bluuebunny/crossref_metadata_2025_split huggingface dataset:
Practice patterns of molecular profiling in colorectal cancer.
Authors: Nweze Nkem , Nadler Ashlie , Reddy Sanjay S. , Luo Biao , Sigurdson Elin R. , El-Deiry Wafik S. , Denlinger Crystal Shereen , Hall Michael J. , Farma Jeffrey M. 
Published: March 2017

641 Background: Colorectal cancer (CRC) is a genetically heterogeneous disease. Molecular profiling (MP) using next-generation sequencing is increasingly used to personalize therapy. No guidelines currently exist regarding patient selection and optimal timing. Our goal was to describe our experience at a tertiary cancer center using MP in CRC patients. Methods: This is an IRB-approved, retrospective study in patients with CRC who underwent MP between March 2007 and August 2016. Tissue samples were sent for analysis in the following MP platforms: Foundation One, Caris, and FCCC Targeted Cancer Panel (FTCP), which tests for the 50 most common mutations. Data regarding patient demographics, mutations, and clinical outcomes were analyzed. Kaplan Meier methods were used for survival analysis using SPSS. Results: We evaluated 248 patients with CRC. 60.1% were male and 80.1% were white. The median age was 59.5 years. 66.5% had colon and 33.5% had rectal CA. Initial stages: stage 1 (2.8%), stage 2 (14.1%), stage 3 (22.9%), stage 4 (59.2%). 82.2% were tested via FTCP, 8.9% via Foundation One, and 9.3% via Caris. 60.9% had the primary tumor tested. 5.2% had no mutations, 19% had 1 mutation, 28.6% had 2 mutations, 27% had 3 mutations and 20.2% had >4 mutations. The most common mutation guiding targeted therapy was KRAS (43.5%). 50% of patients had R0 resection and 19.3% went on to targeted therapy. 76.2% of resectable patients had a metastatic recurrence. 51.9% had targeted therapy for recurrence and/or stage 4 disease. The median time from diagnosis to MP was 9.9 months overall and 2.7 months for stage 4 patients. The median time from date of recurrence to MP was 7.7 months. Median length of follow up was 1.7 years. 14.9% had no evidence of disease at last follow up, 73% were alive with disease and 10.9% had died of the disease. Median overall survival was 55.8 months (CI 41.9 - 69.7). Conclusions: MP is utilized commonly in patients with stage 4 and recurrent CRC and occurs within 2.7 months and 7.7 months respectively. Further research is underway to evaluate if the information provided by MP improves outcomes in CRC, provides novel targets and will lead to increased clinical trial accrual.
Prevalence and survival benefit of adjuvant chemotherapy in stage III colon cancer patients: Comparison of overall and age-stratified results by multivariable modeling and propensity score methodology in a population-based cohort.
Authors: Hines Robert Brooks , Bimali Milan , Johnson Asal , Bayakly Rana , Collins Tracie 
Published: March 2017

649 Background: Few population-based studies have assessed the effectiveness of adjuvant chemotherapy (ACT) in stage III colon cancer patients according to age. We sought to quantify the prevalence of ACT use and the absolute and relative survival benefit of ACT overall and by age in a population-based cohort. Methods: Stage III patients with adenocarcinoma of the colon identified by the Georgia Comprehensive Cancer Registry for the years 2000–07 were eligible (final N = 3057). We utilized Poisson regression to obtain adjusted mortality rates (MR) and Cox proportional hazards models to obtain adjusted hazard ratios (HRs) for 5-year overall survival. We evaluated control of confounding by comparing HRs obtained via multivariable modeling (MM), propensity score weighting (PSW), and propensity score matching (PSM). Results: Just over one-third of colon cancer patients did not receive ACT, and the proportion increased with age. Overall, receipt of ACT conferred an absolute (MR difference [No ACT rate - ACT rate] 25.4 deaths/ 1000 person-years [py], 95% confidence interval [CI]: 19.1–32.7 deaths/1000 py) and relative (MM HR = 0.67, 95% CI: 0.59–0.76) survival benefit. The survival benefit was demonstrated across age groups. mm and propensity score methods yielded highly similar HRs. Conclusions: Unless contraindicated, efforts to ensure receipt of ACT for stage III colon cancer patients up to 84 years of age are needed to improve the prognosis of patients with node-positive disease.
Interaction between regorafenib and warfarin therapy.
Authors: Beg Muhammad S. , Khosama Leticia , Conley Stefanie , Arriaga Yull Edwin , Syed Samira K. , Karri Sirisha , Verma Udit N. 
Published: March 2017

