bluuebunny/crossref_metadata_2025 huggingface dataset:
First report of the correlation of PET Response Criteria in Solid Tumors (PERCIST) criteria and pathologic change in patients with rectal cancer treated with neoadjuvant radiation.
Authors: Kumar Rachit , Dholakia Avani Satish , Smith Jessica A. , Leal Jeffrey P. , Chaudhry Muhammad Ali , Wild Aaron Tyler , Hacker-Prietz Amy , Raman Siva P. , Hruban Ralph H. , Efron Jonathan , Wick Elizabeth C. , Azad Nilofer Saba , Diaz Luis A. , Le Yi , Armour Elwood , Ellsworth Susannah G. , Herman Joseph M. , Gearhart Susan
Published: February 2017

261

Background: High-dose-rate endorectal brachytherapy (Endo-HDR) is a promising technique using a short course of radiation therapy in the neoadjuvant setting for rectal cancer. While clinical exam and standard imaging (CT and MRI) suggest outstanding radiation response in these patients, they cannot reliably predict pathologic complete response (pCR) or high tumor regression grade (TRG). In this study, we investigate the utility of PERCIST criteria to predict pathologic change. Methods: We treated nine patients on a prospective clinical trial investigating Endo-HDR as a single agent neoadjuvant therapy (6.5 Gy x 4 fractions, total dose of 26 Gy) for stage II-III rectal cancer patients. A pre-radiation PET/CT scan was compared to a post-treatment PET/CT scan performed one month following the completion of radiation. All nine patients proceeded to surgical resection with the pathologic specimen analyzed for residual disease. TRG (Mandard et al.) was used to quantify response to treatment. A 50% decrease in SUVpeak by PERCIST criteria was correlated with a TRG 1 or 2 (none or minimal residual cancer cells on the final pathologic specimen). Results: As demonstrated in our table, 3/5 (60%) of patients achieving a TRG 1 or 2 had a SUVpeak that decreased by 50% or more; contrarily, zero of 4 (0%) of patients without a TRG 1 or 2 had a SUVpeak of 50% or more. Despite a trend, the small patient sample limited statistical significance (p=0.17). A minimum decrease of 50% in SUVpeak resulted in a positive predictive value of 100%, a negative predictive value of 67%, a specificity of 100%, and a sensitivity of 60% for predicting TRG 1 or 2. Conclusions: Our results demonstrate the first report of utilizing PERCIST criteria in rectal cancer treated with neoadjuvant Endo-HDR. Reliable clinical predictors following Endo-HDR for excellent pathologic response may identify patients in whom a non-operative rectal cancer treatment is possible. [Table: see text]
Attenuated dose of gemcitabine with cisplatin in patients (pts) with unresectable or metastatic biliary tract cancer (ABC): Results of single Thai institution.
Authors: Charoentum Chaiyut , Chotirosniramit Arnon , Chitapanarux Taned , Sirivanichai Chusak , Lertprasertsuke Nirush , Chewaskulyong Busyamas , Thongprasert Sumitra
Published: February 2017

265

Background: Combination of gemcitabine/cisplatin becomes a recent standard regimen for pts with advanced (ABC). We previously reported the encouraging activity of gemcitabine (1250 mg/m2) with cisplatin and reported grade 3/4 toxicities of anemia and neutropenia in 33% and 22% respectively. (Charoentum et al. World J Gastroenterol 2007.). This study examines the toxicity and activity of attenuated dose gemcitabine (1000 mg/m2) with cisplatin in Thai pts with ABC. Methods: Chemotherapy-naive patients with histological/cytological proven ABC, aged > 18 years, ECOG 0-2 and adequate organs function were treated with gemcitabine (1000 mg/m2 in a 30-min infusion D1, 8 q 21 d) followed by cisplatin (75 mg/m2D1) for maximum 6 cycles. Results: From November 2007 to June 2012, 37 patients were evaluated. Median age was 56 yrs (range 34 - 66), 54% were male, 76% were metastatic disease and 97% were ECOG PS 0/1. The median number of cycle was 4 (range 3-6). Among the 34 pts with measurable disease, there were 11 PR, 15 SD and 8 PD (response rate 32%). The most common hematologic toxicity of interests was gr 3 anemia in 11% and gr 4 neutropenia in 6%. Non-hematologic toxicity was generally mild. No cases of febrile neutropenia or treatment-related death were observed. The median progression free survival was 6 months (range 3-13). Conclusions: Treatment with attenuated dose of gemcitabine in combination with cisplatin in this study appears more tolerable than our previous reports in Thai pts with advanced ABC. The efficacy of both regimen appears similar.
Analysis of gene mutations in KRAS, NRAS, BRAF, and PIK3CA in patients who received systemic chemotherapy with metastatic gastric cancer.
Authors: Fukahori Masaru
Published: February 2017

