bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating tumor cells as a possible prognostic tool in newly diagnosed nonmetastatic colorectal cancer?
Authors: Scholten Loes , Terstappen Leon W. M. M. , van der Palen Job , Mastboom Walter , Tibbe Arjan , Vermes Istvan , de Groot Marco
Published: February 2017

395

Background: The presence of circulating tumor cells (CTC) is associated with poor prognosis in patients with metastatic colorectal cancer (CRC). The current study was conducted to determine if the presence of CTC prior to surgery in patients with newly diagnosed non-metastatic CRC can identify those patients at risk for disease recurrence.

Methods: In a prospective single center study 180 patients with newly diagnosed non-disseminated CRC scheduled for surgery were enrolled and followed up for a median of 41 months. CTC were enumerated with the CellSearch System in 4 aliquots of 7.5 ml of peripheral blood before undergoing surgery. The control group consisted of sixty patients with benign tumors after surgery or colonoscopy.

Results: ≥1 CTC/ 30ml of blood were detected in 9 (15%) persons of the control group, and in 41 (23%) CRC patients. From the 180 CRC patients, 44 developed recurrent disease (24%) and 38 patients (21%) died during follow up. Presence of CTC correlated with disease recurrence (p= 0.040) and death (p=0.006). Patients with CTC had a significantly decreased three year Disease Free Survival (DFS) and overall survival (OS) versus those without CTC (DFS 57%vs. 78%, p=0.018 and OS 70% vs. 80%, p=0.003%).

Conclusions: Patients with stage I-III CRC with CTC before surgery have a significantly lower 3 years DFS and OS. These findings warrant further development of technology to increased the sensitivity and specificity of CTC detection for incorporation as prognostic marker along side Duke Stage to assess which patients need adjuvant treatment.
Epidemiology of rectal and small intestinal carcinoids: Two distinct tumors?
Authors: Taghavi Sharven , Jayarajan Senthil N. , Gaughan John P. , Willis Alliric Isaac
Published: February 2017

399

Background: Gastrointestinal carcinoids (GIC) are most commonly found in the small intestines. However, in this era of screening colonoscopy, the incidence of rectal carcinoids (RC) is increasing. The aim of this study was to determine if differences exist between the two most common carcinoid tumors.

Methods: Small intestinal and rectal cancers were reviewed from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute from 2000-2007. Factors reviewed included age, gender, ethnicity, and survival.

Results: 12,931 small intestinal cancer tumors included 4,731 (36.6%) small intestinal carcinoids (SIC). 57,850 rectal cancer tumors included 4,550 (7.9%) RC. Comparing RC and SIC, RC presented at a younger age (56.2 vs. 64.5 years, p<0.001). RC were more common among women (50.6 vs. 47.0%, p<0.001). The ethnic distribution of SIC and RC were significantly different. SIC were more common among Whites (W) (76.0 vs. 51.0%) while RC were more common among each ethnic minority group: Blacks (B) (19.9 vs. 14.3%), Hispanics (H) (13.0 vs. 6.5%), Asians (A) (14.9 vs. 2.7%), and American Indians/Alaskans (AI) (1.1 vs. 0.4%); p<0.001. RC were more common than SIC among women for every ethnic group (percentage of patients who are women W 48.1 vs. 46.8%, B 59.3 vs. 50.6%, H 50.3 vs. 44.3%, A 46.5 vs. 41.1%, AI 72.0 vs. 47.1%), although this reached significance in only Black females (p=0.001). Mean survival was better in RC (93.4 vs. 65.8 months, p<0.001) by Kaplan-Meir analysis.

Conclusions: This study demonstrates that SIC and RC are epidemiologically distinct tumors with different presentations and outcomes. Minority groups and females are more likely to present with RC. In addition, RC have better prognosis. Further studies are needed to investigate potential biological differences between these two tumors.

[Table: see text]
How many biopsy fragments will be necessary to assess HER2 status for gastric cancer?
Authors: Shinozaki Eiji , Yamamoto Noriko , Chin Keisho , Ogura Mariko , Suenaga Mitsukuni , Matsusaka Satoshi , Mizunuma Nobuyuki , Yamaguchi Toshiharu , Hatake Kiyohiko
Published: February 2017

40

Background: Trastuzumab (T) has been shown to confer overall survival benefit adding to capecitabine or 5-FU and CDDP in HER2-positive advanced gastric cancer in ToGA study. Data from the study, overexpression of HER2 according to immunohistochemistry (IHC) has been confirmed as potential responders. HER2 scoring is essential to decide the strategy of the personalized therapy with T. There are some differences in details to assess HER2 score between surgically resected materials and the biopsy fragments. Moreover it is not unclear how many biopsy fragments will be necessary to assess HER2 status. In this study we attemped to prove the optimal biopsy for HER2 scoring of gastric cancer.

Methods: HER2 status was evaluated in 30 cases who were scored HER2 as 3+ and 44 cases who were selected for reference as HER2 score of 2+, 1+, 0 in previous tests of surgical specimens. In total 74 cases of 232 biopsies we investigated HER2 protein expression by IHC using HercepTest (DAKO) and assessed according to Gastric Cancer Scoring System. We analyzed the concordance of HER2 score between surgically specimens and the biopsy fragments.

Results: Average numbers of biopsy fragments were 3.13(1-6)/case. The concordances between surgical specimens and biopsy specimens were 80.0% in HER2 3+ group of surgical specimens, 47.8% and 47.6% in HER2 2+ and 1+ or 0. The concordances per each biopsy were 73.5%, 34.7% and 69.1%, respectively. Both concordances in HER2 positive group were significant higher than those in HER 2 negative or equivocal groups. There were not statistic differences of the concordances between 3 or less fragments of biopsy and 4 or more.

