bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diagnostic accuracy and value of magnetic resonance imaging (MRI) in planning exenterative pelvic surgery for advanced colorectal pelvic cancer.
Authors: Tekkis P. P. , Georgiou P. A. , Constantinides V. A. , Patel U. , Antoniou A. , Goldin R. D. , Darzi A. W. , Cunningham D. , Nicholls R. , Brown G. 
Published: February 2017

370 Background: Exenterative pelvic surgery is challenging and has been used in colorectal surgery to manage patients with advanced colorectal pelvic cancer. Resection of the tumor needs to be performed en-bloc and if feasible, without exposing the tumor, since this can compromise resection margins. This can only be performed through careful pre-operative staging. This study aimed to assess the diagnostic accuracy of MRI in detecting colorectal tumor invasion into seven intrapelvic compartments and its value in planning exenterative pelvic surgery. Methods: Sixty four consecutive patients underwent preoperative MRI planning for exenterative surgery, for locally advanced (n= 23) and recurrent (n= 41) pelvic colorectal cancer. Two radiologists reported tumor invasion for each of the seven anatomic surgical resection compartments and were blinded to histopathology and intraoperative reference standards. Sensitivity, specificity and predictive values were calculated for each compartments. Kaplan-Meier methodology was used to calculate survival rates. Interobserver agreement was assessed using Cohen's Kappa coefficient (k). Results: The sensitivity of MRI was ≥93.3% in all except for the lateral compartment where it was 89.3%. Its specificity for the posterior (82.2%), anterior below (86.4%) the peritoneal reflection compartments was lower compared to the rest of the compartments. MRI diagnosis of lateral (OR= 11.41, p= 0.033), anterior compartment above the peritoneal reflection (OR= 3.14, p= 0.005) and multicompartmental involvement (OR= 1.99, p<0.001) was associated with higher risk of incomplete resection which was subsequently found to be significant factor in predicting overall and disease free survival (p<0.05). The agreement between the two radiologists was found to be either good or very good for all the compartments (k>0.72). Conclusions: MRI is highly accurate in predicting tumor invasion within the intrapelvic compartments and it should be the pre-operative staging modality of choice when considering exenterative surgery for patients with locally advanced colorectal pelvic cancer. [Table: see text]
Mucinous appendiceal tumors of uncertain malignant potential (UMP): Prognostic factors and implications for treatment and follow-up.
Authors: Fournier K. F. , Royal R. , Lambert L. A. , Taggart M. , Rafeeq S. , Mansfield P. F. 
Published: February 2017

372 Background: The diagnosis of UMP is used for dysplastic mucinous tumors that are difficult to classify as clearly benign or malignant. Given the rarity of this tumor, management of these patients is unclear. Methods: All patients with a pathologic diagnosis of an appendiceal mucinous UMP who underwent evaluation at a single institution between September 1993 and July 2009 were retrospectively reviewed. Patient demographics, operative findings, pathology, tumor markers, procedures performed, recurrence, overall survival, and disease-free survival were determined. Results: Of 688 patients with appendiceal neoplasms, 62 (9%) patients (pts) were identified as having UMP. Initial procedures included: appendectomy - 45, colectomy - 11, cytoreduction - 2, and other - 4. Median follow-up was 43.2 months (range 2-184 mos). Median overall survival (OS) was 11.5 years (range 2-184 mos). Median disease-free survival (DFS) has not been reached. There was a trend towards improved DFS in patients who are: female, < 65 years of age, or have mucin confined to the appendix or its serosal surface. Clinicopathologic factors associated with a significantly worse overall DFS included elevated serum CEA (3.6 years, p = 0.0129) and CA-125 (4.16 years, p = 0.0288). DFS at 8 years follow-up in patients with a normal CEA was as follows: 100% if mucin confined to lumen of the appendix, 90% if mucin confined to serosa, and 69% if mucin was in an extra-appendiceal location. 15 patients developed recurrent disease and had an OS of 4.6 years after recurrence. Conclusions: Mucinous UMP tumors of the appendix have an overall favorable prognosis. In patients with a negative margin and mucin confined to the appendix or serosa, expectant management may be sufficient. Elevation of CEA or CA-125 may warrant closer monitoring or intervention. If confirmed in a larger cohort, these findings may have substantial implications for management of these patients. No significant financial relationships to disclose.
Advanced-stage colon cancer prior to the screening age: Association with age, race, and insurance status.
Authors: You Y. N. , Xing Y. , Feig B. W. , Rodriguez-Bigas M. A. , Skibber J. M. , Chang G. J. , Cormier J. N. 
Published: February 2017