27

Background: Previous studies showed that gene mutations of KRAS, NRAS, BRAF, and PIK3CA are associated with a poor prognosis or resistance of anti-EGFR antibody in metastatic colorectal cancer. On the other hand, the frequency and clinical significance of these gene mutations have not been clarified in metastatic gastric cancer (mGC). Methods: We gathered formalin-fixed paraffin-embedded tumor samples from 168 patients who were diagnosed gastric cancer and underwent gastrectomy between September 1995 and March 2008. Among 168 patients, we selected the mGC patients who received systemic chemotherapy. We retrospectively evaluated the mutation status of KRAS (exon2, 3, 4), NRAS (exon 2, 3), BRAF (exon 15) and PIK3CA (exon 9, 20) and prognosis in patients who received chemotherapy by gene mutation status. Results: A total 125 of patients were included in this analysis. Regimens of first line chemotherapy were 5-FU (24.0%), CPT-11/CDDP (31.2%), S-1 (33.6%), 5-FU/MTX (8.0%) and others (3.2%). Mutations of KRAS codon 12/13 (6.4%), PIK3CA exon9 (4%), PIK3CA exon20 (0.8%), and NRAS codon 12/13 (2.4%) were detected by direct-sequence method. Mutations of KRAS codon 61, KRAS codon 146, BRAF V600E and NRAS codon 61 were not detected. There were no significant differences in overall survival (OS) by mutation status of KRAS and PIK3CA. Patients with NRAS codon 12/13 mutation had poor prognosis (MSTF15.5 vs 9.4 months, adjusted HR: 5.327(95%CI: 1.566-18.096)). Conclusions: Mutations in KRAS codon 61, KRAS codon 146, BRAF V600E, NRAS codon 61 were not detected, and frequency of mutation in PIK3CA exon 9, PIK3CA exon 20 and NRAS codon 61 were rare in mGC. Although our study has several limitations, mutation in NRAS codon 12/13 may be a poor prognostic factor in mGC who received systemic chemotherapy and further accumulation of cases are needed.
Chemosensitivity and clinical characteristics of pancreatic malignancies in BRCA mutation carriers.
Authors: Golan Talia , Kanji Zaheer , Epelbaum Ron , Devaud Nicholas , Dagan Efrat , Holter Spring , Aderka Dan , Kaufman Bella , Gershoni-Baruch Ruth , Moore Malcolm J. , Friedman Eitan , Gallinger Steven
Published: February 2017

278

Background: Somatic inactivation of genes involved in homologous recombination (HR) may confer increased sensitivity to poly (ADP-ribose)- polymerase (PARP) inhibition and DNA cross-linking agents (eg. mitomycin C, platinum-based chemotherapy). Studies in BRCA associated ovarian cancer have demonstrated favorable outcomes with platinum based treatments. The role of BRCA mutations in pancreatic cancer outcome is understudied. In this study, the clinical features and therapeutic responses of BRCA 1/2 mutation carriers with pancreatic malignancies are reported. Methods: Patients with BRCA1/2 -associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994-June 2012 were identified from clinical databases at three participating institutions. Demographic, clinical, and therapeutic response data were collected and analyzed using non-parametric models. Progression-free (PFS) and overall survival (OS) were analyzed. Results: Overall, 63 patients with PDAC and a BRCA1 (n=17), BRCA2 (n=43) or both (n=1) mutations were included. Mean age at diagnosis was 60.2 (range 33-83), 37 (58.7%) were male, 48 (76.2%) were Jewish, 26 (41.3%) were smokers, 55 (87.3%) had a family history of malignancy of which 18 (32.7%) had a history of PDAC. Twenty-five (39.7%) patients underwent a primary resection, and 30 (47.6%) had stage IV disease at presentation. PFS on platinum-based first-line chemotherapy in 12 metastatic BRCA positive cases (median: 90 days) was not statistically different than that of non-platinum chemotherapy treated carriers (n=18, median: 92 days) (p= 0.6412). Two patients with advanced disease were down-staged from unresectable to resectable using combination gemcitabine/cisplatin therapy. One of these is disease free at 50 months after surgery. Median OS for all 51 patients (excluding patients receiving experimental treatments) was 14.02 months (9.48-18.2). Conclusions: The natural history of BRCA associated PDAC appears similar to non-carriers. The role of platinum agents in these individuals remains unclear as data are not mature, however, to date, no difference in median PFS was observed. Surgical downstaging may be possible in a subset of these patients.
Hepatic artery infusion for recurrentor chemoresistant hepatic malignancy.
Authors: Wanebo Harold J. , Taneja Charu , Cummings Francis , Begossi Giovanni , Belliveau James
Published: February 2017

295

Background: Previously treated Hepatic Colorectal Metastases (CRC) and advanced hepato cellular cancer (HCC) are tumor challenges frequently unresponsive to systemic chemo therapy (CT). We reviewed survival outcome in chemo resistant / high risk patients following hepatic artery infusion (HAI) in 21 CRC pts, 10 HCC pts, and 6 miscellaneous metastatic cancers. Methods: Patient groups: 21 CRC pts (16M, 5 F), mean age 63: 16 had metachronous (DFI-17 mos), and 5 Synchronous CA; liver extent: 76% multiple (>5) mets or extensive bilateral; CEA (ng/m), >100, 8 pts > 50 (3 pts) ;< 5 (3 pts),UNK(7 pts). Previous CT:FU/LV (11pts), Oxaliplatin (OX) or Irinotecan (IR) (10 pts). Liver surgery: Partial Resection/RFA – 9 pts. HCC – (9 PTS), cholangioCA(1pt); M/F 5/5; av.age 63yr.. Previous RX Hepatic lobectomy 4 pts, RFA/TACE – 3 patients. Miscellaneous GP (therapy): Hepatic lobectomy + HAI were in metastatic lung (1), Breast (1), advanced gall bladder Ca (GBCA) (T 3-4) (2 pts); HAI alone was done in Br. CA (1) carcinoid (1) Treatment Protocols: CRC: HAI-FUDR 12/15mg/kg/d, dexamethasone 2mg.kg/d, leukovorin (20mg/M2/d) X14 d plus bolus (d1), oxaliplatin OX 130 mg/M2 cisplatin CIS, 100 mg/M2; Systemic RX: d20-30. OX I.V. 130mg/M2, capecitabine 750-1,000 mg/M2/d x 10 days (also used in Miscel. Grp.) HCC Protocol: HAI-14 d as in CRC Protocol. Bolus infusion d1-doxorubicin 75mg/M2or OX or CIS as in CRC schema. Results: CRC:OS-CRC post start HAI = med/16 mos., 2yr/5yr = 27%/6%. HCC OS = 9 mos.( Median); 3->41mos in 9 evaluable pts.; 1 HCC pt with recurrence 2 yr. post hepatectomy survived over 3.5 yrs. with HAI + RFA/TACE – (OS-67mo).Miscellaneous group included lung (11 mos) Br CA (23, 9 mos) adv. Carcinoid (3 mos), GBCA (2 pts > 60 mos), Major Complications; Pump malfunction (4 pts), misperfusion (2) pts, infected pocket (2) pt, duodenal fistula (1) pt. Conclusions: Hepatic artery infusion alternating with systemic chemo therapy has apparent survival benefit in selected patients with persistent or progressive chemo resistant malignancy from metastatic CRC, HCC, or selected miscellaneous cancers (breast, lung, liver, gall bladder cancer) and warrants further study.
Predictors for readmission after pancreatic resection for malignancy.
Authors: Newman Naeem A , Lucas John T , Peacock Diandra A , Trottman Paul A , Winters Shira M , Wentworth Sean S , Levine Edward A. , Shen Perry
Published: February 2017