Conclusions: Our data suggested in HER2 score 3+ according to surgical materials, the concordance of HER2 scoring between surgically resected materials and the prior biopsy specimens was high and at least 3 fragments were seemed enough to assess whether IHC HER2 is positive in biopsy. Other hands in HER 2 negative or equivocal groups, the concordances were low.
Is elevated preoperative CEA level a significant predictor for decreased overall survival in patients with stage I to III rectal cancer?
Authors: Guller Ulrich , Koeberle Dieter , Warschkow Rene , Schmied Bruno , Cerny Thomas , Tarantino Ignazio
Published: February 2017

403

Background: The objective of the present investigation was to assess whether elevated pre-operative CEA level represents a significant predictor for decreased overall survival in stage I-III rectal cancer patients.

Methods: The present study is based on the colorectal database of the authors` hospital, one of the largest tertiary care centers of Switzerland. All patients undergoing a resection for stage I - III rectal cancer were consecutively included between 1991 and 2008. Average follow-up time was 50.3 months. The impact of pre-operative CEA on overall survival was assessed in Cox proportional hazard regression analyses after risk-adjusting for age, gender, body mass index, performance status, tumor stage, tumor distance from the anal verge, and neoadjuvant treatment. Pre-operative CEA levels were classified as normal (< 5 µg/liter) versus elevated (>5 µg/liter). All tests were two-sided, the level of statistical significance was set at 0.05.

Results: Overall, 534 consecutive patients undergoing resection for stage I - III rectal cancer were included. Median age was 65 years (range 24 to 91 years), 62% of patients were male, median ASA was II (range I – IV), median body mass index 25.3 kg/m2 (range 15.4 to 44.9 kg/m2). Pre-operative CEA levels were elevated in 21.7% of all patients. After risk-adjusting in Cox proportional hazard regression analyses pre-operative CEA level (p<0.001; odds ratio: 2.020), distance from the anal verge <5cm (p<0.001, odds ratio: 2.434), older age (p<0.001; odds ratio: 1.069) and higher tumor stage (p=0.004, odds ratio: 2.003) were all significant predictors for poor overall survival. Forward- and backward variable selection including bootstrap analyses confirmed these results.

Conclusions: The present investigation based on a large cohort of consecutive stage I – III rectal cancer patients provides compelling evidence that elevated pre-operative CEA level is a strong predictor of decreased overall survival even after risk-adjusting in Cox proportional hazard regression analyses. Therefore, it is crucial that pre-operative CEA is used as a prognostic factor in the pre-operative assessment of stage I-III rectal cancer patients.
Lymphatic metastasis in well-differentiated appendiceal cancer: Prognostic factors and associations with outcome.
Authors: Hill Joshua S. , Rafeeq Safia , Katz Matthew H.G. , Overman Michael J. , Lambert Laura A. , Royal Richard E. , Mansfield Paul F. , Fournier Keith F.
Published: February 2017

406

Background: Well-differentiated appendiceal adenocarcinomas (WDAA) are rare tumors characterized by peritoneal spread. Lymph node metastasis can occur, yet the association between nodal spread and recurrence is poorly understood.

Methods: A single institution retrospective review of patients seen between August 1993 and January 2010 with a pathologic diagnosis of WDAA who underwent colectomy was conducted. Patients with zero lymph nodes found during pathologic review were excluded. Parameters evaluated included demographics, presence of lymph node metastasis, completeness of cytoreduction and time to recurrence.

Results: Of 688 patients with appendiceal neoplasms, 160 (23.3%) had WDAA. The mean age at diagnosis was 50.7 years and 81 (50.6%) were male. Median follow-up after diagnosis was 58.5 months. One hundred patients (62.5%) had regional or distant metastasis present at the time of colectomy. Seventy-eight (48.8%) colectomies were performed at outside institutions. The median number of nodes examined was 12. Twelve patients (7.5%) were found to have nodal metastasis. The rate of peritoneal metastasis did not correlate with the presence of nodal metastasis (node positive 9/12, 75% versus node negative 91/148, 61.5%; p=0.35). No difference in the ability to perform complete cytoreduction existed for those with and without nodal metastasis (66% versus 51% p=0.19). Examining patients with complete cytoreduction and ≥ 12 months of follow-up, there was an increased risk of recurrence among patients with lymphatic metastasis compared to those without (5/8, 62.5% versus 15/61, 24.6%; p=0.03). In this subset, median disease-free-survival in lymph node positive patients was 53 months compared to 109.1 months in patients without nodal metastasis (p=0.08).

Conclusions: Patients with WDAA tumors have an overall favorable prognosis; however, patients with lymph node metastasis appear to have an increased risk of recurrence and apparent shortened disease free survival. Right colectomy may be warranted in this patient population.
Evaluation of the role of UGT1A1 genotype testing in colorectal cancer patients administered irinotecan and the occurence of grade 3 and 4 neutropenia.
Authors: Patel Sushma M. , Chan Jim , Hui Rita L. , Spence Michele M.
Published: February 2017

412

Background: Irinotecan is metabolized primarily in the liver by the carboxylesterase enzyme to the SN-38 active metabolite and is then inactivated through conjugation by the UGT1A1 enzyme, a polymorphic enzyme. Individuals genotyped with the homozygous allele have an increased risk for grade 3 and 4 neutropenia.

