bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of adjuvant chemoradiation for gall bladder carcinoma: An institutional experience.
Authors: Mallick Supriya , Das Sudeep , Gandhi Ajeet , Joshi Nikhil Purushottam , Madan Renu , Mohanti B. K , Sharma Atul , Julka Pramod Kumar , Rath Goura Kishor
Published: February 2017

288

Background: Adjuvant chemoradiation for gall bladder carcinoma is not a well established treatment modality. Methods: We retrospectively analysed our database between 2000 and 2011. All patients underwent surgery followed by adjuvant chemoradiation. The radiation dose was 45 Gy in 25 fractions planned by either conventional (2D) or 3 dimensional conformal radiation therapy (3D). Adjuvant chemotherapy was either Gemcitabine or 5 FU/leucovorin based. Log-rank test was used to compare survival distribution. The data was analysed using SPSS 16. Results: 75 patients were analysed. The median age was 48 years (range: 22 to 75 years). 16 males & 59 females were noted. 37 had well differentiated carcinoma while 38 had moderately differentiated carcinoma. The stage was IIIA or less in 45 patients and IIIB or more in 25 patients while it was unknown in 5. No patient had metastatic disease at presentation. 17 patients had a simple cholecystectomy, 57 had a radical cholecystectomy while status was unknown for 1. 25 patients had node negative disease while 50 had node positive disease. All patients received the prescribed radiation. 18 patients had 2D while 57 patients had 3D radiation. 13 patients had Gemcitabine based chemotherapy while 36 patients had 5 FU/leucovorin based chemotherapy. The status of chemotherapy was unknown for 26 patients. The median follow up was 12.7 months (range: 0 to 99 months). 22 patients relapsed. 2 patients had locoregional failure, 18 had distant failure while 2 had both locoregional & distant failure. The relapse free survival at 2 years was 57% and at the end of 6 years was 34%. Relapse free survival was significantly better for radical cholecystectomy vs. simple cholecystectomy (relapse free survival at 2 years 59.2% vs. 30.2 %; p = 0.054 on univariate analysis and relapse free survival at 2 years, 60% vs. 30%; p = 0.035 on multivariate analysis). Gender, tumor differentiation, nodal status, radiation technique and type of chemotherapy did not correlate with relapse free survival. Conclusions: Adjuvant chemoradiation resulted in excellent locoregional control. Radical surgery is an important factor for relapse free survival.
A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin in cancer patients.
Authors: Kanai Masashi , Otsuka Yoshihiko , Otsuka Kazunori , Nishimura Takafumi , Mori Yukiko , Matsumoto Shigemi , Kodama Yuzo , Kawaguchi MIchiya , Hatano Etsuro , Murakami Yoshiki , Imaizumi Atsushi , Chiba Tsutomu , Nishihira Jun , Shibata Hiroyuki
Published: February 2017

290

Background: Curcumin is a natural polyphenol derived from turmeric (Curcuma longa). Growing preclinical data suggests that curcumin could be a promising anticancer drug, however, poor bioavailability has been a challenging problem for its clinical application. To overcome this problem, a new form of curcumin (Theracurmin) was developed using a microparticle and surface-controlled drug delivery system. We evaluated the safety and pharmacokinetics of Theracurmin in combination with gemcitabine-based chemotherapy in cancer patients. Methods: Pancreatic or biliary tract cancer patients who failed standard chemotherapy were eligible. Planned Theracurmin doses comprised Level 0: 100 mg/body/day; Level 1: 200 mg/body/day; and Level 2: 400 mg/body/day. Level 1 was selected as a starting dose, and daily oral Theracurmin was added to standard gemcitabine-based chemotherapy. In addition to plasma curcumin levels, quality of life (QOL) score scaled according to the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30), NF-κB activity, cytokine levels (interleukin-6 and tumor necrosis factor–α), and efficacy were investigated. Results: We enrolled 16 patients between February 2011 and January 2012. Peak plasma curcumin levels (median) after Theracurmin administration were 324 ng/mL (range: 47–1,029) at Level 1 and 440 ng/mL (range: 179–1,380) at Level 2. These values were significantly higher than those in our previous data achieved using 8 g of conventional curcumin. Long systemic exposure to high concentrations of curcumin did not increase the incidence of adverse events. Interestingly, fatigue- and functioning-associated QOL scores significantly improved after Theracurmin administration (p< 0.01). Conclusions: Up to 400 mg/body/day of Theracurmin could safely increase plasma curcumin levels in cancer patients receiving gemcitabine-based chemotherapy. Clinical trial information: 000002950.
Circulating biomarkers of sorafenib efficacy in advanced HCC.
Authors: Chelis Leonidas , Anagnostopoulos Kostantinos , Trypsianis Grigorios , Hamalidou Eleni Kyrillos , Xenidis Nikolaos , Amarantidis Kiriakos , Deftereos Savas , Pitsiava Dimitra , Michailidis Prodromos , Christakidis Evagelos , Michailidis Dimitrios , Matthaios Dimitrios , Koukaki Filio , Kortsaris Alexandros H. , Kakolyris Stylianos
Published: February 2017