651 Background: Regorafenib is an oral multi kinase inhibitor with clinical activity in colorectal cancer, gastrointestinal stromal tumors and hepatocellular cancer. Drug- drug interactions are commonly encountered in clinical practice and warfarin continues to be the most commonly prescribed anticoagulant among cancer patients in the clinic. The interaction of regorafenib with warfarin has not been studied. Methods: Patients at a single institution being prescribed regorafenib were identified and charts reviewed for concurrent warfarin therapy. Baseline characteristics, indications for regorafenib and warfarin therapy was determined. Patients were followed up to the first 8 weeks of combination therapy. Results: We identified 6 patients on concurrent regorafenib and warfarin. All patients had refractory colon cancer. Median age was 74, 4 were male and 5 white. Indication for warfarin was venous thromboembolism in 5 and atrial fibrillation in 1. Baseline INR ranged from 1.1 to 2.4. An increase in INR was seen in all six patients (peak INR range 4.5 to > 12) which improved with dose modification. Time to peak INR was less than 6 weeks (INR trends in all patients shown in figure 1). There were no bleeding complications noted in any patient. Conclusions: We report a clinically significant interaction between warfarin and regorafenib with patients demonstrating an increase in INR. Patients who are anticoagulated with warfarin and start regorafenib should be closely monitored and upfront warfarin dose reduction should be considered. Further drug-drug interaction studies are needed to determine the exact mechanism of drug-drug interaction between these medications.
Alterations in small leucine-rich proteoglycans in right-sided colorectal cancer.
Authors: Solis Hernandez Maria Del Pilar , García-Suárez Olivia Pilar , Fernández-Vega Ivan , Quirós Luis M , García Beatriz 
Published: March 2017

652 Background: Colorectal cancer (CRC) is a heterogeneous disease, and there are anatomic, functional and molecular differences between the tumors of the proximal and distal colorectum. Various molecular phenotypes have been associated with aggressive subtypes in these pathologies, and several of these markers show a relationship with proteoglycans, which in turn show significant alterations in colon tumors, which affect both their core proteins and their glycosaminoglycan chains. Small leucine-rich proteoglycans (SLRPs) constitute a family of molecules encoded by 18 distinct genes. They are grouped into five classes and may appear coupled to different glycosaminoglycan chains ––including chondroitin/dermatan sulfate or keratan sulphate–– or not, depending on the specific species. They are ubiquitously expressed in extracellular matrices, and have been found involved in the regulation of organ size and shape during embryonic development. In this study we investigate the expression patterns of SLRPs in right-sided CRCs. Methods: A transcriptomic approach was used, employing qPCR to analyze SLRP core protein transcriptions. Immunohistochemical techniques were also used to analyze tissue expression of particular genes showing significant expression differences of potential interest. Results: Only two proteins displayed significant alterations: biglycan appeared overexpressed approximately 4 fold (p = 0.015), and osteoglycin decreased about 4 fold (p = 0.05). Transcripts for epiphycan, opticin, nyctalopin and podocan-like 1 were not detected in most patients, while chondroadherin was detected in 50% of healthy tissues but not in CRCs. Expression of lumican, decorin, keratocan, asporin, ECM2, fibromodulin, PRELP, tsukushi, podocan and osteoadherin was detected, but with no significant differences compared to healthy tissue. Conclusions: Normal mucosa of the large bowel expresses most SLRPs, and two, biglycan and osteoglycin, appeared altered in right-sided CRCs. These alterations could be related to binding of different ligands and modulation of homeostasis.
Modified Glasgow prognostic score as a selection marker for colorectal cancer patients with multiple metastases who can underwent primary site resection followed by multidisciplinary therapy.
Authors: Shimura Tadanobu , Toiyama Yuji , Saigusa Susumu , Imaoka Hiroki , Okigami Masato , Fujikawa Hiroyuki , Hiro Junichiro , Kobayashi Minako , Ohi Masaki , Araki Toshimitsu , Inoue Yasuhiro , Uchida Keiichi , Mohri Yasuhiko , Kusunoki Masato 
Published: March 2017