301

Background: Readmission after pancreatic resection has been reported as high as 50%. This study was undertaken to determine factors predicting readmission after pancreatic resection for malignancy. Methods: We reviewed the medical records of 202 patients to identify patients that had a pancreatic resection for malignancy between 2003 and 2010. Outcome measures included patient characteristics, medical comorbidities, and perioperative factors. Results: A total of 202 patients underwent pancreatic resection for malignancy. AJCC T stage was T1, T2, T3, and T4 in 10.9%, 26.3%, 52% and 9.2% respectively. Pancreatic head malignancies made up 84.8% of the patients, 2.3% were pancreatic neck, 8.4% were pancreatic body, and 4.5% were pancreatic tail primaries. Preoperative biliary stents were placed in 58% of patients. Adjuvant radiation and chemotherapy were given in 47.8 and 61.39% respectively. The readmission rate following resection was 20% at 60 days. The most common reasons for readmission within 60 days were delayed wound healing and renal insufficiency. On univariate analysis, factors predicting higher readmission rates included positive retroperitoneal margin (p=0.048), delayed gastric emptying (p=0.015), and presence of wound infection (p=0.0020). Conclusions: Factors related to tumor burden and GI/infectious complications were the most common predictors of readmission after pancreatic resection for malignancy. Though tumor size is a relatively immutable variable, improved management of postoperative complications remains an important factor in decreasing readmission rates after pancreatic resection for malignancy.
Does interval from histologic diagnosis (Dx) to start of chemotherapy (Ctx) influence survival in advanced pancreatic adenocarcinoma (PC)?
Authors: Teo MinYuen , Jayaram Anuradha , Naidoo Jarushka , Mohd Sharial Mohd Syahizul Nuhairy , O'Brien Michelle , Bajwa Raazi , McDonnell Felicity , Geoghegan Justin , Conlon Kevin C. , Grogan William , Power Derek Gerard , McDermott Raymond S.
Published: February 2017

306

Background: Pancreatic cancer is known to be aggressive and treatment-resistant. In potentially resectable PC, time from diagnostic imaging to surgery correlates with rates of metastases at laparatomy. In advanced PC, therapeutic benefits of ctx are frequently calculated from start of treatment. In view of its aggressiveness, we investigated if the interval between dx and commencement of ctx influences overall survival (OS) in patients (pts) with advanced PC. Methods: Pts with PC were identified from 4 insitutional databases. Inclusion criteria were unresectable (UPC) or metastatic disease (MPC) and receipt of ctx. Clinicopathologic details were collected. Intervals from histologic dx to ctx were calculated. Analyses were based on receipt of ctx within or after 2 weeks (w), 4w and 6w of dx. OS was presented as hazard ratio (HR) with associated p-value. Results: 212 pts were identified. Median age was 63 years (range: 33 – 83) and 58% were males. 60% of pts had MPC and 24% received doublet ctx. Median number of days from dx to ctx was 24 days (range: 2 – 202). For UPC and MPC, 20 and 31% of pts began ctx within 2w (p=0.08), 48 and 63% within 4w (p=0.03) and 73 and 82% within 6w (p=0.13), respectively. OS for the entire cohort, UPC and MPC were comparable whether ctx was commenced within pre-defined intervals or not (see table). A subgroup of pts treated with doublet ctx was examined. No OS difference was seen when treated within defined time points (HR 1.1, 1.0, 1.5; p=0.76, 0.96, 0.43). For 77% of MPC with hepatic metastases, no improvement in OS in relation to time interval was noted (HR 1.5, 1.0, 1.1; p=0.10, 0.90, 0.85). For 21% of MPC with ≥2 metastatic sites, ctx within 4w and 6w might improve OS but significance was not reached (HR 0.65, 0.61; p=0.43, 0.46). Conclusions: Commencement of ctx for PC could be delayed due pts-, disease- or infrastructural factors. Our data did not suggest a detrimental effect on OS from ctx delay. However, the lack of survival benefit from early ctx might be due to less effective ctx or inherent aggressiveness of the disease. [Table: see text]
Racial differences in patients with hepatocellular carcinoma: A large single-institution experience.
Authors: Venepalli Neeta K. , Nair Tad D. , Berg Stephanie A. , Modayil Mary , Gaba Ron C. , Bui James T. , Huang Yue , Cotler Scott
Published: February 2017

318

Background: Hepatocellular carcinoma (HCC) disproportionately affects minorities with higher age-adjusted incidence and mortality rates in Hispanics (H) and blacks (B) versus non-Hispanic whites (C). While H have the fastest rising rates of HCC of all ethnic groups per SEER analysis, little is known about race specific risk factors and disease characteristics. Methods: We retrospectively reviewed HCC patients (pts) treated at University of Illinois-Chicago between 1998 and 2005. Demographics, disease characteristics, treatment patterns, and survival were analyzed with descriptive statistics and chi-square p values. Results: Mean age of HCC pts (N=195) at diagnosis was 59.7 years + 9.8 (19.5% female; 22% aged 65 or older; 61.5% Medicare or Medicaid; 4.1% without insurance; 22.6% H; 31.2% B). Compared to C and B, H pts were more likely to have ascites and NASH and less likely to have ever smoked or have hepatitis C. Compared to B, H pts were more likely to have metabolic syndrome, diabetes, and encephalopathy (HE). Compared to C, B pts had lower MELD scores. Conclusions: In our patient population, Hispanic patients were significantly more likely to have diabetes and NASH, and lower frequency of tobacco use, HCV, and elevated AFP levels at diagnosis. [Table: see text]
Comparative effectiveness and survival benefit of various treatment modalities in HCC: A SEER-Medicare analysis.
Authors: Hanna Nader , Breunig Ian Michael , Mullins C. Daniel , Seal Brian S. , Chirikov Viktor , Shaya Fadia T.
Published: February 2017