377 Background: Stage-at-diagnosis is a major determinant of outcome in colon cancer. Population-based screening is currently only recommended after age 50, but the number of colon cancers diagnosed before 50 is increasing. We aimed to identify risk factors associated with advanced-stage disease (stage III or IV) among colon cancers diagnosed before 50. Methods: Between 2003 and 2007, 248,716 colon adenocarcinomas (25,383 diagnosed before age 50) were reported to the National Cancer Database. Patients with familial adenomatous polyposis were excluded. Among the cases diagnosed before 50, independent predictors for presenting at advanced stages (stage III or IV) were identified using multivariate logistic regression. Results: 10.2% of all colon cancers occur prior to age 50. Stage III or IV disease accounted for 62.2% of the cases before age 50, and 46.9% of those diagnosed at or after age 50 (p<0.001). Among colon cancers diagnosed before 50, independent risk factors for advanced-stage disease included: very young age groups (age 18-30 and age 30-40 vs. age 40-50), African American race (vs. Caucasian), and having Medicaid, non-Medicare government insurance or no insurance (vs. private insurance), after adjusting for gender, tumor location, geographic region, and treatment facility type (Table). Conclusions: In the unscreened population of patients before age 50, disparities in age, race, and insurance are associated with the stage at presentation. The risk factors identified help alert the treating clinicians toward patients most vulnerable to delays in their cancer diagnosis. [Table: see text] No significant financial relationships to disclose.
Oncogenic mutations in MAPK cascade as novel molecular biomarkers for treatment of gastric cancer patients with EGFR inhibitors.
Authors: Corso G. , Marrelli D. , Pascale V. , Garosi L. , Velho S. , Seruca R. , Roviello F. 
Published: February 2017

39 Background: Mitogen-activated protein kinase (MAPK) cascade and phosphatidylinositol 3-kinase (PI3K) survival pathways are frequently activated in the progression of gastrointestinal malignancies. In this study, we aimed to determine the frequency of gene mutations in members of these pathways-EGFR, KRAS, BRAF, PIK3CA and MLK3 in a series of 63 gastric carcinomas with high levels of microsatellite instability. Methods: Gene mutation analysis was performed by PCR amplification followed by direct sequencing. In selected tumor cases, EGFR expression was evaluated by immunohistochemistry. Association studies between molecular data and clinicopathologic characteristics were performed. Results: Mutations in EGFR (3'-UTR polyA repeat), KRAS, PIK3CA and MLK3 genes occurred in 30 (47.6%), 11 (17.5%), 9 (14.3%) and 2 (3.2%) of the MSI gastric cancer (GC) cases, respectively. No BRAF or EGFR hotspot mutations were identified. Overall, mutations in at least one of these genes were found in 55.6% (35/63) of gastric carcinomas. From those mutant cases 40.0% (14/35) of them had concomitant gene mutations, always involving EGFR polyA deletions. Interestingly, we observed significant associations between oncogenic mutations and female gender (p=0.046) old age of diagnosis (p=0.001) and intestinal subtype (p=0.043). Conclusions: Our results show that MSI gastric carcinoma frequently shows activation of EGFR-MAPK and PI3K pathways. Within all alterations found, deletions of the A13 repeats of EGFR were common, suggesting this molecular event as an important biomarker for stratification of GC patients for treatment with EGFR inhibitors. No significant financial relationships to disclose.
Retrospective review of colorectal cancer specimens in individuals younger than age 50 for microsatellite instability testing and DNA mismatch repair enzyme expression.
Authors: Durie N. , Staszewski H. , Palaia T. , Ragolia L. , Nugent W. 
Published: February 2017

