bluuebunny/crossref_metadata_2025_split huggingface dataset:
Timing of surgery following neoadjuvant chemoradiation in rectal cancer: A retrospective analysis from an academic medical center.
Authors: Chau Justin , Maliske Seth , Berg Daniel James , Bhatia Sudershan , Bellizzi Andrew , Byrn John , Ginader Timothy , Monga Varun 
Published: January 2019

702 Background: Neoadjuvant chemoradiotherapy has been proven to achieve decreased local recurrence in rectal cancer with lower toxicity but data confirming the optimal timing of surgery following neoadjuvant cares is less robust. Methods: The University of Iowa Cancer Registry was queried to identify all patients with rectal cancer between 2000-2012. Individual records were reviewed for all patients with Stage II-III disease who received neoadjuvant chemoradiation. Primary endpoints were time interval from last day of chemoradiation to surgery (TI) and overall survival (OS). Secondary endpoints included hospital length of stay following surgery (LOS), intraoperative blood loss (BL), and major postoperative complication including infection, anastomotic failure, and thromboembolic event. Patient characteristics such as personal and family history of malignancy were studied, and treatment regimens including chemotherapy type, radiation technique and quality of resection were also compared. All postoperative pathology slides were reviewed for completeness of resection by a single pathologist. Univariate logistic regression analyses were used to study the association between TI and OS to help define the optimal interval. Results: 88 patients were identified with Stage II and III rectal cancer after imaging and endoscopic study. There was no significant association between OS and TI when comparing less than 8 weeks to greater than 8 weeks (p = 0.14) or when considering TI as a continuous variable (p = 0.99). There was no significant association between TI and surgical complications including BL (p = 0.60) or LOS (median = 7.00 days, p = 0.06), though patients undergoing pelvic exenteration experienced notably longer LOS (n = 4, mean 24.25 days, max 60 days). Conclusions: Our findings indicate that overall survival is not significantly impacted by longer intervals between chemoradiation and surgery. The incidence of major postoperative complication was rare but cost patients and the healthcare provider significant resources; thus, our results implicate potential benefits to treating some Stage II and III rectal cancers solely with chemoradiotherapy.
A novel 3-dimensional (3D) microfluidics device to model the tumor microenvironment (TME).
Authors: Krasnick Bradley A. , Bi Ye , Goedegebuure Maddy , Goedegebuure Peter S. , Shirure Venktesh S. , George Steven , Fields Ryan 
Published: January 2019

704 Background: In vitro models of cancer have led to significant therapeutic advances. Despite the widespread use of in vitro tissue culture, the ability to directly evaluate human biology is limited by the inability to model the complex, 3D nature of the TME. We introduce a novel, microfluidic-based system of 3D human micro-tumors perfused with a network of human micro-vessels which could overcome the shortcomings of current in vitro systems. Methods: The micro-device was created by casting polydimethylsiloxane (PDMS) onto master molds, which are then bonded to a flat PDMS sheet using air plasma. Normal human lung fibroblasts (NHLF) and GFP labelled endothelial colony forming cell derived endothelial cells (EC-FCECs) were loaded in a fibrin gel at a 1:2 ratio into the central tissue chamber. Media was introduced through the microfluidic lines. The vascular network was developed with complete EGM2 media under nominal interstitial flow. Colorectal tumor cell lines labelled with mCherry were loaded to the side chambers on the seventh day after NHLF and EC loading. Bevacizumab or TGF- β were added on the second day after tumor cell loading. Results: Micro-vessels formed in the central chamber in 5-7 days after loading. The vessels were perfused with 70KDa fluorescent (red) dextran, and displayed intact vessel wall barrier. A suspension of a colorectal tumor cell line was loaded into the device side chambers, next to a fully developed vasculature. The tumor cells drove angiogenesis into the side chambers, and at the same time tumor began to migrate into the central chamber and within the vessel lumen. The angiogenesis induced by tumor cells can be pharmacologically inhibited, and the migration/ intravasation of tumor cells can be stimulated by TGF-β. Conclusions: Our novel micro-device system can be used as a functional in vitro system that can model the tumor micro-environment. This system has the advantage over current in vitro and in vivo systems in that it is high-throughput, rapid, cost-effective, and recreates many features of the 3D TME. We are currently expanding the platform to incorporate immune cells and designing a completely autologous system to test cancer immunotherapeutics.
Selecting patients with stage II/III colorectal cancer for 5-fluorouracil-based adjuvant chemotherapy using proteomic analysis.
Authors: Yan Dongyao , Hong Ji Hyung , Lee Hee Yeon , Byun Jae Ho , Cecchi Fabiola , Tian Yuan , Schwartz Sarit , An Eunkyung , Hembrough Todd A. 
Published: January 2019