Methods: A retrospective cohort analysis was conducted in the Kaiser Permanente California regions. The study period was November 1, 2005 to July 1, 2010 and included patients that were 18 years of age or older, newly initiated on irinotecan for colorectal cancer and had no previous irinotecan therapy within six months of the initiation dose. Patients were excluded if they were enrolled in clinical trials, on granulocyte-colony stimulating factor prophylaxis, and genotype tested for UGT1A1 and subsequently not treated with irinotecan. Patients tested with the UGT1A1 assay were grouped according to their genotype results: wild-type, heterozygous, or homozygous*28. The incidence of grade 3 and 4 neutropenia were compared among patients tested for UGT1A1 variant alleles by their genotype results.

Results: A total of 305 (28%) patients were tested with the UGT1A1 assay with a mean age of 62 (+/- 12) years, and 52% of the population female. There were 161 (53%) wild-type, 123 (40%) heterozygous, and 21 (7%) homozygous patients. The median irinotecan dose was 150 mg/m2 (124-180 mg/m2) and median number of irinotecan cycles were 6 (3-12). The wild-type, heterozygous, homozygous*28 population had a 21% (33/161), 24% (29/123), and 48% (10/21) rate of grade 3 and 4 neutropenia. When the homozygous*28 group was compared to the heterozygous and wild-type genotype the adjusted Cox Proportional Hazard was 3.05 (95% CI, 1.55-5.99), p = 0.001. The Kaplan-Meier Log Rank Test yielded a p-value of 0.002.

Conclusions: The adjusted risk for homozygous genotyped patients was three times higher compared to the wild-type and heterozygous group for grade 3 and 4 neutropenia. Additional investigational studies examining the benefits of UGT1A1 genotyping as a prognostic test and further effect of dosage adjustments in UGT1A1*28 homozygous initiated on irinotecan therapy are needed.
A new strategy for the early detection of colorectal cancer recurrence.
Authors: Motamed-Khorasani Afsaneh , Small-Howard Andrea Lee , Etemadi Hooman
Published: February 2017

416

Background: Several biological markers have been tested for colorectal cancer (CRC) including CEA; however, they are of limited use for recurrence diagnosis due to low sensitivity. Almost 50% of CRC cases experience recurrence and more than 50% of them have low values not detectable by CEA. Therefore, an effective marker for detection of recurrence will vastly increase the quality of life and survival rate. Onko-Sure is an FDA-cleared blood test that is used for the monitoring of treatment/recurrence of CRC. This ELISA assay measures the accumulation of Fibrin/Fibrinogen Degradation products in the serum using an antibody against the DR-70. The goal of this study was to determine whether the combined usage of DR-70 and CEA will improve the sensitivity for detecting recurrences.

Methods: A total of 75 serum samples were retrospectively recruited through a serum bank in two arms including the confirmed healthy control (n=39) and biopsy-confirmed recurrent CRC (n=36) groups. For each patient, the serum sample was tested for DR-70 and CEA concentrations.

Results: The results showed sensitivity of 75% and specificity of 58.97% for DR-70 and CEA combined. The cut points were calculated as 1.3ug/ml for DR-70, and 3 or 5ng/ml for CEA for non-smokers and smokers; respectively. For the combined analysis, if either CEA or DR-70 was positive, the test was considered positive and if both tests were negative, the result was considered negative. The sensitivity for the combined test was much better than that of each of the markers alone (35% higher than that of CEA).

Conclusions: The combined usage of DR-70 and CEA in monitoring of CRC recurrence showed a significant clinical advantage in terms of sensitivity over each marker alone. Improvement in detection of recurrence has important implications to patient treatment options and prognosis. Should an IVD increase early detection of CRC recurrence when used adjunctively with other available diagnostic markers, the annual deaths due to CRC recurrence could be reduced due to the increase in early detection and the survival rate of those early detections.
Rapid screening of SNPs in metastatic colorectal cancer (mCRC) utilizing multiplex sequencing technology (Sequenom).
Authors: Maitra Radhashree , Nayak Jay B. , Basu-Mallick Atrayee , Sood Arjun , Augustine Titto A , Mariadason John , Reynolds David M , Goel Sanjay
Published: February 2017

418

Background: Accurate and fast screening of mutations is essential for designing individualized therapy necessary and critical for efficient disease management and better patient outcome in mCRC. Detection of hotspots by gold standard direct sequencing (DS) is time consuming and cost ineffective. Pyrosequencing (PS) technique is rapid and precisely committed towards SNP detection. Recent introduction of high throughput multiplex PCR based extension on microarray (Sequenom, SEQ) offers a robust platform capable of detecting multiple SNPs simultaneously in a rapid and cost effective manner. The current study analyzes the concordance and efficacy of the cutting edge SEQ technique to the well established DS and PS methods.

Methods: DNA isolated from 122 specimens from 76 mCRC patients were sequenced by all three methods. DS and PS were performed on 4 genes at 10 hotspots. SEQ multiplexing was performed on 31 hotspots in 19 genes by 4 multiplex reactions.

Results: We were able to make "calls" for all samples by DS and PS. With the multiplex system, the “calls” rate was 97.8% of successful reactions. Using PS data as our standard in the assay we calculated the percent concordance of DS and SEQ. Futhermore SEQ offered a more accurate identification of the substituted nucleotide in Kras codon 12 as compared to PS.

Conclusions: The multiplexing of PCR reactions offers an excellent advantage of high throughput with strong feasibility of analyzing several samples for multiple SNPs simultaneously. The concordance rate of > 90% when compared to PS along with the ability to analyze multiple samples/ hotspots plexed together in a time effective rapid mode provided a trifold advantage of the sequenom technology. It is therefore the next generation technology for rapid genetic evaluation of cancer patients.