392 Background: Data from studies performed at tertiary referral centers suggest that the yield of patients with the underlying defect in hereditary non-polyposis colon cancer (HNPCC) could be improved by screening every colon cancer for the phenotypic expression of the MMR defect by immunohistochemistry (IHC) and/or an assay for microsatellite instability (MSI). We propose to determine the incidence of microsatellite unstable colon cancers and the incidence of absence of expression of DNA MMR enzymes in de-identified colorectal cancer specimens from patients under the age of 50 who have presented to Winthrop University Hospital over the past ten years. This incidence will be compared with those suggested by recent large retrospective studies in tertiary care centers. Methods: Immunoperoxidase staining for MLH1, MSH2, MSH6 and PMS2 were performed on formalin-fixed tissue. MSI assays were performed on microdissected DNA from paraffin-embedded tissue blocks. All cases were tested with five mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27) and two pentanucleotide repeat markers (Penta C and Penta D). Tumor samples in which two or more altered monoclonal repeat markers were found out of five were classified as MSI-H. Results: Screening for expression of DNA mismatch repair enzymes and MSI in an enriched selected (by age <50) population of colorectal cancer patients resulted in detection of 7/51 (14%) specimens that were MSI-H and 7/61 (12%) that were “positive” for lack of expression of at least one DNA mismatch repair enzyme. Conclusions: Our results are similar to those reported in the literature in unselected series of patients with colorectal cancer. IHC staining or MSI analysis alone may be insufficient in selecting those colorectal cancer patients that should be referred for genetic testing for HNPCC. However, screening of an unselected population with both these modalities should have a low but clinically significant yield. Since other research have shown that traditional criteria such as the Bethesda guidelines are inadequate, we support the use of both measures prospectively in all colorectal cancer patients. No significant financial relationships to disclose.
Optimising magnetic resonance imaging for preoperative staging and surgical planning in colon cancer at 1.5 tesla and 3.0 tesla.
Authors: Hunter C. J. , Scurr E. , Jeyadevan N. , Collins D. J. , Abulafi M. , Tekkis P. P. , Georgiou P. A. , Leach M. O. , Brown G. 
Published: February 2017

395 Background: The aim of this study was to determine best technique for future preoperative staging and operative planning in colon cancer using MRI at 1.5T, and feasibility at 3.0T. Methods: 39 scans were performed in 4 healthy volunteers comparing bowel distension using different oral contrast techniques; no oral preparation, 1L of water, 1L of poly ethylene glycol (Klean-Prep), and 1L of 2.1% barium sulphate and 3.2% sorbitol solution (E-Z-Cat) at 1.5T. Bowel distension was scored blindly by 2 experienced radiologists. A further 35 scans compared image quality of T2-weighted pulse sequences; 2D-TrueFISP, 3D-TrueFISP, HASTE, 2D-TSE and 3D-TSE. Scans were scored for movement artefact, colon wall and colon mesentery visualisation. Signal to noise ratio (SNR) was calculated. Inter-observer agreement was assessed using Cohen's Kappa. Equivalent optimised protocols were derived at 3.0T and tested for feasibility. Results: Inter-observer agreement for scoring was good (kappa = 0.61-0.67). Sorbitol-barium sulphate gave significantly better small bowel distension than no oral preparation, water and Klean-Prep (mean score 3.8 vs 1.6, 2.2 and 1.9, p≤0.007). 2D TrueFISP sequences gave the highest mean score for scan quality, significantly better than 3D-TSE, 2D-TSE, 3D-TrueFISP and HASTE (mean 10.6 vs 3.2, 7.8, 7.7 and 7.4, p≤0.012). 2D-TSE sequences obtained best SNR, significantly greater than obtained using 3D-TSE (p=0.045). 3.0T sequences were comparable or superior. Conclusions: Colon imaging using MRI requires fast sequences and adequate bowel distension. Our observations indicate that 2D-TrueFISP and 2D-TSE sequences with 1L Sorbitol-Barium sulphate orally give the best T2-weighted images of the colon wall and adjacent structures for cancer staging at 1.5T; equivalent 3.0T protocols are possible. No significant financial relationships to disclose.
Final results of a University of Chicago phase II consortium trial of sorafenib (SOR) in patients (pts) with imatinib (IM)- and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST).
Authors: Campbell N. P. , Wroblewski K. , Maki R. G. , D'Adamo D. R. , Chow W. A. , Gandara D. R. , Antonescu C. , Stadler W. M. , Vokes E. E. , Kindler H. L. 
Published: February 2017