302

Background: Sorafenib represents the only drug with proven efficacy as first-line treatment of hepatocellular carcinoma (HCC). We analyzed 12 cytokines and growth factors related to angiogenesis, inflammation and cell proliferation and evaluated their possible utility as biomarkers of sorafenib efficacy in HCC. Methods: Our study population consisted of 62 HCC patients who received first-line sorafenib and 20 healthy controls. Material was collected at 3 different snapshots: (A) at baseline, (B) after 4 weeks on treatment, (C) at disease progression. Using commercially available ELISA kits we measured the serum levels of: VEGF-A, b FGF, sVEGFR2, Ang2, SDF1, VEGF-C, IL-6, IL-8, AFP, HGF, TSP1, BMP9 (bone morphogenetic protein 9). BMP9, a vascular quiescence factor, was explored for first time in HCC. Results: Patients had significant: (a) higher levels of Ang2, IL-6, IL-8, AFP, HGF, VEGF-A, FGFb , (b) lower levels of SDF1 than controls. At snapshot (B) we found a significant decrease of BMP9 and sVEGFR2 while a trend for significant increase was observed for VEGF-A, bFGF and IL-6. All statistically significant correlations for baseline levels of examined cytokines and their median change at week 4 with overall survival (OS) and progression free survival (PFS) are listed (Table). At disease progression (snapshot C) in comparison with baseline we found statistical significant: (a) increase for AFP, VEGF-A, bFGF, IL-6, (b) decrease for BMP9 and sVEGFR2. Conclusions: The values of circulating cytokines and growth factors examined in the present study showed frequent and statistically significant alterations during the disease course. Whether these factors could serve as potential biomarkers of sorafenib efficacy in HCC is something warranting further exploration and confirmation in bigger studies. [Table: see text]
A single-center experience of modified FOLFOX-6 in locally advanced and metastatic pancreatic adenocarcinomas.
Authors: Sumrall Bradley Thomas , Son Chang O , Fuloria Jyotsna , Satti Suma
Published: February 2017

303

Background: Pancreatic adenocarcinoma has historically been as a disease with a poor prognosis with a 5 year survival rate of about 6%. The recently published ACCORD 11 trial demonstrated an improved overall survival utilizing FOLFIRINOX versus gemcitabine which has been the standard of care. However, FOLFIRINOX was associated with a significantly higher incidence of both hematologic and nonhematologic toxicities at the expense of increased toxicity. At our institution, FOLFIRINOX has been found to have a very similar toxicity profile with a significant impact on quality of life. For that reason, many patients at our institution have been treated with mFOLFOX6 with better tolerability instead of FOLFIRINOX in the palliative setting. Methods: We performed a retrospective chart review to analyze overall survival in patients withof unresectable pancreatic cancer (locally advanced and metastatic). Institutional tumor registry database was used to identify patients with unresectable pancreatic adenocarcinoma from January 2009 to March 2012. Medical records were reviewed to identify patients who were treated with at least 1 cycle of modified FOLFOX-6 as a line of treatment during their disease course. Overall survival was calculated for this cohort of patients. Results: 26 patients (15 male, 11 female) with unresectable pancreatic adenocarcinoma were identified. Mean age was 65.3 years. 19 patients had metastatic disease whereas 7 patients had locally advanced disease at diagnoses. Modified FOLFOX6 as a 1st line, 2nd line and 3rd line therapy was given in 17, 6 and 3 patients respectively. The median overall survival was 9 month while the mean survival was 10.6 months. 7 patients were treated with FOLFIRI as 2nd or 3rd line treatment. Nine patients are still alive. Conclusions: Modified FOLFOX-6 is an acceptable treatment for metastatic and locally advanced pancreatic adenocarcinoma. Even though our sample size is small, overall survival is comparable to that of FOLFIRINOX. A multi-institutional, randomized trial evaluating sequencing of mFOLFOX6 and FOLFIRI and comparing it with FOLFIRINOX would be useful.
Influence of ABO blood group on the natural history of advanced pancreatic adenocarcinoma (PC).
Authors: Teo MinYuen , Mohd Sharial Mohd Syahizul Nuhairy , Naidoo Jarushka , Jayaram Anuradha , Jayaraman Thevaraajan , Bajwa Raazi , O'Brien Michelle , McDonnell Felicity , Conlon Kevin C. , Geoghegan Justin , Power Derek Gerard , Grogan William , McDermott Raymond S.
Published: February 2017

307

Background: An association between blood group (ABO) and PC has been demonstrated at epidemiologic and genomic levels. Variations in ABO type may lead to higher pro-inflammatory cytokines levels with modifications in cellular adhesionand signalling promoting carcinogenesis. This study investigated the influence of ABO on the clinical behaviour of advanced PC in patients (pts) , treated with chemotherapy (ctx). Methods: Pts with confirmed PC were identified from 4 institutional databases. Inclusion criteria were unresectable (UPC) or metastatic disease (MPC), receipt of ctx and availability of ABO data. Clinicopathologic details were collected. 200 random anonymied non-cancer ABO samples were collected as control. Descriptive statistics and survival analyses were performed. Results: Between 2001 and 2012, 222 pts met inclusion criteria. Median age was 63 years (range: 33 – 83) 56% were males. 60% of pts had MPC and 27% received doublet ctx. ABO distribution was: A (40%), AB (5%), B (11%) and O (44%). The incidence of blood type A was higher in PC cohort than control (40 vs 30%, p=.03) but identical between UPC and MPC (41 vs 40%, p=.84). Overall survival between type A and non A were identical for the entire cohort (5.8 vs 6.6 mos, HR 1.04 95% CI 0.76 – 1.40, p=.82), UPC (7.6 vs 9.5 mos, HR 1.08 95% CI 0.65 – 1.76, p=.77) or MPC (5.4 vs 4.7 mos, HR 0.94 95% CI 0.66 – 1.34, p=.78). For UPC, 56 pts (64%) had radiographic documentation of the pattern of progression. Type A pts had lower propensity for developing distant metastasis (7/21) than non A (23/35), at 33 vs 66%, p=0.03. Amongst pts with MPC, the incidence of hepatic and pulmonary metastases for type A and non A were identical (77 vs 74%, p=.83; 21 vs 18%, p=.81). However, peritoneal dissemination was less common in type A pts (6 vs 23%, p=.01). Conclusions: Consistent with existing epidemiologic data, the incidence of blood type A is significantly higher in pts with PC, although this does not appear to be stage dependent. ABO did not appear to influence OS in this cohort. However, our data suggests that the pattern of disease spreadmay be related to the ABO blood type. ABO-related glycosylated products could be a target for disease modulation in further studies.
Association of high-throughput RNAi and drug screening with candidate novel therapeutic targets in esophageal carcinoma.
Authors: Chong Irene Yu-Shing , Hooper Sean D. , Cunningham David , Elliott Richard , Chen Lina , Campbell James , Bajrami Ilirjana , Kozarewa Iwanka , Wetterskog Daniel , Wilkerson Paul M. , Lambros Maryou B. , Rao Sheela , Starling Naureen , Chau Ian , Lord Christopher J. , Ashworth Alan
Published: February 2017