708 Background: 5-fluorouracil (5-FU) is a common adjuvant treatment for stage III and high-risk stage II colorectal cancer (CRC). However, about 20% of patients relapse within 48 months of treatment with 5-FU, even when combined with oxaliplatin. To improve patient selection, tumor biomarkers that predict sensitivity to 5-FU have been proposed. These include proteins involved in 5-FU activation or metabolism such as uridine-cytidine kinase 2 (UCK2) and thymidylate synthase (TYMS). We used multiplexed mass spectrometry to evaluate the utility these biomarkers in the archived tumor samples of patients with stage II/III CRC. Methods: Tumor samples were from 143 patients with stage II/III CRC who received adjuvant 5-FU, folinic acid, and oxaliplatin during 2000-2014; 83% of patients received 12 cycles and the others received ≤ 11 cycles. Tumor cells were microdissected and solubilized, and 67 candidate biomarkers were quantitated using mass spectrometry. Overall survival (OS) and relapse-free survival (RFS) were assessed using the Kaplan-Meier method and log-rank test. Protein expression by tumor stage, lymph node (LN) status, tumor sidedness was compared using the Student’s t-test. Results: Of 143 patients, 45 had recurrence and 98 patients did not. UCK2 was detected in all samples, ranging from 187 to 1606 attomoles per microgram of total protein (amol/µg). Patients with UCK2 expression above 335 amol/μg (n = 109) had significantly longer OS than patients with lower expression (n = 34; HR: 0.42; p= 0.009). There was no significant difference in RFS (HR: 0.6; p= 0.088). UCK2 expression did not differ by disease stage, LN metastasis status, or tumor sidedness. TYMS expression was not associated with survival in this cohort. Analysis of other biomarkers associated with response to 5-FU and platinum is in progress. Conclusions: In stage II/III CRC, UCK2 expression above 335 amol/μg identifies a subgroup of 5-FU-treated CRC patients with longer survival, suggesting that quantitated UCK2 has potential for use in selecting patients for treatment. These findings warrant validation in larger cohorts.
miR-15a regulation of endothelial radiation sensitivity in colorectal cancer.
Authors: Rana Shushan Rajesh , Espinosa Cristina , Ruhl Rebecca , Robinson Latroy , Thomas Charles R. , Anand Sudarshan 
Published: January 2019

709 Background: Radiation dose escalation causes significant changes within the tumor microenvironment (TME) to enhance tumor cell death including altered microRNA (miR) levels. Among endothelial miRs, we identified miR-15a exhibits dose dependent differential regulation. miR-15a targets a key determinant of endothelial cell (EC) radiosensitivity, acid sphingomyelinase (SMPD1), an enzyme that drives rapid EC apoptosis via enhanced ceramide production. In colorectal cancer (CRC) (n = 182 patients), high miR-15a is associated with worse 5-year progression free and overall survival. miR-15a also affects immune function by promoting a pro-inflammatory TME milieu. We hypothesized miR-15a inhibition will increase tumor cell death through preservation of EC SMPD1, enhancing endothelial apoptosis and inflammatory cytokine upregulation. Methods: Using TaqMan Human miR panels, miRs were profiled in human umbilical vein ECs (HUVECs) after single 2 vs 20 Gy treatment. miR-target prediction programs identified miRs targeting SMPD1. In vitro gain and loss of function studies were performed with miR transfections in HUVECs and CT26 CRC cells. CXCL10 expression was measured by qRT-PCR. Caspase 1 activation was measured by a luminescence based assay. A CT26 syngeneic CRC flank murine model was used for in vivo miR-15a inhibitor assessment administered via tail vein injection unencapsulated or encapsulated in vascular-targeted 7C1 nanoparticles. Results: Among miRs targeting SMPD1, miR-15a exhibited the greatest differential change in HUVECs 6h post-IR between low and high dose radiation. Lower dose was associated with higher miR-15a and vice versa. Further, miR-15a levels inversely correlated with SMPD1. Exogenous miR-15a significantly decreased SMPD1 mRNA and protein. miR-15a inhibition decreased proliferation in both HUVECs and CT26 cells and increased apoptosis when combined with radiation. miR-15a inhibition increased endothelial CXCL10 expression and caspase-1 activation. Both systemic and vascular-targeted miR-15a inhibitor significantly diminished tumor growth in vivo. Conclusions: Our data suggests inhibition of vascular miR-15a is sufficient to decrease tumor growth likely due to rescue of endothelial SMPD1.
Influence of liposomal irinotecan (nal-IRI) and non-liposomal irinotecan, alone and in combination, on tumor growth and angiogenesis in colorectal cancer (CRC) models.
Authors: Larsen Annette K , Trindade Cristiano , Bouygues Anaïs , Louadj Lila K , Thouroude Sandrine K , Klinz Stephan G , Kalra Ashish , Henriques João , Chibaudel Benoist , De Gramont Aimery , Escargueil Alexandre E , Mesange Paul 
Published: January 2019