4 Background: GIST pts who develop resistance to IM and SU have few therapeutic options. SOR inhibits KIT, VEGFR, PDGFR-β, and BRAF kinases. In preclinical models, SOR has activity against several IM-RES mutations that are resistant to SU (Heinrich. ASCO 2009). Methods: We performed a multi-center, phase II trial of SOR in unresectable, KIT-expressing GIST pts who had disease progression on IM by RECIST. After FDA approval of SU for IM-RES GIST, the study was amended in 2/07 to require progression after both IM and SU. Pts received SOR 400 mg orally twice daily. CT scans were obtained Q2 28-day cycles. The primary endpoint was objective response rate. A Simon minimax 2-stage design required 1 response in 18 pts to proceed to a second stage, and 4 responses in 32 IM/SU RES pts for further investigation. Results: 38 pts (6 IM-RES, 32 IM/SU-RES) enrolled 1/06-9/09 at 6 centers. Median follow-up for survivors: 31 months (mo). Pt characteristics: male 55%; median age 57 (range 42-85); PS 0/1/2: 47%/47%/6%. Median cycles: 4 (range 1-37). 63% pts had at least 1 dose reduction. Partial response (PR): 13% (1 IM-RES, 4 IM/SU-RES); stable disease (SD): 55% (3 IM-RES, 18 IM/SU-RES). Disease control rate (PR + SD): 68%. Median progression-free survival: 5.2 mo (95% CI: 3.4, 7.4). Median overall survival 11.6 mo (95% CI: 8.8, 18.0); 1-year survival 50%; 2-year survival 29%. Three pts remain on trial receiving study drug (1 PR at 34 mo; 2 SD at 18 and 37 mo). Grade 3/4 toxicities (% pts): hand-foot syndrome 45%, hypertension 21%, diarrhea 8%, hypophosphatemia 8%, GI bleed 5%, rash 5%, thrombosis 3%, GI perforation 3%, fatigue 3%, anemia 3%. Conclusions: SOR is active in IM-and SU-resistant GIST. Some pts treated with SOR experience prolonged disease control. SOR is well-tolerated in GIST pts, but dose reductions are often required. SOR warrants further investigation in GIST. Supported by NCI grant N01-CM-62201. [Table: see text]
Assay result variability during determination of mismatch repair deficiency status using immunohistochemistry: A transatlantic comparative study.
Authors: Hutchins G. , Handley K. , Baehner F. L. , Lopatin M. , Yaziji H. , Lee M. , Seymour M. T. , Kerr D. J. , Gray R. G. , Quirke P. 
Published: February 2017

403 Background: Colorectal cancer patients with deficient mismatch repair (dMMR) have significantly fewer recurrences and may respond less well to chemotherapy. Immunohistochemical (IHC) determination of MMR status is therefore recommended to identify patients in whom adjuvant therapy is not indicated, but little is known regarding the variability of assay results. We aimed to define MMR IHC assay variability in formalin-fixed, paraffin-embedded (FFPE) material from the QUASAR-1 colorectal cancer trial contained within heterogeneity-prone tissue microarrays (TMAs) Methods: TMA sections of FFPE material from the QUASAR-1 trial were distributed to 2 independent laboratories (Leeds, UK and Vitro Molecular Laboratories [VML], FL, USA) for MMR IHC assays. Serial TMA sections were stained with MLH1/MSH2 using techniques blinded to the other laboratory. Each stained section was double-scored independently and results compared to determine inter-assay variability. Results: Matched MMR data were available for 1224 cases of MLH1 and 1223 cases of MSH2. Of these, loss of expression of MMR (dMMR) was reported in 160 cases (13.1%) by VML and 179 cases (14.6%) by Leeds. 140 (11.4%) were dMMR in both labs, 20 cases (1.6%) by VML alone and 39 (3.2%) by Leeds alone. Discordant dMMR status was observed in 56/166 (34%) dMMR cases identified with MLH1 and 10/34 (29%) cases identified with MSH2. Kappa coefficients for inter-assay agreement were 0.798 (95% CI = 0.748 - 0.848) for MMR status overall, 0.778 (95% CI = 0.722 - 0.835) for MLH1 and 0.823 (95% CI = 0.714 - 0.932) for MSH2. 85% (33/39) of discordant Leeds dMMR colon cancers were in the right colon where dMMR is more common, compared to 47% of VML discordant dMMR cases. Conclusions: Independent determination of MMR status by IHC on TMAs is associated with excellent inter-assay agreement. The reasons for MMR case discordance are under further investigation. These results further support routine MMR testing by IHC. No significant financial relationships to disclose.
Measuring the cost-effectiveness (CE) of therapies treating metastatic colorectal cancer (mCRC).
Authors: Lakdawalla D. , Penrod J. , Maclean R. , Humphrey J. S. , Seabury S. 
Published: February 2017