31

Background: Oesophageal cancer is the sixth most commonly diagnosed cancer worldwide and carries a poor prognosis. Targeted therapeutic strategies have relied on the identification of genes which are amplified and overexpressed but the discrimination between genes which drive cancer and those that are coincidental has not yet been fully achieved. Methods: We carried out a functional genetic screen of 714 kinases in 18 tumour cell line models of oesophageal adenocarcinoma (EAC) and squamous cell carcinoma (SCC) to identify genes critical to the survival of specific oesophageal subtypes. High throughput drug screening of 80 compounds, largely comprising those used in clinical trials or in routine clinical practice, was undertaken in parallel to reveal druggable targets and to validate functional screening results. Results: We show proof of principle that the integration of functional and drug profiling results with molecular profiling data is a valid approach for identifying druggable targets by correlating the effects of ERBB2, EGFR and CDK6 gene knockdown with sensitivity to drugs targeting their respective proteins. We have characterised new genetic dependencies for EAC involving TGF beta signalling and the JAK/STAT pathway. Decreased cell viability associated with silencing of ACVR2 and ACVR1C (activin receptors involved in TGF beta signalling) was consistent with sensitivity to nilotinib, a cABL inhibitor that modulates TGF beta signalling. Furthermore, decreased cell viability in EAC models was observed with silencing of JAK2. This strongly correlated with sensitivity to PF-04691502 and BEZ 235, both potent inhibitors of PI3K/mTOR which signal downstream of JAK2. We have validated novel sensitivity to small molecule tankyrase inhibitors in a subgroup of oesophageal models, suggesting that a subset of Wnt dependent oesophageal cancers could be targeted with these agents. Conclusions: The molecular and functional genetics of oesophageal cancer is poorly understood. By generating functional viability and drug sensitivity data for a panel of oesophageal tumour cell lines, we have identified new genetic dependencies and candidate drug targets for this aggressive disease.
Is survival in advanced pancreas cancer (APC) correlated to treatment-related lymphopenia (TRL)?
Authors: Jayaram Anuradha , Teo MinYuen , Mohd Sharial Mohd Syahizul Nuhairy , McDonnell Felicity , Geoghegan Justin , Conlon Kevin C. , Fennelly David , McDermott Raymond S.
Published: February 2017

313

Background: Relationship between TRL and survival has been described in patients (pts) who receive adjuvant chemoradiotherapy. Evidence on TLR in APC treated with chemotherapy (ctx) is limited. We investigate the effect of ctx on TRL and its association with survival. Methods: Pts with APC were identified from two institutional databases. Inclusion criteria were: locally advanced (LA) or metastatic disease (MPC) and receipt of ctx. Baseline clinicopathologic and biochemical details including lymphocyte count at baseline and between day 21 and 28 were collected. Degree of TRL was collected prior to initiation of ctx and graded according to CTCAE v4. Descriptive statistics and survival analyses were performed. Results: Between 2001 and 2012, 97 pts were included. Median age was 64 years (range: 42 – 79), 58% were males. MPC seen in 57% of pts and 46% received doublet ctx. Ca19-9 ≥10,000 was detected in 77% pts. Uni- and multivariate analyses for six variables are described in the table. Major reduction, as defined by a 33% change in TLC, was described as a major reduction, present in 14 pts (15%). A major reduction of TLC was associated with a median overall survival (OS) of 2.5 mths (95%CI=1.2-5.3) versus 7.1 mths in those with no TLC change (95%CI=5.6-9.3) (p=0.0149). When assessed by CTCAE, difference in OS was also noted for G0 (n=47), G1 (n=39), G>=2(n=10) lymphopenia: 95 pts had grade 0-2 TLC 4 weeks post chemotherapy. OS was 9.7, 5.3 and 1.9 mths for grade 0, 1, and 2 lymphopenia. (p=<0.0001) respectively. Conclusions: TRL is an independent prognostic factor for APC. In comparison to existing data where chemo-radiation increases the grade and rates of TRL, APC pts treated with ctx had lower rates of TRL. This raises the question whether TRL is determined by the underlying biology of APC versus radiotherapy related effect. [Table: see text]
Duodenal and ampullary carcinoid tumors: Using size to predict necessity for lymphadenectomy.
Authors: Dogeas Epameinondas , Hatzaras Ioannis , Cameron John L. , Wolfgang Christopher Lee , Hirose Kenzo , Hruban Ralph H. , Makary Martin , Pawlik Timothy M. , Choti Michael A.
Published: February 2017