[Table: see text]
Incidental colonic 18F-FDG uptake in gastric cancer patients: Correlation with colonoscopic and histopathologic findings.
Authors: Song Kyo Young , Shim Jung Ho
Published: February 2017

43

Background: The ability of integrated positron emission tomography and computed axial tomography (PET-CT) to detect synchronous colonic pathology in gastric cancer patients is not fully defined.

Methods: Between Jan 2009 and July 2010, total 370 patients diagnosed as primary gastric cancer underwent curative resection in our institution. Among them 147 patients had taken PET-CT and colonoscopy preoperatively. The FDG uptake pattern were reviewed and classified as focal (showed foci of FDG uptake>3.5 SUV max), diffuse (showed FDG uptake<3.5 SUVmax without any foci of uptake) and absent uptake (showed no FDG uptake pattern). Patients with history of known colonic malignancy or colon surgery were excluded.

Results: Among the 18 patients who had discovered as focal incidental FDG uptake in colon without any previous colonic pathology, in six patients, has revealed unexpected colonic adenocarcinoma. The mean SUVmax value of focal uptake group(Group A) is 7.3 (±2.3), for those six patients, it was 9.4 (±2.9,p=0.02). And in the diffuse uptake group, most common colonic pathology was tubular adenoma with low grade dysplasia following hyperplastic polyp. The age, gender and primary gastric cancer stage was not differed between the groups.

Conclusions: In conclusion, the focal uptake pattern in colon on preoperative PET-CT in gastric cancer patients should be followed by colonoscopy evaluation for incidental significant colonic pathology even colon cancer. However, there was no cut off SUVmax value for the mandatory colonoscopy evaluation based on PET-CT.
Pharmacoeconomic analysis for K-Ras status–based decisions for first-line therapy of metastatic colorectal cancer (mCRC) in Spain.
Authors: Belda Cristobal
Published: February 2017

438

Background: Personalized medicine is a challenge for current oncology practice. Nowadays there are no pharmacoeconomic analyses in Spain dealing with the clinical and financial impact secondary to K-Ras based decisions for first-line therapy in mCRC patients. So, this study was aimed to assess the cost- effectiveness of K-Ras status based decisions in first- line therapy of mCRC patients in comparison with non- K-Ras based selection of available therapies.

Methods: K-Ras mutation prevalence and efficacy of available therapies (measured as response rate and progression free survival) were extracted from randomized clinical trials (RCT) that allowed on-label use of accessible drugs in Spain. Then, we have simulated all possibilities of combination therapies for first-line mCRC based on K-Ras status (wild- type vs mutated) and confronted with all therapies that could be chosen in absence of K-Ras analysis. Prices for all drugs in Spain were used to assume the best- value for each drug including all possibilities to reduce pharmacy costs. For first line, median duration of therapy reported by RCT was used to calculate the final budget. 70 kg and 1.7 m were used as reference for patients dose calculations.

Results: First-line therapy that includes a biological drug in absence of K-Ras status based decisions implies an incremental cost per 1% of increased response rate of 1,237 euros for irinotecan based doublets and 3,193 euros for oxaliplatin based doublets. On the opposite, K-Ras based decisions reduce costs per objective response by 69% and 35% for irinotecan and oxaliplatin- based schedules in K-Ras wild-type population incorporating cetuximab as biological agent. These data mimic all calculi based on incremental costs secondary to improved progression free survival measured as HR when all scenarios without prior determination of K-Ras status were confronted with K-Ras based decisions.

Conclusions: K-Ras based decisions reduces costs per objective response as well as per improved progression free survival. The most cost- effective scenario among all simulated was cetuximab in combination with chemotherapy for patients that harbor wt K-Ras mCRC.
A comprehensive analysis of clinical and tumor characteristics with BRAF and KRAS mutations status in adjuvant colon cancer trial N0147.
Authors: McWilliams Robert R. , Mahoney Michelle R. , Sargent Daniel J. , Nelson Garth D. , Sinicrope Frank , Limburg Paul J , Thibodeau Stephen N. , Grothey Axel , Hubbard Joleen Marie , Alberts Steven R.
Published: February 2017

446

Background: MutKRAS and mutBRAF are important predictive and prognostic markers, respectively, in colorectal cancer (CRC). However, little is known about why some tumors harbor these mutations. N0147 is a phase III adjuvant trial for stage III CRC patients (N=3397) in which patients completed questionnaires and tumor variables and KRAS/BRAF mutation status was assessed.

Methods: 2,323/3,397 patients who were enrolled prior to a 2008 amendment requiring KRAS testing completed a Patient Questionnaire. Primary tumors were assessed for mutKRAS and mutBRAF using standard methods; MMR status was determined using IHC. Multivariate analysis was performed to identify predictors of mutation status.

Results: 60% and 86% of mutKRAS and mutBRAF tumors were right-sided, respectively. MutKRAS was less likely if there was a family history of CRC and in ever-smokers, and was nearly mutually exclusive with mutBRAF. MutBRAF was associated with deficient MMR (dMMR), high grade histology, and 4+ positive lymph nodes at surgery. MutBRAF was more likely in patients age > 70, retired persons, ever-smokers, but was less likely in non-whites and men.

Conclusions: Smoking, family history of CRC, and dMMR status are associated with lower frequency of mutKRAS , but higher mutBRAF. Both mutations tend to be right sided, and mutBRAF is more common in the elderly, females, and non-Hispanic whites.