655 Background: We often encounter the colorectal cancer (CRC) patients with multiple distant metastases who rapidly progress after resection of primary tumor site due to preventing bowel obstruction, tumor bleeding and perforation. However, there has been few knowledge for identification of these patients at the present time. In this study, we evaluated the association between clinicopathological findings, including with preoperative laboratory data and survival outcome, and possibility of multimodality therapy in CRC patients with multiple metastases after resection of primary tumor lesion. Methods: Clinicopathological findings and preoperative laboratory data, including carcinoembryonic antigen (CEA) and systemic inflammatory response markers, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and modified Glasgow Prognosis Score (mGPS) for 92 CRC patients with multiple metastases from 2005 to 2014 were collected. We performed multivariate analysis for overall survival (OS) in cox proportional hazard model. In addition, we performed multivariate logistic regression analysis to evaluate the factors influencing possibility of postoperative multimodality therapy. Results: Postoperative multimodality therapy improved overall survival significantly. Among serum markers, elevated CEA, NLR, and mGPS were significant indicators of poorer OS. Multivariate analysis for OS revealed that elevated CEA (P = 0.026), mGPS (P = 0.038), and undifferentiated histology type (P = 0.02) were independent poorer prognostic factors. In addition, multivariate logistic regression analysis showed that elevated mGPS (P = 0.029) and higher age (P = 0.013) were independent risk factors for difficulty of introducing postoperative multidisciplinary therapy. Conclusions: Preoperative mGPS is useful objective marker for selection of colorectal cancer patients with multiple metastases who can undergo primary resection followed by multidisciplinary therapy.
Effect of sex on treatment outcomes in rectal cancer patients after neoadjuvant radiotherapy or chemoradiation: A combined analysis of Polish-1 and Polish-2 studies.
Authors: Wyrwicz Lucjan , Spalek Mateusz , Michalski Wojciech , Krynski Jacek , Polkowski Wojciech , Rutkowski Andrzej 
Published: March 2017

656 Background: Two independent studies have previously reported the equivalence of short-course radiotherapy (SCRT) and chemoradiation (CRT) in stage II/III rectal cancer patients (Bujko 2006 – Polish-1, Ngan 2012). Recently, in tumors with resection margin at risk (cT4 and fixed cT3), SCRT and chemotherapy when compared with CRT was associated with similar R0 resection rates, but improved overall survival (OS; Polish-2 study; Bujko 2016). The differences in pelvis anatomy and access to surgical field provide the rational for analysis of patients’ sex on treatment outcomes in locally advanced rectal cancers. Methods: We performed individual patients data analysis of Polish-1 (n = 312) and Polish-2 (n = 515) cohorts. The male-to-female ratio was similar in both studies (Polish-1: 65.1%; Polish-2: 65.8%). No major differences in treatment allocation, toxicities, complience to study procedures between males and females were observed. Results: In the combined cohort the prognostic effect of sex on survival was observed (74.5% female and 66.9% of male patients alive at the cut-off time; HR 0.72; p = 0.018). No differences in post-operative mortality were observed with 3-4% of patients dying in 6 months from randomization in each analyzed stratum. When analyzing the treatment outcomes by sex, male patients benefited more from SCRT than CRT. This effect was observed in more advanced tumors from Polish-2 (HR 0.65; 95% CI 0.45-0.95; p = 0.026), while it did not reached the significance in Polish-1 (HR 0.67; 95% CI 0.34-1.33). Conclusions: This individual patients data analysis indicates that female patients with locally advanced rectal has better prognosis than males. This observation is valid either for SCRT or CRT. In the future, rectal cancer studies should be stratified for sex in order to minimize the risk of bias. Although it should be confirmed by other studies, it is very likely that efficancy of SCRT is higher in male patients. Clinical trial information: NCT00833131.
Associations of physical activity with survival and progression in metastatic colorectal cancer: Results from CALGB 80405 (Alliance).
Authors: Guercio Brendan John , Venook Alan P. , Niedzwiecki Donna , Zhang Sui , Sato Kaori , Fuchs Charles S. , Lenz Heinz-Josef , Innocenti Federico , Fruth Briant , Van Blarigan Erin , O'Neil Bert H. , Shaw James Edward , Polite Blase N. , Hochster Howard S. , Atkins James Norman , Goldberg Richard M. , Mayer Robert J. , Bertagnolli Monica M. , Blanke Charles David , Meyerhardt Jeffrey A. 
Published: March 2017