316

Background: The metastatic potential and choice of therapy of duodenal and ampullary carcinoid tumors are poorly understood. We evaluated the local management and outcomes in patients with these uncommon tumors and determined factors predicting risk of nodal involvement. Methods: 117 patients were identified with duodenal or ampullary carcinoid tumors between 1996 and 2012, who were treated in a single high-volume center. Clinicopathologic data and overall survival by local treatment modality were analyzed. Results: Among all patients, 64 (55%) were treated surgically, including 34 (29%) who underwent pancreaticoduodenectomy (PD), 14 (12%) who underwent local resection (partial duodenectomy), and 16 (13.6%) where a carcinoid tumor was found incidentally after PD for another indication. The remaining 53 patients (45%) underwent endoscopic excision. The average tumor size was 1.8 cm (0.1-8.5) and the majority were of duodenal origin (n=93, 80%). Surgical management was more commonly performed for ampullary tumors compared to tumors of duodenal origin (83% vs. 47%, p=0.002), and endoscopic excision was more common with smaller tumors (p=0.001). Most carcinoids were well-differentiated (94%) and 55% were T1/T2. Yet, among the 55 patients in whom lymph nodes were histologically assessed (PD or lymph node sampling), 51% had positive nodes (N+). In addition, on multivariate analysis nodal involvement was strongly associated with tumor size (OR: 9.9, p=0.001). Specifically, tumors larger than 1-cm had positive nodes in more than 70% of cases whereas those ≤1cm had a 5% risk of nodal involvement (1 of 21 patients) (Table). Similar rates of N+ were observed for both duodenal and ampullary carcinoids. With long-term follow-up, only one recurrence was observed (1%). The overall survival was similar among all treatment groups (median=139 months). Conclusions: Lymph node involvement is common in patients with duodenal and ampullary carcinoid tumor, particularly among tumors >1 cm in size. When possible, surgical resection with lymphadenectomy is recommended for such tumors. [Table: see text]
Efficacy and feasibility of chemotherapy and radiation therapy for borderline resectable pancreatic cancer in elderly patients.
Authors: Figura Nicholas , Cruz Alex , Mellon Eric Albert , Chuong Michael , Hoffe Sarah , Springett Gregory M. , Saeed Nadia , Hodul Pamela Joy , Malafa Mokenge Peter , Balducci Lodovico , Shridhar Ravi
Published: February 2017

320

Background: To date there have been few studies evaluating the efficacy and tolerability of aggressive neoadjuvant chemotherapy and radiation therapy (RT) for patients ≥70 years of age with borderline resectable pancreatic cancer (BRPC). Methods: We performed a retrospective review of our institutional experience treating BRPC from 2006 to June 2012. All patients were staged with a pancreas protocol CT scan, endoscopic ultrasound, and PET/CT scan. The diagnosis of BRPC was confirmed by our GI Tumor Board prior to treatment. Our institutional preference for preoperative chemotherapy included gemcitabine, paclitaxel and capecitabine (GTX). RT techniques included intensity modulated radiation therapy (IMRT) or stereotactic body radiation therapy (SBRT). Restaging scans were performed after RT completion and patients were then considered for surgical resection. The data was analyzed using Kaplan-Meier and Cox regression analysis. Results: This study included 72 BRPC patients with a median age of 65 years (range 36-87). 24 patients (33%) were ≥70 years old. Median follow up for all patients was 12.7 months. 56 patients (77%) received preoperative GTX. Of the patients ≥70 years, 7 were treated with IMRT and 17 with SBRT, compared to 8 who were treated with IMRT and 40 with SBRT in the younger cohort. In the older group, 11 patients (46%) underwent surgery with all attaining microscopically negative margins (R0), compared with 32 patients that underwent surgery in the younger cohort (61.7%), 29 of which received R0 margins (90.6%). Median survival for patients ≥70 years old was 12.6 months compared to 12.8 months for the younger patients. There was no difference in overall survival (p =.606) or progression free survival (p = .312) between the two groups. Multivariate analysis showed that surgery in the entire group was significantly associated with an improvement in overall survival (p = .011). Conclusions: Our data indicates that aggressive neoadjuvant chemotherapy and RT is equally effective for older patients. Neoadjuvant therapy for BRPC should not be withheld basely solely on patient age.
Octreotide LAR use among elderly patients with carcinoid syndrome and survival outcomes: A population-based analysis.
Authors: Shen Chan , Xu Ying , Yao James C. , Shih Ya-Chen T.
Published: February 2017

322

Background: Octreotide LAR is indicated for the treatment of carcinoid syndrome, diarrhea related to VIPoma, and may delay tumor growth in neuroendocrine tumors (NETs). The pattern of octreotide LAR use in clinical practice and its impact on survival outcomes has not been well-documented. Methods: Using the SEER-Medicare database, we identified NET patients diagnosed between 7/1999 and 12/2007. We excluded those under age 65, enrolled in HMOs, and without continuous Part A and B enrollment within 12 months of diagnosis. Potential indication for octreotide use was defined as ≥ 2 claims for carcinoid syndrome, flushing, diarrhea, or malignant islet cell neoplasm within first year of diagnosis, with the first claim occurring within 6 months of diagnosis. HCPCS codes, J2352 and J2353, were used to identify octreotide LAR treatment. Multivariate logistic regression and Cox proportional hazard survival analyses were performed to ascertain factors associated with octreotide use and evaluate impact of octreotide use on survival; covariates included age, race, region, comorbidity score, urban/rural status, tumor characteristics, neighborhood socioeconomic status and year of diagnosis. Results: Among those with potential indication for octreotide use (carcinoid syndrome and islet cell), 264 (49%) out of 539 distant stage patients, and 83 (10%) out of 850 patients with local regional disease were started on octreotide LAR within 6 months of diagnosis. Multivariate logistic regression showed that patients living in the southern region were less likely to use octreotide. Multivariate proportional hazard model showed that octreotide LAR provided a significant 5-year survival benefit for distant stage patients (HR=.80, p-value=.047); while this survival benefit was not shown for the local/regional stage patients (HR=.97, p-value=.89). Conclusions: This retrospective study suggests a possible survival benefit for use of octreotide LAR in distant stage elderly patients with carcinoid syndrome. Data also suggest that many elderly patients with claims for carcinoid syndrome did not receive octreotide LAR therapy within 6 months of diagnosis. Further studies and improved education are warranted.
Feasibility and efficiency of automatic treatment planning for stereotactic body radiation therapy (SBRT) in pancreatic cancer patients.
Authors: Dholakia Avani Satish , Moore Joseph A. , Wild Aaron Tyler , Yang Wuyang , Evans Kim , McNutt Todd , Herman Joseph M.
Published: February 2017

