bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of operability classifications to predict outcome of patients with anatomically resectable pancreatic adenocarcinoma treated with neoadjuvant therapy.
Authors: Tzeng Ching-Wei David , Fleming Jason B. , Lee Jeffrey Edwin , Xiao Lianchun , Pisters Peter W. T. , Vauthey Jean-Nicolas , Abdalla Eddie K. , Wolff Robert A. , Varadhachary Gauri R. , Fogelman David R. , Crane Christopher H. , Balachandran Aparna , Katz Matthew H.G.
Published: February 2017

293

Background: We previously introduced a novel classification system for assessing “operability” in patients with localized pancreatic adenocarcinoma (PDAC) that integrates cancer biology, patient physiology, and tumor anatomy. We sought to analyze resection rates, reasons for no resection, and outcomes after neoadjuvant therapy (NT) of patients with both resectable anatomy and either “operable” or “borderline” biology/physiology.

Methods: We evaluated consecutive patients (2002-2007) with radiographically resectable cancers treated with NT prior to potential resection. Borderline resectable anatomy (BR-A) was excluded. We compared clinical factors and outcomes of 217 patients classified by established criteria as “potentially resectable-operable” (PR-OP, no evidence of extrapancreatic disease, performance status [PS] ≤1); “borderline resectable-B” (BR-B, findings suspicious for extrapancreatic disease); or “borderline resectable-C” (BR-C, severe but reversible comorbidities or marginal PS ≥2).

Results: 138 PR-OP, 41 BR-B, and 38 BR-C patients began NT. 62.7% of all patients underwent subsequent pancreatectomy. Resection rates after NT for PR-OP, BR-B, and BR-C were 74.6%, 46.3%, and 36.8%, respectively (p<0.001). Metastases were detected during NT in 23.0% of all patients and were the most common contraindication to resection in PR-OP (15.2%) and BR-B (46.3%) patients. PS rarely precluded surgery except in BR-C patients (31.6%). Factors independently predicting not utilizing surgery after NT were older age, poor PS, new pain medications, and complications on NT (p<0.05). Median OS of all patients was 20.9 (95% CI, 17.1-27.1) mo. Resected and unresected BR-B and BR-C patients had OS similar to that of PR-OP patients (resected medians 33.0, 39.8, 36.0 mo, respectively; unresected medians, 10.1, 12.6, 12.9 mo; p<0.001).

Conclusions: Our operability classification system describes discrete clinical subgroups among PDAC patients with similar, resectable tumor anatomy but vastly heterogeneous physiology and cancer biology. It can be used with NT to predict outcomes, individualize treatment, and optimize survival rates.
Pattern of failure after hepatic arterial concurrent chemoradiotherapy for locally advanced hepatocellular carcinoma.
Authors: Seong Jinsil , Cha Haejung , Keum Woongsub , Yoon Hongin , Han Kwanghyub
Published: February 2017

299

Background: We have previously reported outcome of concurrent chemoradiotherapy (CCRT) in advanced hepatocellular carcinoma (HCC) with median survival 13.1 months. We further analyzed patterns of failure as well as related clinical factors.

Methods: Retrospective cohort analysis was done for 161 HCC patients given CCRT between May 2000 and August 2009. CCRT involved median radiation dose 45 Gy/25 fractions and intraarterial 5-Fu 500 mg thru chemoport. Patterns of failure were categorized; 1) infield, 2) intrahepatic-outfield, and 3) extrahepatic failure. Clinical factors were analyzed using Kaplan-Meyer method and multivariate analysis using Cox-proportional hazard model.

Results: The median age was 55 years and most patients had Child-Pugh A (92%). Infield, intrahepatic-outfield, and extrahepatic failure were observed in 47 (30%), 67 (42%), and 66 patients (42%), respectively. For infield failure, median progression free survival (PFS) of patients treated with CCRT as initial treatment has not yet been reached compared with that in patients with treatment history before CCRT. (Median PFS NR vs. 17 months, p=0.001) For intrahepatic-outfield failure, pretreatment AFP > 500 ng/mL was associated with high incidence of this failure (Median PFS 22 months vs. 10 months, p=0.006). For extrahepatic failure, Age < 55 years and pretreatment AFP > 500 were significant factors for failure, which were also significant in multivariate analysis. Median PFS has not been reached in age <55 years and pretreatment AFP ≤ 500 ng/mL, compared with 10 months in age >55 years (p=0.011) and 14 months in pretreatment AFP > 500 ng/mL. (p=0.042).

Conclusions: Infield, intrahepatic-outfield, and extrahepatic failure were observed in similar proportion. Pretreatment AFP ≥ 500 ng/mL was significant factor for intrahepatic-outfield and extrahepatic failure. Ages <55 years increased incidence of extrahepatic failure. Treatment history before CCRT was associated with infield failure.
The introduction of bevacizumab for the treatment of metastatic colorectal cancer (CRC) in Ontario and its effect on hepatic metastectomy.
Authors: Leeper William Robert , Li Chang Hector Hugo , Welch Stephen , Driman David K , Quan Douglas
Published: February 2017

303

Background: Where possible, the optimal treatment for CRC liver metastases is metastectomy. Perioperative chemotherapy may be associated with improved outcomes in this setting. The government of Ontario approved public funding of bevacizumab (Bev) for metastatic CRC in July 2008. For first-line treatment, funding of Bev has been limited to use in combination with FOLFIRI, an irinotecan-containing regimen. However, the best evidence in support of perioperative chemotherapy for CRC liver metastases involves the use of oxaliplatin, not irinotecan. We sought to analyze changes in prescribing patterns, histologic findings, and clinical outcomes since the funding approval for Bev in Ontario.