[Table: see text]
Correlation of activated AKT and MAPK expression in liver metastases with clinical outcome in colorectal cancer patients receiving irinotecan/cetuximab treatment.
Authors: Scartozzi Mario , Giampieri Riccardo , Mandolesi Alessandra , Maccaroni Elena , Del Prete Michela , Faloppi Luca , Bittoni Alessandro , Bianconi Maristella , Galizia Eva , Silva Rosa Rita , Giustini Lucio , Zaniboni Alberto , Labianca Roberto , Bearzi Italo , Cascinu Stefano
Published: February 2017

449

Background: An aberrant activation of the EGFR downstream signaling pathway via MAP-kinase and Akt could be responsible for resistance to anti-EGFR treatment. We tested the interaction between phosphorylated Akt and MAPK in primary colorectal tumours and corresponding metastases and clinical outcome in terms of response rate (RR), progression free survival (PFS) and overall survival (OS) to identify a group of patients more likely to benefit from EGFR-targeted treatment among those harbouring a K-RAS wild type status.

Methods: Seventy-two advanced K-RAS wild type colorectal cancer patients treated with irinotecan-cetuximab were analysed. Primary tumour were available in all cases, whereas paired tumour samples from metastatic sites were available in 37 patients. Phosphorylated Akt and MAPK were analyzed by immunohistochemistry.

Results: Akt resulted overexpressed in 31 primary tumours (43%) and 23 metastases (62%), whereas MAPK was over-expressed in 32 primary tumours (44%) and 20 metastases (54%). Akt altered expression in primary tumours correlated with a statistically significant worse median PFS (2.4 months vs. 6.5 months, p= 0.0006) and OS (7.8 months vs. 26.7 months, p < 0.0001), without any significant correlation with RR. No significant correlation could be found between MAPK expression in primary tumours and RR, PFS or OS. In metastases Akt expression correlated with RR (9% vs, 58%, p= 0.004), PFS (2.3 months vs.9.2 months p < 0.0001) and OS (6.1 months vs.26.7 months p < 0.0001). Analogously MAPK expression in metastases correlated with RR (10% vs, 47%, p = 0.002), PFS (2.3 months vs.8.6 months p < 0.0001) and OS (7.8 months vs.26 months p = 0.0004). At multivariate analysis Akt and MAPK status in metastases was able to independently predict PFS. Akt status in metastases independently correlated with RR as well.

Conclusions: We suggest that Akt and MAPK expression in metastases may have a relevant role in determining the activity of anti-EGFR treatment strategies. Our observations seem also to indicate that for some molecular determinants of resistance the biological profile in metastases is prominent.
Significance of neuroendocrine component in mixed adenoneuroendocrine neoplasms.
Authors: Chen Ming-Huang , Kuo Ying-Ju , Yeh Yi-Chen , Huang Pin-I , Li Chung-Pin , Chao Yee
Published: February 2017

45

Background: Mixed adenoneuroendocrine carcinoma (MANEC) and adenocarcinoma with neuroendocrine differentiation (ADC-NE) are tumors with divergent exocrine and neuroendocrine differentiation. These tumors display variable quantitative extent of the two components. Some studies reported the extent of two components in primary tumor and lymph node are not always the same. The aim of our study is to analyze the neuroendocrine component in primary tumor, angiolymphatic invasion and metastatic lymph nodes.

Methods: Tumor histology of 15 patients with MANEC or ADC-NE was evaluated in this study. Neuroendocrine component was confirmed by morphology and immunohistochemistry for synaptophysin and chromogranin A. The extent of neuroendocrine components in primary tumor, angiolymphatic invasion and lymph node were reviewed by two independent pathologists.

Results: Fifteen patients with MANEC and ADC-NE tumors were evaluated. Of these, pure neuroendocrine component in angiolymphatic invasion was observed in 9; pure adenocarcinoma component was seen in 4; and both components were seen in 2. The components in lymph node metastases were consistent to angiolymphatic invasion (Table), suggesting the tumor component in angiolymphatic invasion may predict pathology in lymph node metastasis. In high neuroendocrine component group (>50% in primary tumor), 83.3% revealed pure neuroendocrine component in lymph node and 88.9% had angiolymphatic invasion. The pure neuroendocrine component in lymph node and angiolymphatic invasion was higher in high neuroendocrine component group compared to the low neuroendocrine component group, (p=0.012 and p=0.01, respectively).

Conclusions: The components of tumor involved in angiolymphatic invasion is consistent with that in lymph node metastasis. High neuroendocrine component predicts the rate percentage of pure neuroendocrine component in lymph node or angiolymphatic invasion.

[Table: see text]
A novel interaction of genotype, gender, and adjuvant treatment in survival after resection of stage III colon cancer: Results of CALGB 89803.
Authors: Atreya Chloe Evelyn , Warren Robert S. , Niedzwiecki Donna , Mayer Robert J. , Goldberg Richard M. , Compton Carolyn C. , Zuraek Marlene , Bergsland Emily K. , Ye Cynthia , Weinberg Vivian K. , Bertagnolli Monica M.
Published: February 2017

452

Background: The p53 tumor suppressor gene is frequently mutated in colorectal cancer, but reports on the effect of p53 mutations on response to adjuvant chemotherapy and survival are inconclusive. This study investigates whether p53 mutational status (wild-type, zinc or non-zinc binding mutations) impacts survival following adjuvant therapy containing fluorouracil/leucovorin with or without irinotecan (5FU/LV or IFL) in women and men with stage III colon cancer.

Methods: As part of a retrospective analysis of prospectively accrued data, p53 mutational status was determined for 609 patients with stage III colon cancer who were randomized on CALGB 89803, a phase III adjuvant chemotherapy trial. p53 exons 5-8 were analyzed by direct sequencing or sequencing by hybridization. p53 mutations were identified in 276 tumors (45%), of which 134 were in the zinc binding and 142 were in the non-zinc binding regions of the core domain. Cox regression was used to study the impact of p53 mutational status, sex, and adjuvant chemotherapy on disease-free (DFS) and overall survival (OS).