323

Background: Overlap volume histogrmas (OVHs) allow for new plans to be generated based upon prior similar treatment plans. The purpose of this project was to clinically deploy a generic and user-friendly interface for using a database populated with OVHs for planning SBRT pancreas patients. An interface for evaluating adherence to protocol tolerances is also developed to aid in the planning process. Methods: A database of previously treated SBRT pancreas patients is used to query the organ at risk (OAR) dose from patients with similar or harder to plan OVHs. For each OAR in a new plan, the database is queried to find the lowest achievable structure dose from all previous patients with a greater than or equal overlap between the selected structure and the target structure. Queried values are then automatically loaded into the inverse planning optimizer objectives and used to generate an optimized plan. Plans are then evaluated using a protocol interface which queries relevant protocol values and displays the values in a color-coded interface. Upon plan completion the system submits the new patient data to the OVH database and stores relevant DVH metrics in the MOSAIQ database for tracking. Results: The interface has been used to successfully plan 5 SBRT patients. All planned patients met protocol requirements. Automatic plans required fewer iterations to produce an acceptable plan. The physician indicated preference to the automatically generated plans due to better adherence to protocol requirements and lower critical structure doses. Conclusions: Automatic planning can be used to generate clinical plans which reduce dose to normal tissues while achieving the dose distribution required by clinical protocols. The protocol interface allows for more rapid evaluation of plan acceptability during planning and for physician review. The system can be deployed clinically, but requires adherence by all participants to standard naming conventions for targets and OARs.
Survival trends among patients with advanced hepatocellular carcinoma in the United States.
Authors: Ghimire Krishna Bilas , Shah Binay Kumar , Nepal Barsha
Published: February 2017

329

Background: Sorafenib was approved by FDA for treatment of HCC in 2007. This study was conducted to evaluate survival outcome in advanced HCC during 2005-2006 and 2008-2009 using U.S. Surveillance, Epidemiology, and End Results (SEER) cancer registry database.Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER*Stat) database: Incidence - SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2011 Sub (1973-2009 varying) using MP-SIR session. We analysed 1 year relative survival rates among stage IV HCC patients between pre- sorafenib (2005- 2006) and post- sorafenib (2008- 2009) eras. We used seer Z test to compare relative survival rates among cohorts of patients categorized by gender and age groups (<50 and >50 years). Results: There were 2,497 (1,180 in pre-sorafenib era and 1,317 in post-sorafenib era) stage IV HCC patients reported in seer database. Overall 1 year relative survival rates ± standard error (SE) were: 12.5±0.7% (12.5±1% in pre sorafenib era vs 13.1±1.1% in post sorafenib era, Z score= 0.481, p value=0.63). Overall Relative survival rates among men and women were 12.9±0.8% (12.7±1.1% in pre vs 13.4±1.2 in post sorafenib era, Z score=0.254, p value=0.79) and 11.8±1.6% (11.7±2.2% in pre vs 11.5±2.5 post sorafenib era, Z score=0.469, p value=0.63) respectively. There was no significant differences between 1 year relative survival rates by age groups (<50 and >50 years). Conclusions: This study showed no significant difference in 1-year relative survival rates during 2008-2009 as compared to 2005-2006. More studies are required to find out why the findings of SHARP trial have not translated to population-based settings.[Table: see text]
A phase II study of complete neoadjuvant therapy in rectal cancer (CONTRE): The Brown University Oncology Group.
Authors: Perez Kimberly , Pricolo Victor , Vrees Matthew , DiPetrillo Thomas A. , Oldenberg Nicholas , Klipfel Adam , Schechter Steven , Kinsella Timothy J. , Roth Leslie , Cataldo Thomas , Shah Nishit , Olszewski Adam J. , Isdale Debora , Safran Howard , Sikov William M.
Published: February 2017