319

Background: In the United States, the incidence of HCC has increased from 1.6 per 100,000 in 1975 to 4.9 per 100,000 in 2005. Care for HCC patients remains specialized and complex with transplant and surgery offering the only potential for long survival. However no comparative effectiveness of various treatment modalities across various stages of HCC exists. Methods: Medicare enrollees, older than 65 with an initial diagnosis of primary HCC between 2000-2007 were followed up through the end of 2009. For patients with stages I, II, III, and unstaged, data were obtained from the SEER and linked Medicare databases, with claims generated from Medicare parts A and B. Multivariate Cox proportional hazards models were used to assess overall and HCC related mortality in relation to receipt of various/no treatments, adjusting for concomitant therapies, demographics, general health status (Charlson comorbidity index), and liver conditions, moderate-severe liver disease. Results: Distributions across stages: males 64-71%, Caucasians 72-77%, African Americans 8-10%, Hispanics 12-14%; a majority (72-75%) was age 65-84; Hepatitis C was the most prevalent (17-41%). Conclusions: Compared to untreated patients, improved all-cause and HCC-related mortality was observed in all stages in the following order: transplant, surgical resection, liver directed therapy, and chemotherapy. Greater impact on HHC-related mortality was seen across all treatment groups. [Table: see text]
MicroRNA polymorphisms and esophageal cancer outcome.
Authors: Faluyi Olusola Olusesan , Eng Lawson , Qui Xin , Cheng Dangxiao , Renouf Daniel John , Marsh Sharon , Savas Sevtap , Knox Jennifer J. , Darling Gail Elizabeth , Wong Rebecca , Xu Wei , Azad Abul Kalam , Liu Geoffrey
Published: February 2017

32

Background: Better understanding of the biology of esophageal cancer may help improve its treatment. MicroRNAs (miRs) regulate mRNA and can exert some influence on carcinogenesis. Identification of the microRNAs which regulate esophageal cancer development could potentially yield alternative therapeutic options. Objectives: We evaluated polymorphisms in miRs, miR biogenesis, binding sites of miR and their role in the survival of esophageal cancer patients. Methods: 324 esophageal cancer patients of all stages and histological subtypes were evaluated. Using Illumina Custom GoldenGate, 43 polymorphisms in miR pathways were evaluated. Cox proportional hazards models adjusted for clinical prognostic variables and determined the association of polymorphisms with overall survival (OS) and progression free survival (PFS). Adjusted hazard ratio (aHR) and 95% confidence intervals (CI) were calculated. Results: Among our patients, 83% were male while the mean age was 65 years. 73% had adenocarcinomas while 33.6% had advanced tumors (Stage IV). The median PFS was 1.20 years, while median OS was 2.17 years. After adjustment for clinical variables, a 5’UTR polymorphism in pri-mir26a-1 (rs7372209) was significantly associated with reduced PFS [aHR=0.78, CI:0.62-0.98, p=0.04] and OS [aHR 0.71 (0.56-0.89), p=0.003]. Three other polymorphisms were significantly associated with OS but not PFS: these included two polymorphisms of miR processing genes, DDX20 (rs197412) [aHR 1.31 (1.04-1.64), p=0.02] and EIF2C1 (rs595961) [aHR 0.76 (0.60-0.97), p=0.03] as well as the CD86 3’UTR C>G (rs17281995) polymorphism, which has been predicted to affect the binding of miR337, miR582, miR200a, miR184, and miR212 [aHR 1.38 (1.03-1.85), p=0.03]. Conclusions: We report the initial association of miR related polymorphisms with survival in esophageal cancer. We plan to explore additional relationships and validate these findings in other datasets.
Adjuvant chemotherapy in the management of cholangiocarcinoma: A 10-year cohort analysis.
Authors: Shaikh Tahir M. , Asmis Timothy R. , Jonker Derek J.
Published: February 2017

330

Background: The evidence regarding treatment outcomes from chemotherapy for cholangiocarcinomas (CCAs) is limited because of the high mortality rate and a low overall incidence. Most studies are small and include a heterogeneous group of tumors (biliary, pancreatic, hepatocellular, and ampullary cancers) that each have a unique natural history and response to chemotherapy. The aim of this study is to assess the effect of chemotherapy on survival of patients with surgically resected (R0-negative margins/R1-positive margins) and unresectable (R2-gross residual tumor/metastatic) CCAs. Methods: In a retrospective single-center study, data on all CCA patients (n=209) from 1998 to 2008 were evaluated. Survival time was assessed as a primary outcome measure. Patient demographics, pathological diagnosis, performance status, chemo-radiation therapy, surgical resection, relapse rates and laboratory outcomes were assessed. Results: 209 cases of CCA (female n=116, mean age 65, adenocarcinoma n=166 (79.4%), stage 0/1 n=17 (8.1%), stage 2/3 n=99 (47.3%), stage 4 n=93 (44.4 %)) were identified. 162 (77.5%) patients received treatment (surgical resection n=118 (R0 n=53, R1 n=21) chemotherapy n=85, radiation therapy n=33). Median overall survival (months) was 9.8 (no treatment =2.1, treatment =12.4 (R0 and R1 surgical resection =21.9 and 10.9 p<.001). Median survival (months) in patients with surgical resection with and without adjuvant chemotherapy was 22.2 vs 21.9 p=0.75 for R0 resection and 18.1 vs 10.9 p=0.10 for R1 resection. In patients with unresectable tumor, median survival with and without chemotherapy was 10.7 and 2.1 months (p<.05) respectively. Conclusions: CCAs are associated with poor survival if untreated. Complete surgical resection was associated with significantly improved survival outcomes. Adjuvant chemotherapy in the setting of R0 resection did not improve survival compared to surgical monotherapy. In the setting of unresectable or metastatic CCA, survival was significantly prolonged in patients who received palliative chemotherapy. Although not conclusive, these data suggests the use of adjuvant chemotherapy in the setting resection with positive margins (R1) may also prolong survival.
A molecular profile of colorectal cancer to guide prognosis and therapy after resection of primary or metastatic disease.
Authors: Uronis Joshua M. , VanDeusen Jeffrey Bryan , Datto Michael B. , Lucas Joseph , Morse Michael , Mantyh Christopher , Lyerly H. Kim , Clary Bryan M. , Hsu Shiaowen David
Published: February 2017