Results: p53 mutational status did not predict differential survival or response to adjuvant therapy among the 609 patients assessed. However, a significant sex by treatment interaction was observed for both DFS (Pinteraction=0.008) and OS (Pinteraction=0.002). Significant differences in DFS by p53 mutational status were observed among women (logrank P = 0.009). No such differences were observed among men (logrank P = 0.33). Similar results were observed for OS. There was marginal evidence of a treatment-related impact on the interaction between sex and p53 mutational status for both DFS and OS (DFS Pinteraction = 0.07; OS Pinteraction = 0.11). There was a trend toward improved OS when women with zinc binding mutations received IFL versus 5FU/LV (P = 0.08) and toward worse DFS when women with non-zinc binding mutations were treated with IFL versus 5FU/LV (P =0.08).

Conclusions: This exploratory subset analysis suggests that p53 mutational status may be used to predict prognosis in a sex- and potentially chemotherapeutic regimen-specific manner.
Association of gender-related tumor recurrence with a polymorphic variant of LMTK3 in stage II and III colon cancer.
Authors: Zhang Wu , Gerger Armin , Labonte Melissa Janae , Yang Dongyun , Bohanes Pierre Oliver , Ning Yan , Winder Thomas , Wilson Peter M.D. , Benhaim Leonor , El-Khoueiry Rita , El-Khoueiry Anthony B. , Iqbal Syma , Giamas Georgios , Stebbing Justin , Lenz Heinz-Josef
Published: February 2017

454

Background: Recent evidence suggests that Lemur Tyrosine Kinase 3 (LMTK3) activates estrogen receptor alpha (ERα) transcriptional activity in breast cancer. The mutant variants of two single nucleotide polymorphisms (SNPs) in LMTK3 (rs8108419 and rs9989661) were independently associated with reduced time to tumor recurrence (TTR), suggesting these SNPs were functionally significant. In colon cancer (CC), ERβ expression has been shown to be predominant with low levels of ERα also expressed. ERα stimulates cell proliferation, while ERβ negatively regulates the estrogen-dependent activity of ERα. Based on these previous findings, we hypothesized that LMTK3 rs808419 and rs9989661 may predict TTR in stage II and III CC.

Methods: Either blood or FFPE tissue specimens were obtained from 234 patients (107 females and 127 males; median age 59 yrs (range 22–78 yrs)) with stage II (105 pts) or III (129 pts) CC at the University of Southern California. The median follow-up was 4.4 years. LMTK3 rs8108419 and rs9989661 were determined by PCR-RFLP. The primary endpoint of the study was TTR. This study was conducted adhering to the reporting recommendations for tumor marker prognostic studies (REMARK).

Results: The minor allele of LMTK3 rs9989661 (C; frequency=30.5%) showed significantly longer median TTR (5.9 vs 12.2+ yrs; HR: 0.41, 95%CI: 0.15-1.18, log-rank p=0.086; univariate analysis) in female CC patients. After Cox proportional hazards model adjustment for stage and type of adjuvant chemotherapy, this result remained significant (HR: 0.25, 95%CI: 0.077-0.778, Wald test p=0.017). No significant association was found between TTR and LMTK3 rs9989661 in men and rs8108419 in both genders.

Conclusions: This is the first report demonstrating LMTK3 rs9989661 associations with gender-related TTR in CC. We hypothesize that there is an ERα-dependent loop mechanism with higher estrogen levels in females exerting the effect on ERβ. Larger prospective trials are warranted to confirm these findings, and in vitro and in vivo studies are needed to identify the underlying biological mechanism.
Activity of bevacizumab at the time of surgery after 6 weeks of preoperative cessation.
Authors: Starlinger Patrick , Alidzanovic Lejla , Schauer Dominic , Maier Thomas , Sommerfeldt Silvia , Herberger Beata , Tamandl Dietmar , Gruenberger Birgit , Gruenberger Thomas , Brostjan Christine
Published: February 2017

455

Background: The use of bevacizumab (BV), a monoclonal antibody against VEGF, and combination chemotherapy (CTx) together with an increase in hepatic resection has improved the outcome of colorectal cancer (CRC) patients with liver metastasis. However, despite the frequent use of BV, its accurate timing prior to liver resection to avoid surgical complications and to allow for hepatic regeneration remains discussed controversially. In this context, it remains unclear to which extent VEGF is complexed by BV at the time of surgery.

Methods: Fifty CRC patients with liver metastases, potentially curable by resection, were included. Patients received neoadjuvant CTx either with or without concomitant biweekly BV. The last cycle of therapy did not include BV, resulting in 5 weeks between the last administration of BV and surgery. Plasma and wound fluid subcutaneously and intra-abdominally were obtained perioperatively. Immunoprecipitation was applied to determine the proportion of BV-bound VEGF.

Results: 42 patients underwent surgery. Median time of BV cessation was 5-6 weeks. No increased perioperative complications in this BV treated patients were observed (patients without complications: 59 % of BV + CTx patients versus 50 % in CTx patients). At the time of surgery, the majority of plasma VEGF was inactivated by BV. In wound fluid, the actual site of wound healing and hepatic regeneration, VEGF was remarkably low and also complexed by BV. This resulted in a highly significant reduction of unbound/biologically active VEGF levels in plasma and wound fluid of BV treated patients (both: P < 0.001).