335

Background: While preoperative chemoradiation followed by surgery is the standard approach for patients (pts) with newly diagnosed clinical stage II-III rectal cancer, many are unable to tolerate postoperative adjuvant chemotherapy which may compromise disease-free and overall survival. CONTRE is a multicenter phase II study designed to determine the feasibility of administering all chemotherapy prior to surgery and to assess its impact on pathologic complete response (pCR) and complete (R0) resection Methods: Pts with T3-4 and/or N1-2 rectal cancer, staged by endorectal ultrasound (ERUS) and pelvic MRI, receive modified (m) FOLFOX6 every 2 weeks x 8 cycles, followed by repeat MRI and proctoscopy to assess response. Pts then receive 50.4 Gy IMRT with 5-FU 225 mg/m2/day or capecitabine 825mg/m2 BID, 5 days per week during radiation, followed by surgery 4-8 weeks later. Results: Thus far, we have enrolled 36 of a planned 39 pts (median age 58, range 30-79; T2-1, T3-30, T4-2; N1-20, N2-7). 28 of the first 30 (93%) completed 8 cycles of mFOLFOX6. 26 pts have completed chemoradiation while 2 chose to proceed directly to surgery. All patients opted to receive capecitabine during radiation. Grade 3/4 toxicities during chemotherapy and chemoradiation have included diarrhea (16%) and neutropenia (12%), with grade 3 renal and cardiac toxicities reported in one patient each. A clinical complete response after chemotherapy alone was achieved in 3 of 29 (10%). Of the first 21 pts undergoing surgery, pCR has been achieved in 6 (29%) and R0 resections in 100%. Thus far, all pts have been able to undergo sphincter-sparing resections. Study accrual will be completed by the meeting. Conclusions: A larger proportion of stage II-III rectal cancer pts are able to complete mFOLFOX6 (>90% in our cohort) when administered prior to chemoradiation and surgery. Complete neoadjuvant treatment may represent a well-tolerated alternative to the current standard treatment sequence and a platform for the evaluation of novel therapeutics such as targeted agents during preoperative therapy. Funded in part by LIFEcycle, Inc. Clinical trial information: NCT01363843.
Screen detection of serrated polyps by stool DNA multi-target testing (sDNA-MT): Comparison against fecal immunochemical occult blood testing (FIT).
Authors: Heigh Russell I. , Mahoney Douglas W. , Yab Tracy C. , Simonson Julie A. , Boardman Lisa A. , Domanico Michael J. , Berger Barry M. , Lidgard Graham P. , Ahlquist David A.
Published: February 2017

341

Background: Precursors to 1/3 of colorectal cancer (CRC), serrated polyps have historically been underdetected by screening due to their inconspicuous, nonhemorrhagic, and proximal nature. New generation sDNA-MT show high sensitivity for both CRC and advanced adenomas (Gastroenterology 2012;142:248), but screen detection of serrated polyps by this approach requires further validation. Aim: To assess and compare noninvasive detection of sessile serrated polyps >1cm (SSP) by sDNA-MT and a commercial quantitative FIT. Methods: In a blinded prospective study, a single stool sample used for both tests was collected from 456 asymptomatic adults prior to screening or surveillance colonoscopy (criterion standard). All 29 patients with SSP were included as cases and all 232 with no neoplastic findings as controls. Buffered stool samples were processed and frozen on receipt; Exact Sciences performed sDNA-MT in batches using optimized analytical methods (Gastroenterology 2012;142:S770). The sDNA-MT panel targets methylated BMP3 (mBMP3) and NDRG4, mutant KRAS, β-actin, and hemoglobin. FIT (Polymedco OC-FIT Check) was performed in separate lab <2 days post defecation and evaluated at cutoffs of 50 (FIT-50) and 100 ng/ml (FIT-100). Results: Age/sex distributions were similar in cases and controls: 40% vs 45% > 65 years and 51% vs 59% women, p=NS respectively. SSP median size was 1.2cm (range 1-3cm), 93% were proximal, and 64% had synchronous diminutive polyps. Among sDNA-MT markers, mBMP3 proved highly discriminant for SSP detection (AUC=0.87, p<0.00001); other DNA markers were less informative and provided no incremental sensitivity. Hemoglobin alone showed no discrimination (AUC=0.50, p=NS). At matched specificities, SSP detection by stool mBMP3 was significantly greater than by either FIT-50 or FIT-100 (Table). Conclusions: From a screening and surveillance setting, SSP can be detected noninvasively by stool assay of exfoliated DNA markers, especially mBMP3. FIT appears to have no value in SSP detection. [Table: see text]
Concordance of KRAS mutation detection between Illumina next generation gene sequencing (NGS) and CLIA-approved, clinical assays in metastatic colorectal cancer (mCRC).
Authors: Kothari Nishi , Yeatman Timothy Joseph , Schell Michael J. , Greenawalt Danielle , Hardwick James , Nebozhyn Michael , Loboda Andrey , Dai Hongyue , Kim Richard D.
Published: February 2017

345

Background: It is well known that KRAS mutations limit the efficacy of anti-EGFR therapy in patients with mCRC. Therefore, accurate testing of KRAS is needed to ensure that appropriate patients receive anti-EFGR therapy. Most clinical institutions conduct KRAS testing in CLIA approved labs using standard DNA sequencing methods. The purpose of this study is to correlate KRAS mutation detection by Illumina KRAS gene sequencing to standard KRAS testing performed with CLIA. Methods: We analyzed tumor samples collected from 471 patients between 1998-2010. Patients were chosen randomly based on availability of sufficient tissue for DNA extraction. We performed targeted exome sequencing using an Illumina NGS platform with 50-100X coverage of KRAS. The BWA/GATK pipeline was used to identify variants and indels. Because matched normal samples were not available for comparison to identify somatic mutations, filtering of normal variants was performed using 1000 Genomes. Variants identified in 1000 Genomes with an MAF < 0.01 were filtered. Results: Out of 471 patients, 83 pts had KRAS testing done both by exome sequencing & CLIA approved labs. The concordance rate between the two testing methods was 89%. 39 pts (47%) were KRAS mutation negative (wild type) and 35 pts (46%) harbored KRAS mutation as determined by both methods. Of these, 31 pts had codon 12 mutations and 4 pts had codon 13 mutations. However, 6 pts (7%) were found to have no KRAS mutation using CLIA but were found to have KRAS mutations by NGS (two had A146V mutations, the others had Q61 mutations). In addition, 3 pts (4%) were KRAS mutants using CLIA but wild type by NGS. Thus, 10% of samples tested showed a discrepancy in outcome between the NGS & CLIA testing. Conclusions: Standard DNA sequencing methods (CLIA) was able to identify a majority of the KRAS mutants detected by NGS. However 10% of patients had either false positive or false negative results. The main explanation for this discrepancy is that CLIA approved labs generally only test for codons 12 & 13. The clinical role for NGS in tumor KRAS mutation detection should be further investigated to ensure that patients with mCRC receive appropriate therapy.
Impact of the recurrence score (RS) result and mismatch repair status (MMR) on agreement between oncologists (MDs) for stage II colon cancer (CC) recurrence risk (RR) assessment: A novel clinical utility endpoint for prognostic markers.
Authors: Kelley Robin Katie , Lopatin Margarita , Hwang Jimmy , Crager Michael , Brenner Adrienne A , Kuczma Jane , King Ashley , Chao Calvin , Lee Mark , Venook Alan Paul
Published: February 2017