339

Background: Biomarkers used to identify patients at high risk for recurrence after surgical resection of colorectal cancer (CRC) lack predictive capacity and are applicable only to localized disease. As the use of adjuvant therapy in this setting can be controversial, the development of a biomarker that is prognostic, predictive, and applicable after resection of primary or metastatic disease may dramatically improve patient outcomes. Methods: We compiled microarray data from 850 patients with predominantly primary CRC from four publically available datasets to predict activity of 19 oncogenic pathways to generate patterns of pathway deregulation for each patient tumor. Mixture modeling was applied to the samples using affinity propagation to subgroup tumors bearing unique patterns of pathway deregulation. The model was then applied to a dataset of 133 predominantly metastatic CRC samples from patients undergoing curative surgical resection at the Duke University Medical Center. Results: Mixture modeling resulted in the identification of 6 distinct molecular subgroups of CRC (MSCC) based on pathway deregulation for both primary and metastatic CRC. Kaplan-Meier analysis of the primary data set revealed differences in recurrence free survival among the 6 MSCC (p=0.0004) with patients assigned to MSCC3 having the poorest prognosis and patients assigned to MSCC4 having the best prognosis. A similar result was obtained when the model was applied to the metastatic data set (p<0.05). Comprehensive analysis of 41 oncogenes showed that no specific mutations were associated with the any of the subgroups. Finally, we observed that MSCCs demonstrate differential sensitivity to specific targeted agents such as MSCCs 1, 2 and 3 to inhibition of Her2 by Lapatinib and EGFR by erlotinib (p<0.05). Conclusions: Prediction of oncogenic signaling pathway deregulation is a powerful tool that may be used to molecularly sub-classify CRCs into clinically relevant subgroups. These subgroups have prognostic implications for recurrence following surgical resection and may help to identify therapies in the adjuvant setting after resection of either primary or metastatic disease.
The impact of aspirin and statin usage on the likelihood of advanced neoplasia at colonoscopy following a positive FOB screening test.
Authors: Mansouri David , Mcmillan Donald C. , Crighton Emilia M , Horgan Paul G.
Published: February 2017

346

Background: There is increasing evidence that non-steroidal anti-inflammatory drugs, in particular aspirin, and statins can reduce the incidence and progression of colorectal cancer. However, studies examining this relationship within colorectal cancer screening are limited. Therefore the aim of the present study was to assess the impact of aspirin and statins on an individual’s risk of advanced neoplasia in a colorectal cancer screening programme. Methods: A prospectively maintained database of all patients in the first round of screening (April 2009 to March 2011) in our geographical was analysed. Medication usage was recorded prospectively at pre-colonoscopy assessment. The outcome measure was advanced neoplasia, which was defined as cancer or an intermediate or high risk adenomata (>2 polyps, or > 1 polyp >1cm). Results: 4,631 individuals underwent colonoscopy following a positive FOBt of which complete results were available for 4,188 (90%) pts. Overall, 657 (16%) were on aspirin, 880 (21%) were on statins and 537 (13%) were on both. Colorectal pathology was associated with a positive FOBt in 3,043 (73%) pts. Aspirin usage was associated with a reduced likelihood of colorectal pathology being identified (OR 0.79 (0.66-0.95) p=0.012). In the 3,043 pts in whom colorectal pathology was identified, advanced neoplasia was seen in 1,704 (56%) pts. Patients with advanced neoplasia were more likely to be older (OR 1.38 (1.19-1.59)) and male (OR 1.66 (1.43-1.94)) (both p<0.001). In contrast, those on aspirin (OR 0.68(0.56-0.83)), statins (OR 0.65 (0.55-0.78)) or both (OR 0.69 (0.55-0.86)) were less likely to have advanced neoplasia at colonoscopy (all p<0.001). On multivariate analysis, use of both aspirin and statins (OR 0.60 (0.48-0.75) p<0.001) remained independently associated with less advanced neoplasia. Conclusions: In patients undergoing colonoscopy following a positive FOBt with documented evidence of statin or aspirin usage, advanced neoplasia was less likely to be found. This suggests that usage of these medications may have a chemopreventative effect within the context of screening for colorectal cancer.
Characterization of rectal cancer in patients with Lynch syndrome.
Authors: Stadler Zsofia Kinga , Shia Jinru , Goodman Karyn A. , Cercek Andrea , Segal Neil Howard , Reidy Diane Lauren , Yaeger Rona D. , Nash Garrett Michael , Temple Larissa K. F. , Kemeny Nancy E. , Weiser Martin R. , Kelsen David Paul , Markowitz Arnold , Robson Mark E. , Offit Kenneth , Paty Philip , Guillem Jose G. , Saltz Leonard
Published: February 2017

