: No T1 or T2 tumor displayed diffuse nuclear labeling for the NRP2 epitope. In contrast, 13/20 T3 tumors (65%) and 4/4 T4 tumors (100%) displayed diffuse nuclear labeling. The association of diffuse nuclear NRP2 labeling with tumor grade was highly statistically significant (p=0.0055 by Chi-squared test). In contrast to nuclear labeling, cytoplasmic staining was observed in all stages and varied from negative to diffuse, but demonstrated no significant correlation with stage. Conclusions: This pilot study on colon cancer specimens suggests that diffuse nuclear immunolabeling of neuropilin-2 is indicative of a higher tumor stage. This finding suggests a potential use for this marker as a prognostic indicator for colon cancer in small biopsy samples.
Retrospective analysis of pathological response in colorectal cancer liver metastases following treatment with bevacizumab: Updated findings.
Authors: Vera Ruth , Figueras Joan , Gomez Dorronsoro Marisa , Lopez Ben Santiago , Viudez Antonio , Queralt Bernardo , Hernandez Irene , Soriano Jordi , Zazpe Cruz , Ortiz Duran Rosa Maria 
Published: March 2020

e14120 Background: Recent reports have shown that pathological response predicts for better outcome (overall survival) following preoperative chemotherapy and surgical resection of colorectal cancer (CRC) liver metastases. The aim of this retrospective analysis was to evaluate the effect of adding bevacizumab (BEV) to standard chemotherapy on pathological response in patients (pts) with CRC liver metastases. Methods: Pts with stage IV CRC with liver metastases who received neoadjuvant chemotherapy (oxaliplatin-or irinotecan-based) at two Spanish centres were analysed retrospectively. Pathological response was evaluated as follows: complete pathological response (cPR), PR1 (<25% of residual viable tumour cells), PR2 (25–50% of residual tumour), PR3 (>50% of residual tumour). cPR or PR1 was considered to be a good response, and PR2 or PR3 a poor response. KRAS status was determined from tumour blocks. Results: 95 pts were evaluated. Of these, 44 received chemotherapy alone and 51 received chemotherapy + BEV. Baseline characteristics were as follows: median age 61.0 years (range 43.0–80.0 years); male/female (68%/32%); tumour location – colon (72%) / rectum (28%); hepatic metastases – synchronous (74%) / metachronous (26%); extrahepatic disease – yes (26%) / no (74%); KRAS status – mutated (37%) / wild type (29%) / not available (34%). The overall response rate (ORR) by RECIST was 51% (1 CR and 47 PRs) and 48% of pts had stable disease. ORR did not appear to vary in pts who did or did not receive BEV. In terms of pathological response, 49% of pts receiving BEV had a good response (cPR + PR1) compared with 27% of those receiving chemotherapy alone (p=0.0302). Good pathological response (cPR + PR1) was slightly lower in pts with mutant (31%) vs wild type (43%) KRAS status (difference not significant). At the end of the analysis, 45% of pts had relapsed and 67% were alive. Conclusions: Adding BEV to standard chemotherapy in the neoadjuvant setting improves pathological response of liver metastases in pts with stage IV CRC. Further studies are required to examine the potential relationship between pathological response and survival outcomes in pts with CRC and liver metastases.
Demographics and patterns of care for veterans with colorectal cancer.
Authors: Barnes Tanganyika , Wang Trent P , Zhong Fengming , Chang Victor T , Gonzalez Melanie L. , Paz-Querubin Emma R , Crump Barbara , McPherson Monica , Gandhi Arpita , Kasimis Basil 
Published: March 2020

e14124 Background: This study is to analyze demographics and patterns of care for veterans with colorectal cancer. Methods: In an IRB approved protocol, we reviewed the records of pts diagnosed with colorectal adenocarcinoma at a VA Medical Center from 1/1/2003 to 12/31/2007. Demographics including age, sex, ECOG PS, stage, grade, site, CEA, hemoglobin (HGB), liver function tests at diagnosis, treatments and cause of death were reviewed. Results: There were 176 pts with colorectal ca with 112 colon (C) and 64 rectal ca (R) pts. One was a woman and the rest were men. The median age at diagnosis was 71 years (range 45-90). Median survival was 1157 days (5-3256). 95 (54%) pts were dead at this analysis. Median ECOG PS is 0. 160 pts had ECOG PS 0-2, 16pts ECOG 3-4. 4 (2.4%). 4 (2.4%) pts has stage 0, 51 (30.7%) stage 1, 42 (25.3%) stage 2, 35 (21.1%) stage 3, and 34 (20.5%) stage 4. 6 (3.7%) has grade 1, 111 (68.1%) grade 2, and 46 (28.2%) grade 3. Median CEA at diagnosis was 2.9 (0-3117), HGB 12.4 g/dl (6.6-16.7), albumin g/dl 3.98(1.7-4.7), AST 23 units/L (4-107), ALT 20 units/L (8-107), ALKP 77 units/L (37-352), Total bilirubin 0.7 mg/dl (0.1-4.5). 29 pts has liver metastasis at diagnosis. 147 pts (85.4%) received surgical resection. Total 43 pts had adjuvant treatment. 17 pts with rectal cancer had neoadjuvant chemoradiation . 7 pts had down staging and 3 pts had no residual disease after neoadjuvant chemoradiatoion. Total 14 pts had recurrence. 23 pts received palliative chemotherapy when metastatic. 54 of 95 pts (57%) died from cancer progression. Conclusions: This study provides a basis for understanding the epidemiology of colorectal cancer patient in a VA medical center.