349

Background: Appropriate use of prognostic and predictive markers depends on quality of evidence for clinical utility in addition to clinical validity. In stage 2 CC, RR assessment is based traditionally on clinicopathologic factors (CP) with limited clinical validation and varies substantially across providers. We hypothesized that the validated Oncotype DX Colon Cancer RS and MMR tests may impact clinical decision-making by decreasing variation in RR assessment across MDs. We conducted a survey to compare the level of MD agreement on stage 2 CC RR assessment using CP alone vs CP+RS+MMR (CP+). Methods: A clinical trial database was randomly sampled for 100 cases of stage 2 CC stratified on T-stage, MMR and RS groups. Anonymous internet surveys asked each MD to assess 3-year RR for 10 cases with CP and 10 different cases with CP+. MDs were divided into panels of 5; all members of each panel reviewed the same cases. Agreement in RR among MDs was assessed using within-panel mean squared difference in RR assessments and analyzed using generalized linear models. Results: 30 community (C) and 20 university-based (U) MDs (Assoc of Northern California Oncologists or NCCN, respectively) completed evaluable surveys April-June 2012. For C vs U, median years in practice were 5 and 2; prior use of RS 13% vs 25%; and routine MMR use 21% vs 55%. The standard deviation of the differences (SDD) in RR assessments for CP alone was high overall (7%), and greater for U vs C MDs (8.2% vs 6.4%). CP+ produced higher agreement in RR assessments vs CP for both C (p<.001) and U (p=0.04) MDs, with 23% and 20% proportional reduction in SDD. ForT3 MMR-proficient (P) patients (n=70), CP+ produced higher agreement in RR for both C (p<0.001) and U (p=0.01) MDs with 37% and 29% reduction in SDD. Conclusions: Addition of RS+MMR to CP significantly increased MD agreement on RR assessment in stage 2 CC, including T3 MMR-P patients. Agreement was higher among C than U MDs. MD agreement on stage 2 CC RR assessment and Tx decision-making warrants consideration as a novel endpoint for clinical utility of RS, MMR, and other prognostic markers.
Anal intraepithelial neoplasia progression to squamous cell carcinoma.
Authors: Gami Bhavna , Ziprin Paul , Goldin Robert D , Osborn Michael , Greene Linda , Walsh John
Published: February 2017

353

Background: In the U.K., the annual incidence of anal cancer is up to 1.5 per 100,000 per year. Anal intra-epithelial neoplasia (AIN) is believed to be a precursor to squamous cell carcinoma whose incidence is still undetermined. This cell transformation has been associated with human papillomavirus (HPV) infections, in particular HPV 16 and 18. Our aim was to determine the frequency of progression to squamous cell carcinoma (SCC) of the anus in patients with known AIN. Methods: Study subjects with diagnosis of AIN from January 1st 1997 to January 1st 2009 were identified from a prospective database in a single hospital trust. The incidence of a subsequent diagnosis of anal SCC was determined from the local pathology and anal cancer database and cross referenced with the regional cancer database, Thames Cancer Registry. Results: We identified 397 patients (303 males) diagnosed with AIN in the database and HPV infection was identified in n= 395 patients. 15 (4%) patients were diagnosed with anal SCC a median of 5 months, Interquartile range 27 (2- 29 months) after their initial diagnosis. The distribution of AIN 1, 2 and 3 at presentation was 2, 1 and 12 respectively. Of interest, number of patients developed other HPV related cancers during the study period, such as vulva (n=8), cervical (n=3) and penile cancers (n=1). Conclusions: The incidence of anal cancer is higher in patients with known AIN compared to the general population. This justifies surveillance of these patients for anal and other HPV related intraepithelial neoplasia, however the nature of this, anoscopy or clinical examination alone, has yet to be determined.
Impact of body mass index (BMI) and weight changes on recurrence and survival in stage III colon cancer (CC).
Authors: Vergidis Joanna , Alipour Sina , Cheung Winson Y.
Published: February 2017