350

Background: Lynch syndrome (LS), resulting from a germline mutation in a DNA mismatch repair (MMR) gene, is associated with ~70% lifetime colorectal cancer (CRC) risk. Although LS-associated colon cancer is associated with both favorable prognosis and lack of efficacy to 5-fluorouracil, clinical features of LS-associated rectal cancer (RC) have not been characterized. Methods: Clinical genetics database review (1998–2012) identified all probands with CRC and a deleterious germline mutation in a MMR gene (MLH1, MSH2, MSH6, PMS2) diagnostic of LS. Probands without identifiable mutations or variants of unknown significance were excluded. Clinical history and pedigree was extracted from medical records and Progeny. Results: Of 119 LS patients with CRC, 16 (13.4%) had RC. Mean age at RC diagnosis was 40.6 (range, 23-56) with 31% having synchronous (n=3) or metachronous (n=2) colon cancer. All RC patients met Revised Bethesda and 63% met Amsterdam II criteria. As opposed to LS-associated colon cancer, the majority of RC patients harbored MSH2 mutations (36% colon vs 69% RC, p value 0.01). 11 tumors were analyzed for MSI or defective MMR protein expression by IHC; results were abnormal and thereby concordant with germline test results in all cases. Of 14 RC patients with clinical data, 5 proceeded directly to surgery (4 stage 0/I; 1 stage II). Nine patients received pre-op treatment for clinical stage II/III (n=7) or IV (n=2) disease, with all receiving chemoradiation and five also receiving pre-op FOLFOX. Downstaging of primary tumor occurred in 66.6% (6/9) and of lymph nodes in 77.7% (7/9) of cases. All nine patients underwent R0 resections; however, pCR was not observed in any of the cases. Notably, one patient with clinical T3N+ disease (by MRI and EUS) had upfront surgery identifying pT2N0 disease with prominent tumor infiltrating lymphocytes. Of 14 patients, mean follow-up of 4.3 years (range, 0.3-13.5), none had disease recurrence; however, one was diagnosed with a new primary colon cancer. Conclusions: Although less common than colon cancer,RC is an important component of LS and may be overrepresented in MSH2 mutation carriers. Given high risk of synchronous or metachronous cancers, appropriate surveillance for second malignancies is necessary.
Knowledge of the French population on colorectal cancer screening: Data from the EDIFICE 3 survey.
Authors: Viguier Jérôme , Coscas Yvan , Touboul Chantal , Morere Jean F. , Blay Jean-Yves , Pivot Xavier B. , Lhomel Christine , Eisinger François
Published: February 2017

352

Background: In France, following a pilot population-based screening program in 2002-2003, a national organized program targeting 17 million people was progressively implemented from 2005 to 2009. EDIFICE surveys are iterative polls focusing on cancer screening behavior. The EDIFICE 3 survey was conducted in 2011 and partly dedicated to knowledge of the colorectal cancer screening process. Methods: This third nationwide observational study, EDIFICE 3, was conducted via phone interviews among a representative sample of 946 subjects aged between 50 and 74 years, who had never been treated for cancer. 59% of the population declared having undergone colorectal cancer screening (fecal test or colonoscopy). Results: Interviewed about the screening process, 510/946 (54%) of the French population were unaware of the procedure after a positive fecal test and 782/946 (83%) were unaware of how soon a new test should be performed after a negative result. Only 79/946 (8%) were aware of what to do after either a positive or a negative test and 47% in one out of the two cases. 84% of subjects over assessed (by a factor 2 to 10) the probability of having cancer after a positive test. In contrast, 65% were aware of the possibility of a false negative test. Only 3% of our sample know both the right screening agenda (every other year) and the need for a colonoscopy after a positive test. Neither gender, educational level and socio economic level significantly impacted the rate of right answers. Conclusions: This study demonstrates a lack of detailed knowledge on the colorectal cancer screening process in the French national program. This raises the issue of the fairness of the process (an ethical issue) and may be a reason for the current poor uptake (an effectiveness issue). This should be tackled by improving the transmission of information, preferentially via general practitioners, institutional letters sent directly to subjects (in our survey these two media were found to be readily accepted) and lay press.
The impact of number of cycles of targeted therapy on cost evaluation in metastatic colorectal cancers.
Authors: Guirgis Helmy M.
Published: February 2017

359

Background: Increasing the number of cycles of cetuximab and bevacizumab in metastatic colorectal cancer might limit affordability and impact cost-effevctiveness. Methods: Average wholesale prices (AWPs) in U.S. dollars (US $) of cetuximab and bevacizumab were divided by reported median survival gain in days. Cost/survival of 90% of drugs was <$750. A reference scale between 0% and 100% was constructed with 0% assigned to cost/overall survival (OS) > $750, life threatening/fatal adverse events (AEs) and worsened quality of life (QoL). A plan was designed to correct for AEs and QoL. Results: Expressed as cost/overall survival (OS), crude and corrected scores (Table). Conclusions: Increasing number of cycles of cetuximab and bevacizumab increased the cost/survival and decreased scores. A limit on the purchase price of the entire treatment course of targeted therapy is recommended. [Table: see text]
KRAS testing of mCRC patients in a community-based oncology setting.
Authors: Cuyun Carter Gebra , Landsman-Blumberg Pamela , Johnson Barbara H , Sedgley Robert , Shankaran Veena
Published: February 2017