711 Background: The long circulating liposomal irinotecan nal-IRI (MM-398/PEP02, Onivyde) is approved for treatment of metastatic pancreatic cancer after disease progression with gemcitabine-based therapy. Besides their direct cytotoxic activity, camptothecins are thought to inhibit tumor angiogenesis via downregulating hypoxia-inducible factor 1 leading to attenuation of VEGF expression. Due to different deposition kinetics, irinotecan HCl and nal-IRI are likely to show different activities in vivo suggesting that a combination of the two agents may optimize intratumoral exposure and improve treatment efficacy. Methods: The activities of nal-IRI, irinotecan and their combination were compared in three human CRC xenograft models with different sensitivity to SN-38, the active metabolite of irinotecan, in vitro. Nal-IRI was dosed at 5 mg/kg q7d, while irinotecan HCl was dosed at 25 mg/kg at days 1 and 2 q7d. The activity of different regimens on tumor cell viability, hypoxia markers and the microvascular density was determined by quantitative biomarker analysis. Results: The relative antitumor activity of nal-IRI was most pronounced in tumor models with natural or acquired irinotecan resistance. Combinations of nal-IRI with irinotecan HCl was significantly better than irinotecan HCl alone in all tumor models although nal-IRI only provided 10% additional irinotecan. The antitumor activity of nal-IRI and Irintecan HCl in combination was accompanied by up to two times more tumor cell death and a marked 3-7 fold reduction of the microvessel density. Despite the strong antiangiogenic effect resulting in tumor hypoxia, the increase in HIF1α and, to lesser degree, HIF2α, was relatively modest and VEGF signal intensity remained at 85-115% of control values. Conclusions: Our results suggest that both irinotecan HCl and nal-IRI can counteract the hypoxia-mediated increase of HIF1α in vivo as previously reported in vitro. Furthermore, the combination of the two formulations demonstrated significant efficacy benefits. A combination of irinotecan HCl and nal-IRI merits further clinical investigation.
Prognostic relevance of human papillomavirus infection in anal squamous cell carcinoma: Analysis of the National Cancer Database.
Authors: Jhaveri Jaymin , Rayfield Lael , Liu Yuan , Chowdhary Mudit , Cassidy Richard John , Madden Nicholas Andrew , Tanenbaum Daniel G , Abugideiri Mustafa , Gillespie Theresa Wicklin , Patel Pretesh R , Patel Kirtesh , Landry Jerome Carl 
Published: January 2019

735 Background: To examine the prognostic relevance of human papillomavirus (HPV) infection for anal squamous cell carcinoma (ASCC) patients treated with chemoradiation in the National Cancer Database (NCDB). Methods: The 2014 NCDB was queried for non-metastatic, histologically confirmed, ASCC patients diagnosed between 2004 and 2013. Patients were required to have HPV status documented in order to be eligible. Patients were then stratified into two groups: HPV+ and HPV-. Univariate analysis was performed using the χ2 test for categorical covariates and ANOVA for numerical covariates. Multivariable analysis (MVA) was performed using Cox proportional hazard model for overall survival (OS). Hazard ratios (HR) and 95% confidence intervals (CI) were generated for each covariate. To minimize selection bias, propensity score (PS) weighting was implemented to balance OS related variables between the groups including: age, education level, stage, diagnosis year, insurance type, and agent of chemotherapy. Results: A total of 1,063 patients were eligible. Patients were stratified into HPV+ (n = 498, 46.8%) and HPV- (n = 565, 53.2%). After PS weighting, MVA for OS showed that for men, HPV infection was associated with better OS (HR 0.60, CI 0.38-0.96; p = 0.034). However, for women, HPV infection did not significantly influence survival (HR 1.47, CI 0.96-2.25; p = 0.074). Conclusions: To our knowledge, this is the largest patient series evaluating the impact of HPV infection on OS in patients with anal cancer. We found that HPV infection is associated with a statistically significant better survival for men with ASCC. In contrast, for women, HPV infection did not significantly influence survival.
Planned organ preservation for selected T2-3 rectal cancer: French experience using chemoradiotherapy and contact xray boost.
Authors: Gerard Jean-Pierre , Barbet Nicolas N. , Dejean Catherine , Evesque Ludovic , Benezery Karine , Coquard Regis , Chateau Yann , Gal Jocelyn , Doyen Jerome , François Eric 
Published: January 2019