Methods: A single centre, retrospective review was performed of all patients receiving metastectomy for CRLM between 2004 and 2010, and archival hematoxylin-eosin slides were reviewed.

Results: A total of 121 patients underwent metastectomy for CRLM during the study period. Of these, 54 were treated with perioperative chemotherapy, 37 before and 16 after funding approval of Bev. A marked increase was seen in Bev and irinotecan-containing regimens since funding approval (p < 0.01). Pathologic examination of the surgical specimens did not reveal any increase in steatosis or steatohepatitis. However, there was a trend towards more R0 resections (p = 0.3) in the post-bev era. A significant reduction in the occurrence of post-operative hepatic dysfunction was observed in the post-Bev era (p = 0.04). Overall survival (OS) and disease-free survival (DFS) were similar.

Conclusions: Public funding of Bev-FOLFIRI for metastatic CRC has led to an increased and yet incomplete utilization of this regimen for CRLM. Pathologic and clinical data do not suggest harm and may show early signs of benefit. Further research is needed to determine the optimal utilization of bev in the setting of CRLM.

[Table: see text]
The use of peptide receptor radionuclide therapy in patients with metastatic low-grade neuroendocrine tumors.
Authors: Naraev Boris , Sharma Nancy , Engelman Eric Steven , Bushnell David L , O'Dorisio Thomas M. , Halfdanarson Thorvardur Ragnar
Published: February 2017

308

Background: Peptide receptor radionuclide therapy (PRRT) is frequently used for patients (pts) with metastatic low grade neuroendocrine tumors (mNETs) in Europe, but it is not readily available in the USA. We report on 108 patients seen at the University of Iowa who underwent PRRT.

Methods: Cases were identified by searching our institutional NET database. Early stage (AJCC 1-3) and high-grade tumors were excluded. Groups were compared using a Wilcoxon rank-sum test and survival calculated with the Kaplan-Meier method.

Results: Men were 62% and women 38%; median age at diagnosis was 52 years (25 – 78). The origin of the primary tumor was small bowel (SBNET) 43.5%, pancreas (PNET) 27.8%, lung 4.6%, unknown primary 11.1%, other sites 13%. PRRT was performed at the University of Basel, Switzerland in 72%, University of Iowa, USA in 26%, and elsewhere in 2%. 97 patients received two treatments. 90Y was used in 86% and 177Lu in 13% for the first PRRT. The survival of patients is shown in the table 1. Radiographic responses (any) at 1-6 months after PRRT were observed in 62%, 11% had a mixed response and 18% progressed. A biochemical response (>50% reduction) in chromogranin A and pancreastatin was seen in 16% and 19% respectively but data was frequently missing.

Conclusions: Patients with mNETs enjoy a relatively long survival. The OS from 1st PRRT was considerably less than OS after diagnosis, suggesting that PRRT is used late in the disease course. PRRT appears to be a valuable treatment option for mNETs, especially SBNETS, and its role earlier in the disease course warrants investigation.

[Table: see text]
Assessment of gastric cancer malignancy based on CD133 and thrombospondin1 (THBS1) expression and the role of histone acetylation.
Authors: Sato Hirohiko , Shimada Mitsuo , Kurita Nobuhiro , Iwata Takashi , Nishioka Masanori , Morimoto Shinya , Yoshikawa Kozo , Miyatani Tomohiko , Goto Masakazu , Kashihara Hideya , Mikami Chie
Published: February 2017

31

Background: Epigenetic modification by HDAC (histone deacetylase) plays important roles in the development and progression of cancer. It has been reported that CD133 positive cancer stem cells were induced through the HDAC → HIF-1α (Hypoxia Inducible Factor-1α) pathway, and Thrombospondin1 (THBS1) is associated with tumor angiogenesis. The aim of this study is to evaluate relationship between the HDAC, CD133, THBS1 and prognosis in gastric cancer.

Methods: 65 patients of gastric cancer were enrolled in this study. HDAC1, CD133 and THBS1 expressions were evaluated in immunohistochemical (IHC) staining of surgical specimens. Relationship between the expressions of HDAC1, CD133, THBS1 and clinicopathological factors was investigated.

Results: HDAC1-positive patients were 52% and had significantly poor prognosis compared with negative patients. There were more frequent liver metastasis and lymphatic invasion in positive patients. CD133-positive patients were 23.1% and had significantly poor prognosis compared with negative patients. There were more frequent depth wall invasion, distant metastasis, peritoneal recurrence. THBS1-positive patients were 26% and had significantly better prognosis compared with negative patients. In THBS1 positive patients, there was less lymph node metastasis, positive peritoneal cytology in ascites, distant metastasis and lymphatic invasion. CD133 expression is positively correlated with HDAC1. THBS1 expression revealed negative correlation with HDAC1. The survival rate of HDAC1 (+) / CD133 (+) group was significantly poor prognosis compared to the other group (HDAC1 (+) / CD133 (-), HDAC1 (-) / CD133 (+), HDAC1 (-) / CD133 (-)). HDAC1 (-) / THBS1 (+) group revealed significantly higher survival rate compared to the other group (HDAC1 (-) / THBS1 (+), HDAC1 (+) / THBS1 (+), HDAC1 (+) / THBS1 (-)).

Conclusions: It was suggested that HDAC1 promoted CD133, suppressed THBS1 in gastric cancer and their interaction were increased the degree of malignancy.
Pharmacogenetic dosing by UGT1A1 genotype as first-line therapy for advanced small-bowel adenocarcinoma: A North Central Cancer Treatment Group (NCCTG) trial.
Authors: McWilliams Robert R. , Mahoney Michelle R. , Marchello Benjamin T. , Jatoi Aminah , Krewer Keith D. , Ames Matthew M. , Schneider Daniel Jay , Seeger Grant R. , Mowat Rex B. , Alberts Steven R. , Goetz Matthew P.
Published: February 2017

314

Background: Small bowel adenocarcinoma (SB-ACA) is rare, having little prospective data guiding management. A prior phase I study evaluated UGT1A1 genotype specific dosing of oxaliplatin, irinotecan, and capecitabine. Our prospective, multicenter clinical trial assessing tumor response in pts having metastatic SB-ACA, used a similar dosing strategy.