364

Background: In late 2008, treatment guidelines were updated to recommend KRAS testing for patients at diagnosis (Dx) of metastatic colorectal cancer (mCRC). This study explored KRAS testing rates over time and compared characteristics of those mCRC patients who were tested and those not tested in a community-based setting. Methods: Patients ≥18 years old, with a mCRC Dx between 1/1/2008 - 12/31/2011, no other primary cancer, and 2+ outpatient visits were selected from the ACORN Data Warehouse (Memphis, TN). Text mining of progress notes and random forests modeling predicted if KRAS testing was done. If tested, test date and result were abstracted from charts. The proportions of those tested overall and at Dx (pre and ≤ 60 days post-mCRC Dx) were calculated by year. Chi-square and t-tests were used to compare demographic and cancer characteristics at Dx and clinical history of those tested and not. Results: Among 1,363 patients identified, 47.5% (n=648) were KRAS tested. Overall 48.1% were KRAS WT, 42.3% KRAS mutant, and 9.6% unknown. Proportion of eligible patients who underwent KRAS testing in pre-2008, 2008, 2009, 2010, and 2011 was 5.8%, 15.9%, 29.1%, 26.9%, and 28.0% respectively. Of those tested, 6.2% were tested at Dx pre-2008 and 27.4%, 65.4%, 73.2%, and 78.4% were at Dx in 2008, 2009, 2010, and 2011 respectively. KRAS tested patients were younger (59.5% vs. 51.5% <65 years, p=0.004), had more baseline comorbid conditions (3.7±4.0 vs. 2.7±3.4, p<0.001), were more likely to have bone (12.1% vs. 8.5%), lung (36.6% vs. 26.2%) and liver (73.5% vs. 66.2%) metastases, were less likely to have peritoneal (3.7% vs. 10.1%) metastases (all p<0.05), and had poorer performance status (PS) (ECOG >1: 41.9% vs. 34.0%, p=0.042). No significant differences were found by cancer location (colon, rectum, both), if the cancer was newly diagnosed or a recurrence, or in tumor histologic grade. Conclusions: While KRAS testing increased in 2008-2009 corresponding to changes in treatment guidelines and anti-EGFR product labels, the majority of patients were not tested. The proportion tested at diagnosis continued to increase annually from 2008-2011. Patients with greater comorbidities and poorer PS are more likely to undergo KRAS testing than healthier patients.
A nomogram based on clinical factors to predict locally advanced stage of rectal cancer.
Authors: Cai Guoxiang , Song Baorong , Huang Liyong , Xu Ye , Guan Zuqing , Sheng Weiqi , Cai Sanjun
Published: February 2017

376

Background: Preoperative staging of rectal cancer is important for designing treatment strategy. The standard treatment for locally advanced rectal cancer is neoadjuvant radiochemotherapy followed by surgery. Magnetic resonance imaging (MRI) and transrectal ultrasonography are major staging approaches with a prediction accuracy of about 70-80% but not widely available in hospitals in China. We sought to define possible clinicopathological predictors and establish a simple nomogram as a reference tool for patients and clinicians to predict stage of rectal cancer and make decisions about neoadjuvant therapy. Methods: Preoperative staging of rectal cancer is important for designing treatment strategy. The standard treatment for locally advanced rectal cancer is neoadjuvant radiochemotherapy followed by surgery. Magnetic resonance imaging (MRI) and transrectal ultrasonography are major staging approaches with a prediction accuracy of about 70-80% but not widely available in hospitals in China. We sought to define possible clinicopathological predictors and establish a simple nomogram as a reference tool for patients and clinicians to predict stage of rectal cancer and make decisions about neoadjuvant therapy. Results: In the training set, 77.1% of patients had locally advanced stage by pathology. The multivariate analysis indicated that tumor size (Odds ratio (OR)=1.55, p< 0.001), differentiation (OR =0.38, p< 0.001), location (OR =1.06, p=0.038), serum CEA (OR =0.24, p< 0.001) and CA19-9 level (OR =0.13, p< 0.001) were associated with tumor stage. A nomogram consisting of these 5 factors was developed and predicted locally advanced stage with a concordance index of 0.756. The concordance index of this nomogram was 0.800 in the validation set. Conclusions: Large tumor size, far from anal verge, poor differentiation, elevated serum CEA and CA19-9 level were high-risk factors of locally advanced stage of rectal cancer. The nomogram based on these clinical factors can predicte locally advanced rectal cancer with a considerable accuracy and thus helpful for making neoadjuvant therapy recommendations.
Correlation of messenger RNA expression patterns of ERCC1, TS, EGFR, and VEGFR2 with KRAS and BRAF mutational status in advanced colorectal cancer: Implications for targeted therapies.
Authors: Maus Martin K. H. , Stephens Craig , Astrow Stephanie H. , Grimminger Peter Philipp , Yang Dongyun , Loupakis Fotios , Hsiang Jack , Zeger Gary , Huang Xu , Lenz Heinz-Josef
Published: February 2017

383

Background: Gene expression levels of ERCC1, TS, EGFR and VEGFR2 may have predictive value for the personalized use of standard chemotherapeutics as well as agents targeting the EGFR and VEGF pathways and the efficacy of EGFR directed monoclonal antibodies like panitumumab and cetuximab has been confirmed to be dependent on wt KRAS and wt BRAF in patients with advanced colorectal cancer. We investigated the correlations between KRAS/BRAF mutational status and the mRNA expression levels of these genes. Methods: Formalin-fixed paraffin-embedded tumor specimens from 600 patients with advanced colorectal adenocarcinoma were microdissected and DNA and RNA was extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codon 12 and 13 of KRAS, V600E mutations in BRAF and the expression levels of ERCC1, TS, EGFR and VEGFR2 by RT-PCR. Results: Mt KRAS tumors had significantly lower TS and EGFR gene expression levels compared with wt KRAS (p<0,001), whereas mt BRAF tumors showed significantly increased TS and EGFR mRNA levels compared to wt BRAF (p<0,001). Mt BRAF tumors showed significantly higher mRNA levels than mt KRAS tumors (p<0,001). ERCC1 and VEGFR2 mRNA levels were significantly down-regulated in mt KRAS specimen (p<0,001), but showed no significant correlation with BRAF mutational status. Conclusions: KRAS and BRAF mutations are associated with opposite mRNA expression levels for TS and EGFR. Recently, resistance to BRAF inhibition in mt BRAF colorectal tumors has been shown in preclinical models to be associated with up-regulation of EGFR. Our data suggests that BRAF mutants are associated with high EGFR levels at the time of diagnosis, and not necessarily part of an acquired mechanism of resistance. Significantly lower mRNA expression levels of VEGFR2 in mt KRAS tumors may explain lower response to angiogenesis inhibition seen in the TML study.
Results from Ion AmpiSeq Cancer Panel in 200 cases of gastric and gastroesophageal junction cancer.
Authors: Lim Howard John , Kollmannsberger Christian K. , Gill Sharlene , Kong Esther , Ng Ying , Lum Amy , Woo Michelle , Huntsman David , Yip Stephen
Published: February 2017