659 Background: Regular physical activity (PA) is associated with reduced risk of recurrence and mortality in non-metastatic colorectal cancer. Its influence on patients with metastatic colorectal cancer (mCRC) is largely unexplored. Methods: 1231 patients participating in CALGB 80405 (first-line phase III chemotherapy trial for mCRC) completed questionnaires that included self-report on PA at time of chemotherapy initiation and total metabolic equivalent task (MET)-hours/week were determined based on responses. The primary endpoint of the clinical trial and this companion study was overall survival (OS), with progression-free survival (PFS) as a secondary endpoint. To minimize confounding by poor and rapidly declining health, we excluded patients who experienced progression or died within 60 days of activity assessment and adjusted for known prognostic factors, comorbid illness, and weight loss over the previous six months. Results: Compared with patients engaged in less than three MET-hours/week of PA, patients engaged in 18 or more MET-hours/week experienced an adjusted hazard ratio for OS of 0.81 (95% CI 0.67 to 0.98, P for trend 0.03) and for PFS of 0.84 (95% CI 0.71 to 1.00, P for trend 0.03). Greater nonvigorous PA and walking duration were both associated with improved OS ( P for trend 0.01 and 0.04, respectively). Conclusions: In mCRC patients from CALGB 80405, greater total PA was associated with improved PFS and OS, while greater walking duration and non-vigorous PA were associated with reduced risk of all-cause mortality. Support: U10CA180821, U10CA180882. ClinicalTrials.gov ID: NCT00265850 [Table: see text]
The behavior of colorectal liver metastases in the time frame between the end of preoperative chemotherapy and liver resection: A new selection criterion for technically resectable patients.
Authors: Vigano Luca , Darwish Shadya Sara , Rimassa Lorenza , Cimino Matteo , Carnaghi Carlo , Donadon Matteo , Procopio Fabio , Personeni Nicola , Del Fabbro Daniele , Santoro Armando , Torzilli Guido 
Published: March 2017

665 Background: Not all the patients with resectable colorectal liver metastases (CLM) benefit from liver resection (LR). To date, patients with disease progression during chemotherapy are excluded from surgery. The present study aims to elucidate if the CLM behavior in the interval between the end of chemotherapy and LR (stable disease vs. progression) impacts prognosis. Methods: All the consecutive patients undergoing LR for CLM between 2004 and 2014 after a tumor response or stabilization during chemotherapy were considered. The patients having received two separate imaging modalities after chemotherapy (one at the end of chemotherapy and one before LR) with an interval between the two > 3 weeks were included. Any variation of CLM size was registered. Tumor progression was defined according to the RECIST criteria. Results: Overall, 130 patients were analyzed. One fourth of the patients with partial response or stable disease during chemotherapy had a disease progression after the end of chemotherapy before LR, 16% if the interval chemotherapy-surgery was < 8 weeks. The risk of progression was not associated with the response to chemotherapy. Patients with progression after the end of chemotherapy had lower survival than patients with stable disease (5-year overall survival (OS) 19.0% vs. 27.6%; three-year recurrence-free survival (RFS) 6.7% vs. 21.3%, p < 0.001 for both). Survival was extremely poor in case of early progression ( < 8 weeks) (0% two-year RFS and OS). Progression was an independent prognostic factor of OS and RFS (HR = 3.243 and HR = 2.874, p < 0.0001). Eleven patients had a complete radiologic response to chemotherapy and underwent LR at disease reappearance without further chemotherapy after a median delay of 8.7 months. They had excellent survival (five-year OS 39.0%, three-year RFS 36.4%). Conclusions: Early disease progression between the end of chemotherapy and LR occurs in ~15% of patients. It is associated with extremely poor survival and should be considered a contraindication to surgery. Patients with a complete radiologic response can be resected upfront at recurrence without further chemotherapy.
Molecular and clinical characterization of a claudin (CLDN)-low subtype of gastric cancer (GC).
Authors: Nishijima Tomohiro F. , Kardos Jordan , Chai Shengjie , Smith Christof C , Bortone Dante S. , Mose Lisle E. , Selitsky Sara R. , Sanoff Hanna Kelly , Parker Joel S. , Lee Michael Sangmin , Vincent Benjamin Garrett 
Published: March 2017