Methods: Genotypes were determined via central lab. Previously untreated pts were dosed by UGT1A1*28 genotypes 6/6, 6/7, and 7/7 receiving 100/85/85 mg/m2 oxaliplatin d1, 150/150/75 mg/m2 irinotecan d1, and 1600/400/200 mg/m2 capecitabine (BID) d2-15 of 21 days. The study design was such that 1 confirmed response in 16 pts expanded enrollment to 33 pts, with 7 required for demonstrating efficacy.

Results: 28 pts (13-6/6, 10-6/7, 5-7/7) have been enrolled [75% male, mean age 62.5 (range 41-77)]. Location of primary included: duodenum (63%), jejunum (26%), and ileum (7%), with pts having >1 metastatic site (abdominal-41%, bone-7%, liver-56%, lung-30%, nodal-52%, subcutaneous-4%, other-19%). Gr 3+ treatment related toxicity was not significantly different by genotype (50%-6/6, 44%-6/7, 20%-7/7, p=0.48) and included (pts): diarrhea(5), vomiting(5), leukopenia(5), neutropenia(7), and nausea(6). 57% (13 of 23) pts achieved responses during therapy, with a confirmed response rate of 39% (95% CI 0-58%). 18 have died, with a median follow-up of 8.3 mos (range 0-43).

Conclusions: UGT1A1 genotype directed dosing with oxaliplatin, irinotecan, and capecitabine appears to result in prolonged response in this population. Larger studies are needed to determine comparability to CapeOx alone or if response/toxicity differs among genotypes. Supported by NIH Grant CA25224, Sanofi-Aventis, and Pfizer.

[Table: see text]
Does age count in pancreatic resection? An Irish experience.
Authors: Connell Louise Catherine , Mulvihill Erica , O'Keeffe Margaret , O'Reilly Seamus , Geoghegan Justin , O'Suilleabhain Criostoir , Power Derek Gerard
Published: February 2017

348

Background: Radical resection offers the only potential cure in pancreas cancer. The majority of patients (pts) are >65 years(yrs) at presentation. Age alone is often a key factor in deciding to resect. The elderly represent 11.5% of the population of Ireland, with an anticipated growth of 26% in the over-65 age group by the end of 2011. Appropriate treatment for elderly potential candidates for pancreatic resection has become increasingly important. We assessed our national experience of pancreatic resection for elderly pts.

Methods: Prospectively maintained institutional databases were retrospectively reviewed for all pts undergoing pancreatic resection from 2006 to 2011, in the 2 specialised pancreas cancer centres in Ireland. Demographic, laboratory, treatment and outcome data were obtained and analysed.

Results: In a single institution,of the 69 pts who had surgery for pancreas neoplasm, 19 (28%) pts were ≥ 70 yrs. Surgical procedures included pancreaticoduodenectomy (n=16, 84%) and double biliary bypass (n=3,16%). Pathologies included adenocarcinoma (AC) (n=16,84%) and NET (neuroendocrine tumour)/IPMN(intraductal papillary mucinous neoplasms) (n=3, 16%). Number of R0 resections was 15 (15/16,94%). Median baseline ECOG was 1 (range, 0-2).There was no perioperative mortality. Median length of hospital stay was 13 days (range,9-50). Thirteen pts who underwent pancreatico-duodenectomy for AC (81%) received adjuvant chemotherapy (with expected toxicities). Ten pts, after pancreatico-duodenectomy and adjuvant therapy had at least 2 yrs follow-up with median overall survival of 21.5 mths (range,12-44). A further 3 pts aged ≥ 80 yrs underwent pancreaticoduodenectomy followed by adjuvant chemotherapy in the past 12 mths, with no peri-operative complications or significant acute chemotherapy-related toxicities. The data set from the second specialised pancreas cancer centre, with similar survival outcomes, is currently being added to provide overall national results.

Conclusions: Age alone should not be a contraindication to pancreatic resection in elderly pts with pancreas cancer. This group can undergo pancreatic resection, with acceptable post-operative morbidity, mortality and overall outcome as evidenced by our national experience.
The utility of PET-CT in predicting malignant potential of GIST.
Authors: Yoshikawa Kozo , Shimada Mitsuo , Kurita Nobuhiro , Sato Hirohiko , Nishioka Masanori , Iwata Takashi , Morimoto Shinya , Miyatani Tomohiko , Goto Masakazu , Kashihara Hideya , Mikami Chie
Published: February 2017

38

Background: The risk category of gastrointestinal stromal tumors (GIST) is usually determined by tumor size and mitotic count. Because of technical complexity and tumor heterogeneity in biopsy, accurate preoperative evaluation of malignant potential of GIST is very difficult. The aim of this study is to evaluate the utility of preoperative PET-CT examination for predicting the malignant potential of GIST.

Methods: Ten patients with GIST who underwent preoperative PET-CT examination were enrolled. They were divided into two groups (low/intermediate-risk or high-risk) by risk category (tumor size, mitotic index). The relationships between the standardized uptake value (SUV) and GIST parameters including the size, mitotic index and Ki67 index were examined.