39

Background: We used the Ion AmpiSeq Cancer panel which contains multiplex PCR primers covering 739 potential cancer- related mutations in 46 genes to profile 200 gastric and gastroesophageal cancers. Methods: The assay requires only 10ng of genomic DNA isolated from formalin-fixed paraffin-embedded (FFPE) archival tissue blocks. Samples were retrieved from biopsies from either the primary or metastatic lesion. All samples generated usable DNA and the resultant amplicons were sequenced on the Ion Torrent PGM platform to achieve in depth coverage of potential mutations. Results: Mutations in the tumour suppressor gene TP53 (39.5%) are most commonly identified in our cohort which is consistent with known mutation profiling of gastric carcinoma. We have also identified mutations in MET (8%), PIK3CA (7.5%), KRAS (4%), BRAF (4%) in addition to other known oncogenes. Lastly, We identified two cases with hotspot mutations in IDH1 (R132H and R132C), hotspot mutation traditionally associated with glioma and acute leukemia, which suggest novel role(s) of this mutant protein in the pathogenic progression of this cancer. Conclusions: These findings might predict response to targeted therapeutic agents or have prognostic implications. This study highlights the potential of focused profiling of cancer related genes using the Ion Torrent platform and its advantage of utilizing small amount of DNA from archival pathology specimens.
Association of tissue factor pathway inhibitor gene polymorphism -33T→C with disease-free survival in colorectal cancer.
Authors: Bazzarelli Amy K , Scheer Adena S , Tai Lee-Hwa , Seth Rashmi , Tanese de Souza Christiano , Jonker Derek J. , Maroun Jean Alfred , Carrier Marc , Auer Rebecca Ann C
Published: February 2017

395

Background: Tissue Factor Pathway Inhibitor (TFPI) is an anticoagulant protein exhibiting antimetastatic properties in preclinical models. The homozygous CC polymorphism on intron 7 of TFPI (-33T-->C) is associated with higher TFPI protein levels and a lower risk of venous thromboembolism (VTE). The present study is the first to evaluate the impact of the inherited TFPI polymorphism on disease-free survival (DFS) in cancer patients following curative resection. Methods: A prospectively maintained colorectal tumour bank with associated clinical data was used to identify patients who underwent curative surgery for colorectal cancer between 1994 and 2006. Germline DNA was extracted from formalin fixed, paraffin embedded normal colonic mucosa. Single nucleotide polymorphisms (SNPs) for Tissue Factor Pathway Inhibitor (TFPI, -33T-->C), Factor V Leiden (FVL, G1691A), and Prothrombin (PT, G20210A) were determined by polymerase chain reaction. DFS was described using the Kaplan-Meier method. Multivariable regression analysis, with known prognostic factors, was performed using the Cox Proportional Hazard model. Results: Of the 139 patients identified, the prevalence of the wildtype (TT) TFPI genotype was found in 57.3% of samples, the heterozygous genotype (TC) in 29.4%, and the homozygous genotype (CC) in 10.5%. The incidence of VTE was 21.6% in the TT/TC genotypes and 6.7% in the CC genotype (p=0.4). The CC genotype was associated with superior DFS (HR 0.38, [95%CI 0.17-0.88]; p=.02) with 5 year DFS 56.3% vs. 24.6% for CC vs. TT/TC respectively. In multivariate analysis female sex (HR=0.61, p=.02), chemotherapy (HR=0.66, p=.05), node negative (HR=0.47, p=.005) and TFPI CC polymorphism (HR=0.35, p=.01) were independently associated with improved DFS. The prevalence of FVL (0.7%) and PT (2.2%) polymorphisms was too low to detect any interaction with TFPI polymorphism and DFS. Conclusions: These findings indicate that the inherited anticoagulant homozygous -33T-->C TFPI polymorphism may protect against colon cancer recurrence, and suggest a causal role for the coagulation system in cancer outcomes.
Molecular profiles of appendiceal adenocarcinoma: The UCSD experience.
Authors: Shen John P. , McGee Devon Marcus , Lowy Andrew M. , Fanta Paul Timothy
Published: February 2017

397

Background: Appendix cancer is rare, which precludes its study in randomized trials. As such, no evidence-based guidelines currently exist regarding the optimum systemic therapy for this disease entity. Typically, these patients are treated with regimens for colorectal carcinoma. Previous studies have shown high intra-tumoral mRNA levels of EGFR were significantly associated with response to irinotecan based chemotherapy, and that mucinous colorectal cancer overexpresses markers of resistance to 5-FU and oxaliplatin. We examined pharmacogenomics markers for appendiceal cancer and colon cancer to understand underlying similarities and differences between these tumor types. Methods: Intratumoral gene expression levels were assessed from paraffin-embedded tissue samples, using laser capture microdissection and quantitative real-time PCR from 69 colorectal and 34 appendiceal adenocarcinomas. A retrospective chart review was performed to correlate gene expression with overall survival. KRAS and BRAF mutational analyses and gene expression levels of ERCC1, TS, and EGFR were correlated with overall survival. Results: Appendiceal tumors had significantly higher expression of EGFR, (2.66 vs 1.4, p<.0001). No BRAF V600E mutations were found in the appendiceal tumors, incidence was 8.97% of the colon patients. UPDATE: In appendix cancer, KRAS mutations were noted in 65.5% of patients, there were no BRAF mutations. Median ERCC1, TS, EGFR, and VEGFR2A expression was 1.4, 1.21, 1.57, 2.19 respectively. Patients with metastatic appendiceal cancer had a significantly longer median OS than metastatic colon patients, (113 mo vs 43.9 mo, p = .0154). For appendiceal cancer patients, there was no significant correlation between any of the biomarkers and OS, although the sample size was underpowered for such an analysis. Conclusions: Metastatic appendiceal cancer patients have significantly better outcomes than metastatic colon cancer patients. Molecular analyses reveal significant differences between these tumor types. Further molecular study of appendiceal cancer is needed, as this study and others suggest fundamental differences in biology from colon cancer.