Conclusions: These data documents that, after the clinical standard cessation time point of 5-6 weeks, BV is still fully active and binds to the majority of circulating and local (wound fluid) VEGF. Despite the potent VEGF inactivation, at the time of liver resection no substantial increase in perioperative morbidity after neoadjuvant BV therapy has been documented in our study and the current literature.
Prognostic value of chromosomal imbalancies and the colon gene expression signatures in rectal cancer.
Authors: Doyen Jerome , Letouze Eric , Romestaing Pascale , Chapet Olivier , Gérard Jean-Pierre
Published: February 2017

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Background: Some studies have suggested colon and rectal cancer as two different entities when considering DNA mutations or chromosomal imbalances. We therefore wondered if two colon gene expression signatures could predict specific survival. We also tested the influence of chromosomal imbalancies on prognosis in rectal cancer.

Methods: Between 1998-2001 a series of 94 patients (pts) with rectal adenocarcinoma (T1-2-3 M0) were treated with preoperative radiotherapy (RT) with or without concurrent chemotherapy (CT) (78 pts) or with curative RT alone using contact X Ray therapy (CXRT) (18 pts). High-throughput analysis of genomic imbalancies and DNA expression were performed within the frame of the Carte d’Identité des Tumeurs (CIT) programme of Ligue du Cancer- France. Biostatistical analysis were performed and correlated with metastasis-free survival (MFS) and specific survival (SS). Coloprint and Oncotype DX colon signatures were tested on this cohort.

Results: The median survival of the 96 patients was 105 months. The overall specific survival rate at 8 years was 75% for the preoperative group and 65 % for the RT alone group. Overall the rate of distant metastases was 30 % at 8 years (26 pts). A validated biopsy specimen was analysed in 67 pts for DNA expression and for genomic imbalances. Deletion of 8p and 1p36-35 correlated with MFS (p=0.001 and p=0.02 respectively) and SS (p=0.0002 and p=0.008 respectively). Multivariate analysis identified -8p as an independent prognostic factor of MFS (p=0.004) and SS (p=0.003). Validation of this deletion on an independent cohort is on-going. Regarding mRNA profile analysis, no stable consensus could identify clusters that accurately separate patients of bad and good SS or MFS, whatever the method used (28 methods of clustering). Coloprint signature could discriminate patients with the worst prognosis (SS: p<0.05) whereas Oncotype DX colon signature did not (SS: p=0.4).

Conclusions: By analysing this series of patients from a single center we have been able for the first time in rectal cancer to identify -8p as an independent prognostic factor of MFS and SS. mRNA analysis suggest that colon and rectal cancer may not always share the same DNA expression profile.
Development and validation of a genomic signature to identify colorectal cancer patients with microsatellite instability.
Authors: Salazar Ramon , Tian Sun , Santos Cristina , Rosenberg Robert , Nitsche Ulrich , Mesker Wilma E , Bruin Sjoerd , Roepman Paul , Capella Gabriel , Simon Iris
Published: February 2017

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Background: Microsatellite Instability (MSI-H) occurs in 10-20% of colon tumors and has been attributed predominantly to gene silencing of DNA mismatch repairs (MMR) genes by mutation or methylation, including MSH2, PMS2 and in particular MLH1.

Methods: MSI status for 276 primary stage II and III colorectal tumors have been determined (n=29 MSI-H, n=247 MSS and MSI-L) by immunohistochemically staining of MLH1 and PMS2 (for 90 patients) or by PRC amplification of six microsatellite DNA regions from paired normal and tumor tissues (for 186 patients). Full genome gene expression data for the same 276 tumors was available and used to identify genes that correlate with MSI-H status. All samples had full clinical information including 5-year follow-up and ColoPrint results (as described in Salazar et al. JCO 2011).

Results: Most MSI-H patients were classified as ColoPrint low risk (26 of 29 patients; 90%) however this is only as subgroup of the 195 patients identified by ColoPrint as low risk. While ColoPrint had great prognostic power in this dataset (HR 2.37, p=0.0006), it does not identify MSI-H patients with high specificity. We therefore developed a MSI-gene signature of 64 genes using a 10-fold cross validation procedure to complement ColoPrint. The MSI-signature identifies MSI-H patients with high sensitivity (93.1% (27/29)) and high specificity (87.9% (217/247)) and an overall accuracy of 88.4% (244/276). The MSI-signature has prognostic power in the subset of stage II patients (n=215) with HR = 2.38 (95% CI 1.15-4.93, p=0.06. However, in multivariate analysis of MSI status and all clinical factors, ColoPrint was the only significant prognostic factor (HR 3.2; p=0.0014). The MSI-signature is currently validated in an independent patients set of 132 stage II patients (31 MSI-H, 101 MSS).

Conclusions: The diagnostic MSI signature identifies patients with MSI-H status with high accuracy. In combination with the prognostic power of ColoPrint, the identification of MSI-H patients might add additional information for treatment of stage II patients.
Phase II study of ganetespib, an hsp-90 inhibitor, in patients with refractory metastatic colorectal cancer.
Authors: Cercek Andrea , Shia Jinru , Gollub Marc , Raasch Pamela Joan , Hollywood Ellen , Reidy Diane Lauren , Janjigian Yelena Yuriy , Stadler Zsofia Kinga , Segal Neil Howard , O'Reilly Eileen Mary , Ilson David , Kemeny Nancy E. , Saltz Leonard
Published: February 2017

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Background: To evaluate the safety and efficacy of ganetespib, a heat shock protein 90 (Hsp90) inhibitor, as monotherapy in patients with refractory metastatic colorectal cancer.