Results: There was a significant correlation between the mitotic index and the SUV (p=0.029) but tumor size is not correlated with SUV. The SUV was significantly higher in the high-risk group (11.0 ± 3.04) than in the low/intermediate-risk group (2.1 ± 1.5). The Ki67 labeling index was also significantly higher in the high-risk group (8.63 ± 6.2) than in the low/intermediate-risk group (1.75 ± 0.52). There was a significant correlation between the Ki67 labeling index and the SUV (p=0.028). A mitotic index of 5/50 HPF was equivalent to an SUV of 4.3, and a Ki67 labeling index of 5 was equivalent to SUV of 6.3. SUV of 5 can predict the malignant potential between the high and low/intermediate risk.

Conclusions: PET-CT can predict malignant potential. Cases with a high SUV, using a criterion of 5, might have malignant potential.
Clinical and technical validation of a genomic classifier (ColoPrint) for predicting outcome of patients with stage II colon cancer.
Authors: Tabernero Josep , Moreno Victor , Rosenberg Robert , Nitsche Ulrich , Bachleitner-Hofmann Thomas , Lanza Giovanni , van den Akker Jeroen , Roepman Paul , Simon Iris , Salazar Ramon
Published: February 2017

384

Background: Between 25 and 35% of stage II colon cancer patients will experience a relapse of their disease and may benefit from adjuvant chemotherapy. ColoPrint is a gene expression classifier that can predict disease relapse in patients with early-stage colorectal cancer (Salazar et al. JCO 2011).

Methods: ColoPrint was developed using gene expression data from whole genome microarrays and was validated in in-silico datasets and independent patient cohorts from 5 European hospitals. Fresh frozen tissues, clinical parameters, MSI-status and follow-up data for patients were available. Samples were hybridized to Agilent microarrays and the ColoPrint index was determined. Uni-and multivariate analysis was performed on the pooled stage II patient set (n=320) who had a median follow-up of 70 months. Reproducibility and precision studies were performed using clinical and control samples specific for each outcome level (high risk, low risk). Experiments were performed on 20 days with 2 runs per day by multiple technicians reflecting daily diagnostic conditions.

Results: Performance of the prognostic classifier was confirmed in reproducibility and stability assays and stringent quality controls were established. In the clinical validation, ColoPrint classified two-third of patients (209/320) as low risk. The 3-year relapse-free survival was 94% for low risk patients and 79% for high risk patients with a HR of 2.74 (95% CI 1.54-4.88; p=0.006). MSI-status and the number of assessed lymph nodes were the only significant clinical parameters in the univariate analysis. Using parameters from the ASCO recommendation (T4, perforation, less than 12 LN assessed and/ or high grade) for the identification of high risk patients was not significant (HR 1.43, 95% CI 0.81-2.55; p= 0.22) and no clinical parameter added power to the ColoPrint classification in multivariate analysis.

Conclusions: ColoPrint is available as a routine diagnostic test with a high precision and reproducibility. ColoPrint significantly improves the prognostic accuracy of pathologic factors and MSI and facilitates the identification of low risk patients with stage II disease who may be safely managed without chemotherapy.
Prognostic impact of hexokinase and glucose transporter expressions and clinicopathologic features related to F-18-FDG uptake in esophageal cancer.
Authors: Schreurs Liesbeth M , Pultrum Bareld B , Pavlov Kirill , Pruim Jan , Groen Henk , Hollema Harry , Plukker John Theodorus
Published: February 2017

39

Background: Elucidation of prognostic predictors based on biological viability may be useful for a better detection of patients with a high risk of relapse or death from esophageal cancer.

Methods: Maximum standardized uptake values (SUVmax) were measured in the preoperative 18F-FDG positron emission tomography (PET) scans of 47 patients who had a radical esophageal resection without previous treatment. Expression levels of hexokinase-II (HK-II), glucose transporter I (GLUT-I), hypoxia inducible factor-1α (HIF-Iα), vascular endothelial growth factor (VEGF), p53 and the proliferative activity (MIB-I score) were determined immunohistochemically on paraffin-embedded tumor tissue. Correlations and survival functions were calculated to identify independent correlations between FDG-uptake and prognostic expression levels.

Results: High HK-II expression was significantly correlated with reduced SUVmax values (p= 0.002) and HK-II expression was significant higher among adenocarcinomas than squamous cell carcinomas (36/37 vs. 5/9, p= 0.004). The five years survival was significant better for patients with SUVmax≤ 3 in their primary tumors (75% vs. 25%) and a lymph node (LN) ratio ≤0.20 (40% vs. 6%). There were also significant disease free survival benefits for different expression rates of GLUT-I, p53 and MIB (log rank p= 0.03, p= 0.03 and p= 0.04 respectively) in patients with a lymph node ratio >0.20.

Conclusions: FDG-uptake and LN ratio are strong prognostic predictors in patients with esophageal cancer. The level of GLUT-I and p53 expression and the MIB score may be useful prognostic markers that provide information about tumor aggressiviness in esophageal cancer.
Known colorectal cancer susceptibility loci and survival after colorectal cancer diagnosis.
Authors: Phipps Amanda , Garcia-Albeniz Xabier , Hutter Carolyn , White Emily , Fuchs Charles S. , Nan Hongmei , Peters Ulrike , Newcomb Polly A. , Chan Andrew T.
Published: February 2017

394

Background: Beyond clinicopathologic stage, there are few established markers of prognosis in colorectal cancer (CRC). Recent genome-wide association studies have identified 17 germline single nucleotide polymorphisms (SNPs) significantly associated with incident CRC. However, it is unclear if these CRC susceptibility SNPs influence survival after CRC diagnosis. Although the functionality of many of these SNPs remains unknown, a few, including rs4939827 in SMAD7, map to genes with plausible biological mechanisms associated with both cancer risk and prognosis. We examined 17 CRC susceptibility SNPs in relation to survival after CRC diagnosis.