751 Background: The Lyon R96-02 randomized trial has demonstrated in T2-3 rectal cancer that external beam radiotherapy (EBRT) with Contact X Ray brachytherapy (CXB) boost was increasing clinical complete response, sphincter preservation and in early cases organ preservation. We report French experience in 3 radiotherapy departments using CXB boost with chemoradiotherapy (CRT) in early T2T3N0. Methods: Selection based on digital rectal examination, colonoscopy, MRI (and/or Endorectal-ultrasound). Inclusion : adenocarcinoma (distal, middle rectum), T2 T3a-b, tumor diameter ≤ 4cm, N0, M0. Treatment : CXB (80-110 Gy/3-4 fr) followed by CRT (CAP 50). Tumor response assess on week 14 : DRE, rigid rectoscopy and MRI. Clinical complete response (cCR) defined as no visible tumor, supple rectal wall and TRG 1-2 on MRI. In case of cCR a close surveillance or local excision was proposed. Results: Between 2002 -2016, 84 patients treated. Median age: 75 years, Male: 59, Female: 25. Operable patients: 69 (83%). T2 : 52, T3 : 32 (Lyon Villeurbanne : 16, Macon : 11, Nice : 57). Median follow-up time : 53 months. cCR was achieved in 94% of cases. Local excision performed in 17 patients (ypT0 : 16). At 4 years, the cancer specific survival was 82% [CI:96-70] and the local relapse rate 12% [CI: 2-22]. No isolated perirectal lymph node relapse observed. After 4 years, 3 more local relapses observed (4, 6, 7 years). Main late toxicity ( > 6 months after treatment) was rectal bleeding (radiation telangiectasia) which required plasma argon coagulation in 5 patients. No TME surgery was performed and organ preservation was achieved in all cases. Bowel function was good in 85% of patients (LARS score < 20). Conclusions: When combining CXB with CRT, rectal cancer T2T3a-b N0 ≤4cm achieve a high rate of cCR (≥85%) with organ preservation, good bowel function, low rate of local relapse ( < 15%) and low toxicity. As rectal adenocarcinoma is radioresistant, the treatment must use a CXB boost. Like anal squamous cell cancer, planned organ preservation can be proposed to operable patients. The ongoing European OPERA trial aims at bringing evidence to this option.
Outcomes for metastatic colorectal cancer (mCRC) based on microsatellite instability.
Authors: Price Timothy Jay , Karapetis Christos Stelios , Joanne Young , Roy Amitesh , Padbury Rob , Maddern Guy , Moore James , Piantadosi Cynthia , Roder David , Townsend Amanda Rose 
Published: January 2019

759 Background: Microsatellite instability (MSI) has been associated with improved survival outcomes in early stage CRC. In stage IV disease, MSI represents only 3-5% of cases and currently the prognostic implications are less clear. There is however evolving evidence that treatment pathways should include anti-PD-1 antibodies given the encouraging results in heavily pre-treated MSI mCRC patients. We undertook an analysis of the South Australian mCRC population based registry to explore the relevance of MSI status in this population based registry. Methods: The registry was analysed to assess patient characteristics and survival outcomes comparing patients with MSI or microsatellite stable (MSS) disease. K-M survival analysis was used to assess OS. Results: 4359 patients are registered on the data base. 598 (14%) patients had been tested for MSI. 62 (10.1%) of these patients had demonstrable MSI. Patient characteristics and outcomes are summarized in the table. There are statistically higher rates of right sided primary, poorly differentiated pathology and BRAF mutation in the MSI group associated with a trend to reduced survival. Chemotherapy and biological therapy received in the MSI v MSS groups was as follows; 5FU 31% v 25%, 5FU/irinotecan 17% v 12%, 5FU/oxaliplatin 52% v 58%, bevacizumab 31% v 42%, anti-EGFR 0 v 4.6%. Conclusions: The patient characteristics of MSI mCRC are in keeping with those previously reported. MSI in this population based mCRC registry is not associated with a favorable outcome as seen in earlier stage disease compared to patients with MSS disease. The trend to poorer outcomes may support routine testing and potentially an alternate treatment pathway, which may include PD-1 inhibitors.[Table: see text]
Chemotherapy dose reductions in obese patients undergoing adjuvant chemotherapy for colorectal cancer: secondary analyses of trial data and the Greater Manchester and Cheshire Cancer Network Audit.
Authors: Srivastava Prakhar , Malcolmson Lee , Saunders Mark P. , Renehan Andrew 
Published: January 2019