405 Background: Traditional CE approaches often produce results that appear to be at odds with patients' (pts) behavior. Patients with terminal disease often value gains in survival much more highly than is suggested by standard CE estimates. In the context of metastatic cancer, CE classifies as cost-ineffective many therapies that pts appear to value highly. This study assesses whether CE analyses conflict with estimates of pt value for mCRC therapy. We infer pt value from the willingness to pay (WTP) of cancer pts for therapy out-of-pocket (OOP), and compare these estimates to the value implied by traditional CE. In contrast to traditional CE approaches, this study uses real-world data on pts' own WTP for therapy OOP. Methods: Revealed preference analysis is performed on retrospective claims data, including the pt OOP spending component, to infer the value metastatic cancer pts (N=13,938) place on 29 different therapies for CRC, breast, lung or head and neck cancer. The primary outcome measure is the average value placed by pts on therapy. Secondary outcomes are: utilization of therapy, total expenditures on cancer drugs, and the price elasticity of demand for therapy. Results: Utilization of therapy displays a negative but inelastic relationship with OOP spending on drugs (the estimated price elasticity is -0.007, with p<0.01). The estimated annual WTP OOP for treatment of mCRC specifically was $207,555, approximately 19 times the average annual cost of therapy ($10,775). Approximately 99% of mCRC pts value the therapy more than the cost. The analysis implies that the average mCRC pt values a statistical life year at approximately $282,000. In comparison, traditional CE analyses employed by regulators assign much lower values for a statistical life-year; for example, the UK's NICE uses a threshold of <$50,000 per year. Conclusions: Traditional economic valuations of medical treatment perform poorly in the terminal care setting, because they fail to recognize that pts place higher value on care provided at the end of life. As a result, these methods vastly understate the CE of treatment for mCRC and other terminal diseases. Use of pts' own OOP spending behavior appears to produce different conclusions for the value of therapy. [Table: see text]
Evaluation of the derivation of human colon adenocarcinoma from Lgr5 colon stem cells.
Authors: Chiu V. K. , Paty P. , Chiu T. K. , Le Rolle A. , Shia J. , Zeng Z. , Jarnagin W. R. , Weiser M. R. , Rafii S. 
Published: February 2017

410 Background: Human colon stem cells share phenotypic hallmarks of self-renewal and proliferation that are associated with tumor cells. Lgr5 is a marker of colon stem cells and not colon differentiated cells. In mice, deletion of the adenomatous polyposis coli gene in colon stem cells but not in colon differentiated cells, rapidly gives rise to macroscopic adenomas. We investigated the role of Lgr5 colon stem cells in human colon tumors in relation to tumor cell of origin, tumor progression, tumor recurrence, and overall survival. Methods: Using in situ hybridization, we determined the histological distribution of Lgr5 mRNA in human colon specimens at different stages of tumor development and tumor recurrence after chemotherapy. Using gene expression analysis, we analysed Lgr5 mRNA expression levels in human normal colon (n = 33), normal liver (n = 13), colon adenomas (n = 45), primary colon adenocarcinomas (n = 170), liver metastates (n = 48) and lung metastates (n = 20). We examined the correlation between Lgr5 mRNA expression, K-ras mutation status and overall survival in stage IV colon adenocarcinomas. Results: Human normal colon Lgr5 mRNA was always expressed at basal level and restricted to human colon stem cells. In contrast, we observed an all (Lgr5(+)) or none (Lgr5(-)) expression in human colon adenomas, adenocarcinomas and liver metastases. When present Lgr5 mRNA expression was increased 3-10 fold compared to normal colon. The Lgr5 gene expression analysis provided similar results with increased expression in 66% of human colon adenomas, 62% of primary colon adenocarcinomas, 72% of colon liver metastases and 55% colon lung metastases when compared to normal colon. We have determined that 22.5% (18/80) of Lgr5(+)and 46.4% (26/56) of Lgr5(-) colon adenocarcinoma specimens have K-ras mutations. Kaplan-Meier estimates of median overall survival in Lgr5(+) and Lgr5(-) Stage IV colon adenocarcinomas were 20 months and 15 months, respectively. Conclusions: Human colon adenocarcinomas are derived predominantly from Lgr5 colon stem cells. Lgr5(+) colon adenocarcinomas required less frequent K-ras mutation for tumor progression then Lgr5(-) colon adenocarcinomas. No significant financial relationships to disclose.