Methods: We genotyped 2,611 men and women enrolled in five prospective cohort studies who were diagnosed with invasive CRC during study follow-up: the Physicians’ Health Study (N=281), Health Professionals Follow-up Study (N=268), Nurses’ Health Study (N=367), Vitamins and Lifestyle Study (N=281), and the Women’s Health Initiative (N=1414). Analyses were limited to Caucasians with known vital status, cause of death, and survival time. We used Cox proportional hazards regression to assess associations between each SNP and CRC-specific and overall survival in study-specific models adjusted for age, sex, and stage; SNPs were modeled additively to reflect associations per copy of the minor allele. Study-specific results were combined via fixed-effects meta-analysis.

Results: The G allele in rs4939827 was associated with poorer CRC-specific survival [hazard ratio (HR)=1.16, p=0.02] and overall survival (HR=1.13, p=0.03) in CRC patients. The A alleles in rs10795668 and in rs4925386 were associated with a 1.14-fold increased risk of overall mortality (both p-values=0.03) but not CRC-specific mortality. Other evaluated SNPs were not associated with survival.

Conclusions: Genetic variation in rs4939827 (SMAD7) is associated with CRC-specific and overall survival. These results suggest that SMAD7 may have a role in CRC progression, and provide proof-of-principle that common germline variation may provide prognostic information beyond traditional considerations such as stage.
DPD deficiency: Medicoeconomic evaluation of pretreatment screening of 5-FU toxicity.
Authors: Traoré Sory , Boisdron-Celle Michele , Hunault Gilles , Andre Thierry , Morel Alain , Guerin-Meyer Veronique , Capitain Olivier , Gamelin Erick
Published: February 2017

410

Background: Deficiency of DPD activity is associated with severe toxicity or even death after the first two cycles 5-fluorouracil (5-FU) based of chemotherapy. The objective of this study was to assess the cost-effectiveness of a screening test before treatment of the deficiency of DPD activity combining two approaches (genetic and phenotype (UH2 / U)). The main measure of effectiveness was the number of avoided severe toxicities (grade 3-4), but the number of quality adjusted life days was the secondary endpoint.

Methods: The analysis was based on retrospective data from a population of patients treated for colorectal cancer. 856 patients were screened (5-FUODPM Tox, ODPM, France) before being treated with adjusted doses (5-FUODPM Protocol, ODPM, France) versus a population of 886 patients treated according to standard doses (2400 mg/m²). The main point of view was society perspective and the time horizon was 2 cycles of chemotherapy. A multi-state Markov-type was used to estimate the mean cost and results for each of the two strategies. The cost of the strategy with screening was composed of the cost of the screening test and the cost of remaining toxicities, the cost of the standard strategy was just the cost of toxicities. The incremental cost-effectiveness ratio (ICER) was calculated: (COSTStandard - COSTWithScreening)/(EffStandard - EffWithScreening) COSTA : Cost of the strategy A, EffA : Effectiveness of the strategy A.

Results: In the screened and adapted arm, the prevalence of severe toxicities at 1 cycle of chemotherapy was 0.5%, at 2 cycles was 0.9%. In the arm with standard doses, they were 5.80% and 6.90%, respectively. Any toxicity associated death was observed in the screened arm versus 1 death in the standard arm. The screening strategy was dominant, it allowed avoiding toxicities and saving money. The avoided cost per patient screened was 313 € for two cycles of treatment and a saving of 2780 € per toxicity avoided. The incremental net benefit (INB) per patient screened is 426 €.

Conclusions: Pre-treatment screening test combining genetic and phenotype reduced the incidence of toxicities associated with 5-FU, it avoided deaths due to 5-FU and its additional cost was less than the cost of care of toxicity that it avoided.
Screening for colorectal cancer in France: Third edition of the EDIFICE survey.
Authors: Viguier Jérôme , Morere Jean F. , Pivot Xavier B. , Coscas Yvan , Blay Jean-Yves , Roussel Claire , Eisinger Francois
Published: February 2017

411

Background: In France, after a pilot population-based screening program (2002-2003), a national organized program targeting 17 million persons was progressively implemented starting in 2005 and generalized after 2009. The EDIFICE 3 survey was conducted in 2011, after EDIFICE 1 (2005) and EDIFICE 2 (2008), to provide a better understanding of the participation of the French population in the colorectal cancer screening program and to assess the evolution between the three periods.

Methods: This third nationwide observational study, EDIFICE 3, was conducted through phone interviews among a representative sample of 1603 subjects aged between 40 and 75years, using the quota method. This analysis focused on the target population of the national screening program (50-74 years old).

Results: In 2011, 59% of subjects between 50 and 74 years (N=946) declared having performed a screening test for colorectal cancer (including fecal test or colonoscopy) versus 38% in 2008 (p<0.05) and 25% in 2005 (p<0.05). Colorectal cancer screening increased significantly in all age groups, especially between 65 and 69 years, and for both sexes. Among the screened population, the recommended interval between two tests was respected in 51% of cases in EDIFICE 3. 62% of unscreened individuals plan to undergo a screening test in the near future. The main factors increasing the probability of screening were: being encouraged by one’s family, the existence of a case colorectal cancer in the family circle, higher frequency of medical consultation, better knowledge of the screening process and being reassured by the screening. The main reasons for not undergoing the screening were: not feeling concerned, fear of exams or results, no recommendation by the GP and carelessness.

Conclusions: The European guideline objective rate of participation for colorectal cancer screening (65%) is not yet reached. This goal could be achieved by motivating the unscreened population already planning to perform a test. The trend for increasing testing will probably be confirmed in the future if the reasons for non-attendance in an organized program are addressed.
Breast cancer in Irish families with Lynch syndrome.
Authors: Jordan E. J. , Farrell M. P. , Clarke R. M. , Kell M. R. , McCaffrey J. A. , Connolly E. M. , Boyle T. , Kennedy M. J. , Morrison P. J. , Gallagher D. J.
Published: February 2017

413

Background: Breast cancer is not a recognised malignant manifestation of Lynch Syndrome which includes colorectal, endometrial, gastric, ovarian and upper urinary tract tumours. In this study we report the prevalence of breast cancer in Irish Lynch Syndrome families and determine immunohistochemical expression of mismatch repair proteins (MMR) in available breast cancer tissue.