355

Background: Research suggests that physical activity can lower the risk of relapse and mortality from CC. However, it is unclear if such benefits are mediated through an effect on weight. Our aims were to (1) evaluate the impact of pre-treatment BMI on recurrence and survival in early stage CC, (2) examine how changes in weight from baseline may affect outcomes, and (3) explore if the effects of different body compositions are modified by adjuvant therapy (AT). Methods: Patients (pts) diagnosed with stage III CC from 2006 to 2008, evaluated at any 1 of 5 cancer centers in British Columbia, and who had their weights measured serially throughout their AT period were reviewed. Using Cox proportional hazards models, we compared outcomes among (a) BMI<25 [normal] vs. 25-30 [overweight] vs. >30 [obese] and (b) weight increase or decrease of < vs. >/=5% and < vs. >/=10%, while controlling for confounders. Results: A total of 821 pts were included: median age was 65 years, 50% were men, and 83% were ECOG 0/1. At baseline, 43, 37, and 20% were normal, overweight, and obese, respectively. Compared to pts with normal BMI, those who were overweight or obese did not show an increased risk of recurrence (HR 0.81, 95%CI 0.42-1.58 and HR 1.09, 95%CI 0.48-2.51, respectively, p trend=0.74) or death (HR 0.54, 95%CI 0.26-1.13 and HR 0.62, 95%CI 0.22-1.74, respectively, p trend=0.24). A number of pts experienced weight gain or loss during their AT period, but none of these weight changes affected outcomes (Table). Receipt of AT did not modify the effects of BMI or weight change on outcomes. In Cox models, advanced age and poor performance status were the main factors that consistently correlated with an increased risk of recurrence and death (p<0.05). Conclusions: Neither baseline BMI nor short-term weight changes during AT appear to affect outcomes in stage III CC. Physical activity likely exerts its benefit on relapse and survival by influencing long-term weight changes or by alternative mechanisms. [Table: see text]
Level of arterial ligation in sigmoid colon and rectal cancer surgery.
Authors: Yasuda Koji
Published: February 2017

358

Background: Curative resection of sigmoid colon and rectal cancer includes "high tie" of the inferior mesenteric artery (IMA). However, IMA ligation compromises blood flow to the anastomosis, which may increase the leakage rate and it is unclear whether this confers a survival advantage. Accodingly, IMA may be ligated at a point just below the origin of the left colic artery (LCA) ("low tie"), with lymph node (LN) dissection around IMA. No study has investigated the detailed prognostic results between "high tie" and "low tie, with LN dissection around IMA". The aim of this study was to assess the utility of "low tie, with LN dissection around IMA" on survival in patients with sigmoid colon or rectal cancer. Methods: A total of 268 sigmoid colon or rectal cancer patients who underwent curative operation from 1998 to 2007 were enrolled in this study. The patient's medical records were reviewed to obtain information about operative method, the number of LN dissection, the number of metastatic LN, the site of metastatic LN, recurrence pattern, complication. Overall survival and relapse-free survival were calculated using the Kaplan-Meier method, with differences assessed using logrank test. Results: We divided all patients into three groups according to the ligation level of IMA. 41 patients were ligated at the level of IMA root (Group A: "high tie"). 164 patients were ligated just caudally to the origin of the LCA ("low tie"), with LN dissection around IMA. 63 patients were ligated at the level of superior rectal artery just caudally to the sigmoid artery. The significant difference was not observed in a complication rate in three groups. The significant difference was not observed in the survival rate and the relapse-free survival rate according to each stage in group A and group B either. Also, the significant difference was not observed in the survival rate and the relapse-free survival rate in node-positive cases in group A and group B. Conclusions: "Low tie,with lymph node dissection aroud IMA" is anatomically less invasive and is not inferior to the ligation in the IMA root ("hige tie") in prognostic point.
Clinical and preclinical evaluation of taxane sensitivity in gastric cancer (GC): Relevance of GC histology.
Authors: Galletti Giuseppe , Cleveland Kyle , Matov Alex , Hayes James E. , Klein Robert J. , Hassane Duane C. , Nicacio Leonardo V. , Giannakakou Paraskevi , Shah Manish A.
Published: February 2017

37

Background: Docetaxel (D) is a standard treatment for advanced gastric cancer based on the TAX-325 study (van Cutsem, JCO 2006). We asked the question, do all subtypes of GC benefit equally from D therapy? Methods: We performed a post-hoc analysis of the TAX-325 study. We classified randomized patients as diffuse or non-diffuse histology and correlated histology with clinical outcomes using a Cox proportional hazards model. Preclinical studies involved 13 GC cell lines (4 intestinal subtype, 7 diffuse subtype, 2 unknown), assessed for D sensitivity using the Sulforhodamine B (SRB) cytotoxicity assay, microtubule bundling, mitotic arrest by immunofluorescence as evidence of drug-target engagement, and apoptosis assessment by Caspase 8, Caspase 3, and PARP cleavage by Western Blot. Results: In post hoc analysis of TAX-325, patients were classified as diffuse (n=206) or non-diffuse (n=239). Non-diffuse GC showed a significant improvement in overall survival with the addition of D (12.1 v 8.8 mo, p=0.002), whereas diffuse histology was not associated with an improvement in survival (8.3 v 8.5 mo, p=0.66). Preclinical studies similarly reveal that 5/7 diffuse GC cell lines were resistant to D by SRB assay compared with 1/4 intestinal GC cell lines (IC50 > 600 nM). To examine drug target engagement, a dynamic measure of D activity, 4/6 diffuse GC cell lines showed lack of D engagement on the microtubule network at physiologic D concentrations (0-100 nM). 5/6 diffuse cell lines demonstrated no apoptosis. Additionally, we found that 0/9 GC cell lines expressed P-glycoprotein, ruling out multidrug resistance as an etiology for diffuse GC resistance to D. Conclusions: In exploratory analysis, we observed diffuse GC to be resistant to the addition of D to standard chemotherapy in a random assignment phase III clinical trial. In vitro analyses support these clinical findings and demonstrate intrinsic D resistance in diffuse GC, unrelated to multidrug resistance. Ongoing mechanistic studies focus on the molecular basis of taxane sensitivity in GC to predict treatment efficacy. These findings will inform future clinical studies aimed at individualized therapy.