67 Background: A CLDN-low subtype has been identified in breast and bladder cancers and is characterized by low expression of tight junction proteins CLDN, enrichment for epithelial-to-mesenchymal transition (EMT) and tumor initiating cell (TIC) features. Given the genomically stable (GS) subtype of GC defined by TCGA has features suggestive of CLDN-low tumors, we evaluated whether the CLDN-low subtype also exists in GC. Methods: 415 tumors from TCGA GC mRNA dataset were clustered on the CLDN, EMT and TIC gene sets with significance testing using SigClust2 to identify CLDN-low GC. A minimal set of genes that could accurately classify CLDN-low GC was defined by prediction analysis of microarrays (PAM). Tumors identified by SigClust2 or the PAM were called CLDN-low GC regardless of the original subtype call. The 300 GCs in the Asian Cancer Research Group (ACRG) dataset [GSE62254] were used to validate the predictor. We characterized clinical and molecular (gene expression, mutation and copy number alteration) features of CLDN-low GC. Results: We identified 46 tumors that had consensus enrichment for CLDN-low features in TCGA. CLDN-low tumors were most commonly diffuse (35/42=83%, 4 tumors=mixed) and GS (36/46=78%). CLDN-low GC showed high expression of immune gene signatures including T and NK cell signatures, but not an immunosuppression signature. Compared to GS subtype, CLDN-low GC had increased frequency of CD44, GATA4, and GATA6 amplification. In ACRG, 28/300 GCs were CLDN-low using the PAM predictor. The CLDN-low GC in ACRG was phenotypically similar to the CLDN-low GC in TCGA based on the CLDN, EMT and TIC gene signatures. Clinically, CLDN-low GC was associated with the shortest overall survival of the 5 subtypes (CLDN-low plus TCGA defined 4 subtypes). Notably, a hazard ratio comparing CLDN-low GC vs GS was 2.10 (95%CI; 1.07-4.11) in TCGA and 2.32 (95%CI; 1.18-4.55) in ACRG cohort, adjusting for age and pathological stage. Conclusions: We identified a CLDN-low GC which has a poor prognosis likely related to the resistance to conventional chemotherapy due to its EMT and TIC-like properties. Further development of targeted therapies against these molecular features is warranted to improve the outcome of CLDN-low GC.
Longitudinal trajectory of cancer survivorship in patients with recurrent rectal cancer: Anatomy of recurrence in relation to quality of life and pain.
Authors: Sammour Tarik , Malakorn Songphol , Chang George J. , Rodriguez-Bigas Miguel A. , Bednarski Brian , Eng Cathy , Das Prajnan , Skibber John Michael , You Y. Nancy 
Published: March 2017

679 Background: Multiple treatment modalities are utilized for patients with recurrent rectal cancer (RRC). While recurrent pelvic tumor can be highly symptomatic, treatments often carry significant morbidity risks. Patient reported outcomes such as quality of life (QoL) and pain can supplement traditional clinical endpoints in assessing the effectiveness of salvage treatments, and thus aid in treatment decision making. We aimed to examine the longitudinal trajectory of cancer survivorship in RRC. Methods: A prospective protocol enrolled patients diagnosed with RRC between 2008 and 2015. Participants prospectively self-reported QoL (measured by the validated EORTC QLQ-C30 and EORTC QLQ-CR29) and pain (measured by the Brief Pain Inventory, BPI), at presentation, and then every 6 months for 5 years. After accounting for repeated measures, trajectory of mean scores over time was assessed for patients amenable to surgical salvage vs those who were not, using linear mixed-effects modeling. Results: A total of 104 patients were enrolled of which 73 (70.2%) were amenable to salvage surgery with curative intent. Surgical salvage was associated with 30 day morbidity of 68.5% (13.7% and 5.5%, Grade 3 and 4 respectively). Three year overall survival was 56.7% (68.5% in surgical and 29.0% in non-surgical patients). Mean baseline QoL scores did not differ between surgical vs nonsurgical patients but were significantly impacted by the anatomical site of recurrent disease (lowest scores in posterior pelvic recurrence; P=0.012). On longitudinal analysis with a median followup of 33 months, surgically salvaged patients showed gradual sustained improvement in QoL but not pain scores. Anatomy of initial recurrence had an ongoing impact on QoL long term with posterior recurrences having the worst scores. Both QoL and pain scores worsened in patients not amendable to surgical salvage. Conclusions: Disease anatomy determines QoL at baseline and long term in patients with RRC. Surgery improves QoL but not pain in selected resectable cases.