Methods: Breast cancer prevalence was determined among Lynch Syndrome kindreds from two institutions in Ireland, and a genotype phenotype correlation was investigated. One kindred was omitted due to the presence of a biallelic MMR and BRCA1 mutation. The clinicopathological data that was collected on breast cancer cases included age of onset, morphology, and hormone receptor status. Immunohistochemical staining was performed for MLH1, MSH2, MSH6, and PMS2 on all available breast cancer tissue from affected individuals.

Results: The distribution of MMR mutations seen in 16 pedigrees was as follows; MLH1 (n=5), MSH2 (7), MSH6 (3), PMS2 (1). Sixty cases of colorectal cancer and 14 cases of endometrial cancer were seen. Seven breast cancers (5 invasive ductal and 2 invasive lobular cancers) and 1 case of ductal carcinoma in situ were reported in 7 pedigrees. This compared with 4 cases of prostate cancer. Six MSH2 mutations and 1 MSH6 mutation were identified in the 7 Lynch syndrome kindreds. Median age of breast cancer diagnosis was 49 years (range 38-57). Hormone receptor status is available on 3 breast cancer cases at time of abstract submission; all were ER positive and HER 2 negative. All cases had grade 2 or 3 tumours. Final results of immunohistochemistry for mismatch repair protein expression on breast cancer samples are pending and will be reported at the meeting. One breast cancer has been tested to date and demonstrated loss of MSH2 protein expression in an individual carrying an MSH2 mutation.

Conclusions: Breast cancer occurred at an early age and was more common than prostate cancer in Irish Lynch Syndrome pedigrees. All reported breast cancer cases were in kindreds with MSH2 or MSH6 mutations. Enhanced breast cancer screening may be warranted in certain Lynch Syndrome kindreds.
Association of interval appendectomy with risk of neoplasm.
Authors: Furman Matthew Jason , Cahan Mitchell , Cohen Philip , Whalen Giles Francis , Lambert Laura A.
Published: February 2017

430

Background: The role of interval appendectomy after conservative management of perforated appendicitis remains controversial. Determining the etiology of perforated appendicitis is one reason to perform interval appendectomies. This study hypothesizes that there is an increased rate of neoplasm in patients undergoing interval appendectomy.

Methods: This is a retrospective review of all patients over 18 years of age who underwent appendectomy for presumed appendicitis from January, 2006 to December, 2010 at a single, tertiary care institution. Demographic data, pathologic diagnosis, clinico-pathologic characteristics, interval resection rate, and complication data were collected and analyzed.

Results: During the study period, 376 patients underwent appendectomy. The mean age was 41 years (range 18 to 94). Interval appendectomy was performed in 18 patients (5.0%) (age 28 to 74). Neoplasms were identified in 14 patients (3.7 %); 6 were found in patients who had undergone interval appendectomy (33%). Nine were mucinous tumors (69.2%), 5 of which were associated with interval appendectomies. Neoplasms were identified in 8.3% of patients between 35 and 55 years old.

Conclusions: Mucinous neoplasms of the appendix were found in 33% of patients undergoing interval appendectomy. Interval appendectomies should be considered in all patients 35 years and older due to increased risk of appendiceal neoplasm.

[Table: see text]
Timing of testing for K-ras mutational status in metastatic colorectal cancer (mCRC).
Authors: Corral Mitra , Sotak Michelle , Chastek Benjamin , Penrod John R. , Cairns Jessica , Williams David A.
Published: February 2017

441

Background: The objective of this study was to examine physician perspectives on K-ras testing in mCRC at two time points: diagnosis of mCRC and after treatment failure.

Methods: Interviews were conducted with 16 oncologists experienced in treating mCRC to obtain information on treatment patterns. Based upon the interview data, a two-round Delphi panel web survey was then used to obtain consensus on specific percentages of patients in a separate sample of 25 oncologists. Both samples were asked to respond to two scenarios: at metastatic diagnosis and after treatment failure.

Results: The majority of interviewed physicians reported that they primarily test at diagnosis of mCRC versus later in treatment. Both the interviewed physicians and Delphi respondents said most patients have a tissue sample available at metastatic diagnosis for K-ras testing (Delphi median 90%, mean 81.2% at diagnosis, 78.8% after treatment failure). For patients without tissue, it was stated that a tissue sample would be obtainable in most patients (Delphi median 90%, mean 87.8% at diagnosis, 85.8% after treatment failure). Of patients with K-ras wild-type mCRC, the Delphi panel estimated that 75-80% would receive an EGFR inhibitor (mean 75.5% at diagnosis, 81.5% after treatment failure, median 80%) while only 0-5% of patients with K-ras mutated mCRC would receive an EGFR inhibitor (mean 4.6% at diagnosis, 5.3% at EGFR decision, median 0%). For a scenario where K-ras information is unknown, the Delphi panel estimated that a small percentage of patients may receive EGFR inhibitors (at diagnosis: mean 12.2%, median 5%; after treatment failure: mean 14.1%, median 0%) although it was noted this is uncommon and many insurers will not cover EGFR inhibitors without K-ras status.