Methods: A phase II study utilizing a two-stage design was performed in which patients received Ganetespib 200 mg/m2 intravenously (IV) one time per week for three weeks followed by a one week break. Patients underwent pre and 48 hour post treatment tumor biopsies. Immunohistochemistry (IHC) was performed for p/Erk, CyclinD1, p/Akt, HIF-1a, VEGFr2 , p70S6 and Hsp70. Archived and pre dose biopsy tissue was utilized for KRAS, BRAF and PIK3CA genotyping using a Sequenom platform.

Results: Fifteen patients were treated (median age 58, range 44-79). There were no responders. Two patients had stable disease lasting 31 and 23 weeks. The most frequent grade 1/2 toxicities were diarrhea, fatigue, nausea/vomiting and elevated transaminases ( Table ). These complications did not result in any treatment interruption. The most frequent grade 3 adverse events were diarrhea (12%), fatigue (24%), and elevated AST(12%) and Alk phos(29%). Three (20%) patients required dose reductions, 1 grade 3 AST, 1 grade3 ALT and 1 grade 3 fatigue.

Conclusions: This was the first study of an Hsp90 inhibitor in colorectal cancer. Ganetespib treatment did not produce tumor responses when administered as a single agent in refractory metastatic colorectal cancer with this dosing regimen. Overall the drug was well tolerated and the toxicity profile was minimal. Ganetespib may be used in combination in future studies. Correlative IHC analyses will be presented.

[Table: see text]
Comparative effectiveness of treatment options in elderly patients with colon cancer receiving adjuvant chemotherapy.
Authors: Satram-Hoang Sacha , Ramanan Devi , Lee Luen F. , Yu Shui , Reyes Carolina M. , McKenna Edward
Published: February 2017

470

Background: While colon cancer (CC) is predominantly a disease of the elderly, older patients are underrepresented in clinical trials. We sought to evaluate whether the treatment patterns and benefits realized by trial participants pertain to older patients in the real-world setting.

Methods: Using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we conducted a retrospective cohort analysis of 3390 stage II and III CC patients diagnosed between 1/1/ 2004 to 12/31/2007, who were >66 years, enrolled in Medicare Parts A and B, and received adjuvant treatment with 5FU/LV (n=1368), FOLFOX (n=1398), CAP (capecitabine; n=507), and CAPOX (CAP + oxaliplatin; n=117) within 3 months after surgery. Date of last follow-up was 12/31/2007. Chi-square test and ANOVA or t-test assessed differences in patient and disease characteristics by treatment. Propensity score weighted Cox regression assessed the relative risk of death by treatment.

Results: Patients treated with CAP were older (mean age 77 years; p<.0001), more likely female (61%; p<.05), more likely non-white (19%; p<.05) and had higher co-morbidity score (p<.0001) compared to the other treatment groups. The mean time to chemo initiation after surgery were similar between the groups (mean 46-49 days) while mean duration of treatment were longer for 5FU/LV (149 days) and FOLFOX (144 days), compared to CAP (121 days) and CAPOX (111 days); p<.0001. The incidence of adverse events (AEs) within 180 days after initiation of treatment were higher in patients treated with FOLFOX (82%) and 5FU/LV (78%) compared to CAP (74%) and CAPOX (71%); p=0.0002. Propensity score adjusted multivariate analysis demonstrated comparable survival for CAP-based regimens vs. 5-FU/LV- based regimens ( table ).

Conclusions: Treatment outcomes for elderly patients observed in routine clinical practice were comparable between CAP-based and 5FU/LV-based regimens and consistent with results reported in randomized clinical trials. AEs associated with medical resource utilization were less frequent with CAP-based regimens.

[Table: see text]
Conversion to complete surgical treatment using hepatic artery infusional chemotherapy in patients with unresectable liver metastases from colorectal cancer.
Authors: Ammori John Brian , Kemeny Nancy E. , Cercek Andrea , DeMatteo Ronald P. , Allen Peter J , Paty Philip , Fong Yuman , Jarnagin William R. , D'Angelica Michael Ian
Published: February 2017

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Background: Hepatic artery infusional (HAI) chemotherapy effectively treats colorectal liver metastases (CRLM). This study analyzes the combination of HAI and systemic chemotherapy for treating unresectable CRLM, focusing on the conversion to complete resection and/or ablation (R/A) and long term outcomes.

Methods: All patients with initially unresectable CRLM treated with HAI and systemic chemotherapy from 2000-2009 were included. Patients who responded sufficiently to undergo complete R/A were compared to those who did not convert.

Results: 373 patients were included. 296 (79 %) were previously treated and 77 (21 %) were chemo naïve. 115 (31 %) were on protocol and 258 (69 %) were not on protocol. 93 patients (25%) subsequently underwent complete R/A (conversion group). Of the 115 protocol patients, 47 (41 %) underwent complete R/A. The percentage of patients submitted to complete R/A increased from 16% during 2000-2003 to 30% during 2004-2009. 43% of patients who were chemotherapy-naïve prior to HAI therapy eventually underwent complete R/A, compared to 15% who were initially treated with systemic therapy (p<0.001). Factors associated with conversion on multivariate analysis were more recent treatment (2004-2009), no prior chemotherapy, and a clinical risk score < 3. Overall survival was greater in the conversion group, with a median and predicted 5-year survival from the time of HAI pump placement of 54 months and 49%, compared to 19 months and 6%, respectively (p<0.001).

Conclusions: One-quarter of patients with unresectable CRLM responded sufficiently to undergo complete R/A following HAI plus systemic chemotherapy. Conversion was more likely in patients who were chemotherapy-naïve (43 %), had a clinical risk score < 3, and were treated in the more recent era. Survival in the conversion group was significantly better.