763 Background: In patients with stage II/III colorectal cancer receiving adjuvant chemotherapy, doses are calculated using body surface area (BSA) but often capped at BSA > 2.0. Dose capping might be a mechanism of reported poorer survival in obese patients. We aimed to investigate the different dosing schedules across BMI categories, using trial and ‘real world’ audit datasets, and determine its impact upon overall survival. Methods: Data was accessed for 1122 patients from the control arm of the MOSAIC trial (accessed via the Data Project Sphere) and 327 patients from the Greater Manchester and Cheshire Cancer Network (GMCCN) audit. Pearson’s χ2 and correlation coefficient were used to assess the relationship between BMI (expressed as normal, overweight and obese: and as continuous, respectively) and dose reductions. A multiple logistic regression model was constructed to compare the odds of receiving dose reductions in each BMI category. 4-year overall survival was calculated for each BMI category and dose status. Results: In MOSAIC, there were increasing dose reductions by BMI category: normal, 3%; overweight, 5%; and obese, 11%, with similar patterns in the GMCCN OxMdG group. Obese patients in MOSAIC and the GMCCN OxMdG group had 3- and 12-fold higher odds (OR = 3.4 and 12.5, CI = 1.6-7.0 and 2.0-78.1), respectively, of receiving dose reductions. However, these differences did not translate to differences in overall survival by BMI category or dose status. Conclusions: In our investigated datasets, there appears to be a relationship between increasing BMI and dose reductions, though it is modest and does not manifest as a detrimental influence on overall survival. Our findings agreed with other studies performed using stage IV cancer patients, although the relationship between increasing BMI and dose reductions is more prominent in patients with metastatic disease. Investigating other outcome measures such as cancer-specific survival and chemotherapy related toxicity is required for clarity.
Microsatellite instability and adjuvant chemotherapy in stage II colon cancer.
Authors: Koenig Julie L. , Lin Albert Y. , Pollom Erqi L. , Chang Daniel Tandel 
Published: January 2019

767 Background: Randomized control trials and population-based studies have not demonstrated a definitive benefit for adjuvant chemotherapy in stage II colon cancers. Tumor side and microsatellite instability (MSI) have been proposed as prognostic and predictive factors, but there is little consensus about their utility. Previous studies have been limited by the availability of MSI data. Because microsatellite stability (MSS) is associated with worse prognosis and higher risk of metastases, we hypothesized patients with MSS would have increased benefit from chemotherapy. Methods: Using the National Cancer Database, we preformed a retrospective cohort study of patients with resected stage II colon cancer diagnosed 2006-2013. Patient and disease characteristics were compared with chi-square tests. Survival was evaluated with Cox proportional hazard models. Results: We identified 59,475 patients with stage II colon cancer. 11.4% of patients had known MSI status (n = 6,763) of which 88% had MSS (n = 5,953) and 12% had MSI (n = 810). Patients with MSS were more likely to receive chemotherapy (28.2% vs 19.9%, p < 0.001) and have left-sided tumors (38.8% vs 16.7%, p < 0.001). MSI (adjusted hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.48-0.87; p = 0.003) and receipt of chemotherapy (HR 0.54, 95% CI 0.42-0.69; p < 0.001) were associated with better survival after controlling for multiple characteristics including tumor side. Although left-sided tumors had better survival on univariate analysis (HR 0.91, 95% CI 0.88-0.94; p < 0.001), side was not an independent predictor of survival after controlling for MSI and other characteristics (HR 1.01, 95% CI 0.86-1.20; p = 0.860). Among patients with MSS, chemotherapy remained associated with improved survival (HR 0.54, 95% CI 0.43-0.70; p < 0.001) and this benefit did not vary by tumor side (interaction p = 0.380). There was no interaction between MSI status and chemotherapy (p = 0.139), but we observed less of a survival benefit for chemotherapy in patients with MSI (HR 0.81, 95% CI 0.38-1.75; p = 0.595). Conclusions: Our data suggest a benefit for adjuvant chemotherapy in stage II colon cancer even after adjusting for MSI status. However, tumor side was not prognostic after controlling for MSI status.