Conclusions: Current guidelines for mCRC recommend that K-ras testing be conducted as part of the diagnostic workup. In this study, two samples of oncologists reported that the majority of patients they treat are tested for K-ras mutations at metastatic diagnosis rather than later in therapy. Both samples reported minimal use of EGFR inhibitors in patients with K-ras mutated mCRC or patients with unknown K-ras status, consistent with clinical guidelines and many insurance policies.
Colorectal cancers in United Arab Emirates nationals: The Sheik Khalifa Medical Center's experience.
Authors: Dehni Nidal , Al Hassani Ali , Nimeri Abdulrahman
Published: February 2017

442

Background: Previous reports suggested that colorectal cancers (CRC) appear at younger age in the United Arabs Emirates (UAE). However, these reports included nationals and expatriates in their analysis with heterogeneous population leading to biased analysis. our objective was to determine age and stage of disease in newly diagnosed UEA nationals with CRC treated at one major referral hospital in Abu Dhabi (SKMC)

Methods: Charts of all patients diagnosed and/ or treated for CRC at SKMC between January 2000 and May 2011 were reviewed. Ultimately, only UEA nationals with diagnosis of adenocarcinoma of the colon and rectum were retained for further analysis.

Results: Two hundreds six patients were diagnosed at SKMC as having colon or rectal carcinomas. Ninety two were expatriates and in 10 out of 113 nationals, the final diagnosis was squamous or adenosquamous carcinoma leaving 103 patients forming the population of this study. Median age was 57(10-100 years), with 59 men. The patient’s condition necessitated emergency operation in 38 and 15 either refused or were unfit for treatment mainly because of very advanced disease or severe co morbidity. The tumor location was: sigmoid: 46%, rectum: 33:, right colon :17% and 4% for descending and transverse colon. The stage of the disease was I; 4 pts, II: 16 pts, III 25 pts, IV in 49 pts and undetermined in 7. Resection was curative for 46 pts, palliative in 45, unknown in 10 and 2 refused surgery. Fifty one patients had their treatment essentially at SKMC and the others were treated both at SKMC and abroad. Average follow-up was 2 years and at last FU 39 were confirmed deceased, 29 were alive and the outcome in the remaining was unknown.

Conclusions: UAE nationals with CRC presenting to our facility have relatively young age but presented with stage IV disease in half of the cases. Screening program for this population is warranted. Because a substantial number of patients had had their treatment abroad, rigorous follow-up and cancer outcome assessment was unreliable.
Phase II study of EZN-2208 (PEG-SN38) with or without cetuximab in patients with metastatic colorectal cancer (CRC).
Authors: Goldberg Richard M. , Garrett Chris R. , Berkowitz Noah C. , Bekaii-Saab Tanios S. , Ryan Theresa , Fisher George A. , Clive Sally , Kavan Petr , Shmueli Einat , Buchbinder Aby
Published: February 2017

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Background: EZN-2208 is a water-soluble, parenterally-delivered PEGylated conjugate of SN38 that increases solubility, exposure, and apparent half-life of SN-38.

Methods: Patients with metastatic or locally recurrent CRC previously treated with fluoropyrimidines, oxaliplatin and irinotecan, and no more than 2 distinct progressions, were screened for K-Ras mutation and stratified accordingly. Patients with K-Ras tumor mutation (Mut) were treated with EZN-2208 (9mg/m2 SN-38 equivalents) over 1-h IV on days 1, 8, 15 in 4-wk cycles (Arm A). Patients with K-Ras wild type (WT) tumors were randomized (2:1) to EZN-2208 (as above) and cetuximab (250mg/m2 weekly following 400mg/m2 on D1) (Arm B) or to irinotecan (125mg/m2) over 90min IV days 1, 8 in 3 week cycles and cetuximab (as above) (Arm C). The primary objectives of the study were to determine the overall response rates (ORR) and progression free survival (PFS) (Arm A) and compare PFS (Arms B and C). A comparison of safety and toxicity of EZN-2208 and irinotecan was planned as well.

Results: Demographic and efficacy parameters are summarized in the table . Common adverse events (Arms A%, B%, C%), observed in > 25% of patients in at least one arm of the study, were diarrhea (45%, 64%, 55%), fatigue (56%, 56%, 39%), nausea (43%, 59%, 47%), vomiting (31%, 46%, 39%), constipation (27%, 26%, 37%), abdominal pain (25%, 28%, 32%), anemia (33%, 21%, 21%), dermatitis acneiform (0%, 28%, 26%), hypokalemia (17%, 28%, 26%), and alopecia (12%, 28%, 3%).

Conclusions: EZN-2208 in combination with cetuximab is active in patients in the 3rd line setting of CRC and comparable to irinotecan in combination with cetuximab. EZN-2208 monotherapy did not result in responses in patients with CRC following progression on irinotecan. EZN-2208 has an acceptable safety and tolerability profile as monotherapy, and in combination with cetuximab.

[Table: see text]
Circadian robustness as an independent predictor of prolonged progression-free survival (PFS) and overall survival (OS) in 436 patients with metastatic colorectal cancer (mCRC).
Authors: Levi Francis , Parganiha Arti , Karaboué Abdoulaye , Innominato Pasquale F. , Giacchetti Sylvie , Garufi Carlo , Dispersyn Garance , Focan C. N. J. , Iacobelli Stefano , Bjarnason Georg A , Moreau Thierry , Dugue Pierre Antoine , Waterhouse Jim ,   ARTBC International Chronotherapy Group
Published: February 2017

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Background: The rest-activity rhythm is a biomarker of the circadian timing system (CTS), whose disruption accelerates cancer progression in experimental models. Prior studies in cancer pts identified a reliable measure of CTS function in cancer pts based on non invasive wrist actigraphy monitoring.

Methods: The prognostic value of I48 h in 436 mCRC pts from 3 international cohorts. Data were stratified per cohort, and analyzed with Kruskall-Wallis ANOVA, log rank tests, and multivariate Cox analyses.

Results: Median age was 59.2 y. Pts were mainly men (62.6%); had good performance status (PS = 0, 58.2%; 1, 33%); > 2 metastatic sites (51.6%); metastases in liver (79%) or lung (38.8%); were chemotherapy-naïve (54.6%). After baseline actigraphy recording, pts received a median of 8 courses of oxaliplatin- or irinotecan-based chemotherapy, including chronomodulated schedules (chrono; 81.4%). Despite a strong correlation with PS (p< 0.0001), I<O independently influenced both PFS and OS. Thus, both median PFS and OS nearly doubled in the pts with I<O above 97.5% (upper two quartiles) as compared to those with I<O below 93.2% (lowest quartile). Median PFS ranged from 4.8 to 10.6 months (log rank, p<0.001) and median OS from 10.1 to 20.6 months (p<0.001). In multivariate analyses, I<O ranked as the second best independent predictor of PFS, after metastases surgery, with a hazard ratio (HR) of 0.967 [95% C.L., 0.95-0.98] (p<0.001). I<O ranked as first independent predictor of OS, with a HR of 0.95 [0.94-0.97] (p<0.001). Forrest plots revealed consistent HR of I<O for PFS and OS in each cohort.

Conclusions: The circadian biomarker indicator I<O is a robust, consistent and independent quantitative predictor of both PFS and OS in mCRC pts. Rest-activity rhythm monitoring deserves further testing for helping accurate determination of mCRC prognosis. The biological significance of I<O implies that specific treatments of circadian disruption could enhance survival in cancer pts.
Is there a clinical benefit in testing for UGT1A1*28 prior to irinotecan therapy?
Authors: Kularatne Bihani Yoshana , Marinaki Anthony , Karavasilis Vasilis , Spicer James F. , Ross Paul J. , Pectasides Dimitrios G. , Makatsoris Thomas , Pentheroudakis George E. , Fountzilas George
Published: February 2017

478

Background: Irinotecan is used in the treatment of colorectal cancer, with severe neutropenia and diarrhoea being the main dose limiting toxicities. UGT1A1 variants have been shown to predict irinotecan associated toxicity. Despite an FDA warning in 2005, few centres have undertaken UGT1A1 testing prior to the commencement of therapy. The reason for this has been the lack of consistent data supporting its use as a marker of either neutropenia or diarrhoea. Where significance has been shown, sample sizes have been small and confidence intervals wide.

Methods: We retrospectively correlated the presence of UGT1A1*28 polymorphism with severe neutropenia or diarrhoea in Greek patients receiving irinotecan-based chemotherapy for metastatic colorectal cancer. Severe (grade 3 or 4) neutropenia or diarrhoea (Common Terminology Criteria version 4) for cycles 1-4 were recorded for all patients using electronic case notes. Patients were genotyped for UGT1A1*28 polymorphism.

Results: Of the 362 patients evaluated, 205 (56.6%) received irinotecan (180-255 mg/m2, 3 weekly) in combination with capecitabine and 155 (42.8%) received irinotecan (160-200 mg/m2, 2 weekly) in combination with 5-FU. Forty four (12%) patients experienced severe diarrhoea and 19 (5%) severe neutropenia. Clinical response data was unavailable in 162 (45%) patients. A favourable radiological response (stable disease, partial or complete response) was seen in 170/200 (85%) patients. A homozygous UGT1A1*28 genotype was detected in 38/362 patients. Of these, three (8%) experienced grade 3 or 4 diarrhoea during cycles 1-4 and three (8%) experienced severe neutropenia. There was no statistically significant correlation between genotype and toxicity in this patient group.

Conclusions: Our study of a Caucasian group of Greek patients, the largest study to date, failed to show any correlation with UGT1A1*28 polymorphism and the occurrence of grade 3 or 4 neutropenia or diarrhoea. The results of this study suggest that testing for the UGT1A1*28 mutation prior to the start of irinotecan therapy may not be clinically useful.
Discovering pathways in the tumor microenvironment important for recurrence-free survival in patients with colorectal liver metastasis.
Authors: Rhodes Terence Duane , Morse Michael , Lyerly H. Kim , Nevins Joseph R. , Clary Bryan M. , Hsu Shiaowen David
Published: February 2017

480

Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Curative treatment for CRC liver metastasis can be achieved by surgical resection, but 5 year survival ranges between 20-40%. Current treatment strategies to prevent recurrences after resection of CRC liver metastases have focused on the use of chemotherapy cytotoxic to malignant epithelial cells of the tumor. However, stromal components within the tumor microenvironment have recently been implicated as contributors to the aggressiveness of the malignancy. We hypothesized that genomic based signatures associated with tumor stroma would be prognostic for recurrence after CRC hepatic metastasectomy.

Methods: Thirteen independent CRC liver metastatic samples were subjected to laser-capture microdissection to isolate the tumor epithelium and tumor-associated stroma separately. Microarray analysis using class neighbors and gene set enrichment analysis (GSEA) was applied to the stromal mRNA to identify differentially expressed genes and pathways between samples from patients with early recurrence (<1yr) after resection (Group R) and those who remain disease free (>2yrs) (Group NoR).

Results: Class neighbor analysis revealed a greater number of genes associated with immunity and cell to cell adhesion in Group R compared to Group NoR (p<0.05). Using GSEA, gene sets associated with T-cell immunity, Wnt pathway, and homeostasis were enriched in stroma Group R when compared to stroma Group NoR (p<0.05).

Conclusions: These findings suggest several pathways are prognostic for recurrence of CRC liver metastasis. Development of stroma-directed therapy combined with tumor-directed therapy in preclinical models could hold the promise of major advances in the treatment of colorectal cancer liver metastasis in order to improve the clinical outcomes of these patients.