bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving the AJCC/TNM staging for adenocarcinomas of the appendix: The prognostic impact of histologic grade.
Authors: Overman Michael J. , Fournier Keith F. , Hu Chung-Yuan , Wolff Robert A. , Eng Cathy , Taggart Melissa W. , Royal Richard E. , Mansfield Paul F. , Chang George J.
Published: February 2017

402

Background: Though histological grade is known to have a major prognostic impact in metastatic mucinous appendiceal adenocarcinomas; the prognostic impact of grade in localized disease, and the validity of the AJCC Cancer Staging Manual 7th edition decision to combine moderately and poorly differentiated mucinous adenocarcinomas into a single mucinous high-grade category, is not known.

Methods: Patients with adenocarcinoma of the appendix diagnosed between 1988-2007 were identified from the SEER database. Cancer-specific survival (CSS) stratified by histological subtype, stage and grade were calculated; and Cox proportional hazards regression analyses were performed.

Results: We analyzed a total of 2,469 appendiceal adenocarcinomas, of which 1,375 had mucinous histology, 860 had non-mucinous histology, and 234 had signet-ring cell histology. Though overall CSS was similar for mucinous and non-mucinous subtypes, differences in stage distribution and stage-stratified CSS were seen. Female gender (57% vs.45%, P<0.01), stage IV disease (48% vs. 25%, P<0.01), and well differentiated histology (31% vs. 14%, P<0.01) were more common in mucinous as compared to non-mucinous adenocarcinomas. While histological grade for stage I-III cases was not statistically significant, it had strong prognostic impact for stage IV disease. The adjusted hazard ratios for stage IV well, moderately and poorly differentiated histological grade were 1 (reference), 1.63 (95%CI: 1.14-2.34) and 4.94 (95%CI: 3.32-7.35) for mucinous, in comparison to 1 (reference), 1.44 (95%CI: 0.82-2.52) and 1.90 (95%CI: 0.95-3.80) for non-mucinous histological subtypes, respectively.

Conclusions: The strong prognostic impact of histological grade for mucinous adenocarcinomas is primarily restricted to stage IV disease. Stage IV moderately and poorly differentiated mucinous adenocarcinomas have distinctly different CSS and this data does not support the combination of these two histological grades in the recent AJCC 7th edition.
Intensive radiographic and CEA screening and salvage resection in patients with stage II and III colorectal cancer.
Authors: Fora Ahmad Ali , Patta Annie M , Attwood Kristopher , Wilding Gregory E. , Fakih Marwan
Published: February 2017

405

Background: The objective of this study was to determine the rate of salvage resection in patients with stage II and III colorectal cancer following intensive surveillance.

Methods: Patients with stage II and III colorectal cancer with a minimum follow-up of 3 years were included. CEA was obtained every 3 months for 2 years and then every 6 months for years 3 to 5. CT of the chest, abdomen and pelvis was performed every 6 months for 2 years and then yearly for years 3 to 5. Colonoscopy was performed at year 1 and then every 3 years.

Results: 177 patients were followed for a median of 59.5 months. 51% were male, and 65 % had colon cancer. Compliance with screening was excellent with 92 % of patients undergoing all scheduled studies within 2 months of the planned date. At the time of this report, the median follow-up of the overall population was 5 years. 44 patients were diagnosed with recurrent disease. 91% of the recurrences were in the first 3 years of follow-up. CT and CEA were the first signs of recurrence in 68% and 14% of patients, respectively. Among the 30 patients diagnosed radiographically, 20 had a normal CEA. 25 patients (57%) with recurrent disease underwent curative intent resection, 12 of whom are still cancer free, with a median follow-up of 6.7 years from salvage surgery. The DFS and OS in the operated recurrent population from the time of salvage resection was 18.8 months (95% CI: 15.5 – 29.4) and not-reached (95% CI: 37.4, NR), respectively. The corresponding OS (from the time of recurrence) of the recurrent population without resection was 20.7 months (95% CI: 21.9, 63.4). The difference in OS between the two groups was highly significant (p = 0.0003). Among the patients undergoing resection, a significant difference was detected in the DFS of resected lung or liver metastases vs. extra-hepatic/pulmonary disease (p = 0.03) and a trend towards improved survival was noted (p = 0.07).

Conclusions: Our intensive surveillance strategy resulted in the highest reported salvage rate in stage II and III colorectal cancer and led to a high rate of sustained remissions following salvage surgery. Intensive, 6-monthly, radiographic surveillance and its duration should be investigated further in randomized studies.
Sensitivity of second-generation blood-based methylated Septin9 assay for early-stage colorectal cancer.
Authors: Weiss Gunter , Fassbender Anne , Koenig Thomas , Tetzner Reimo
Published: February 2017

419

Background: Early detection of colorectal cancer (CRC) has been shown to decrease mortality, although compliance to CRC screening is low. Availability of a blood-based test is expected to improve CRC screening compliance. Specific detection of CRC using the Septin9 biomarker (mSEPT9) in a large prospective trial of an average-risk CRC screening population exhibited 67% sensitivity for CRC with 88% specificity. Laboratory-developed tests detecting mSEPT9 in plasma are now available in North America and a 2nd generation molecular diagnostic blood test for mSEPT9 is available as a CE-marked kit in Europe. The current research evaluated the clinical performance of the 2nd generation mSEPT9 assay.

Methods: Bisulfite-converted DNA (bisDNA) was prepared from 3.5 mL human plasma using the 2ndgeneration plasma DNA preparation kit. Resulting bisDNA was analyzed in triplicate on the ABI7500 Fast Dx (Life Technologies, Inc.) using proprietary HeavyMethyl real-time PCR technology for mSEPT9 and the 2nd generation real-time PCR kit. In a case – control design, plasma from 98 CRC patients (n = 87 stages I - III) and 99 age-matched, colonoscopy-verified normal individuals were processed with the mSEPT9 assay. In addition, plasma from 150 prospectively enrolled average risk individuals scheduled for screening colonoscopy was tested. mSEPT9 was qualitatively analyzed such that any detection of mSEPT9 in a PCR was called “positive”.

Results: The revised mSEPT9 assay exhibited 95% sensitivity (95% CI: 89-98%) for CRC. Sensitivity for stage I was 89% (95% CI: 72-96%, n = 27) and sensitivity for stage II was 93% (95% CI: 78-98%, n = 29). The control group was positive at a rate of 16% (95% CI: 10-25%). Specificity of the mSEPT9 assay in the screening cohort was 85% (95% CI: 78-89%).

Conclusions: The 2nd generation mSEPT9 assay demonstrated improved sensitivity for CRC without significant impact on specificity. The enhanced design and robustness of the assay will further facilitate its standardized use in routine laboratory settings. Finally, the increased sensitivity of the revised mSEPT9 assay improves the detection of early stage disease and demonstrates the feasibility of a blood-based CRC screening technology.
Clinicopathologic characteristics of patients with appendiceal adenocarcinoma (AA) and intra-thoracic metastasis.
Authors: Hill Joshua S. , Rafeeq Safia , Rice David C. , Overman Michael J. , Royal Richard E. , Mansfield Paul F. , Fournier Keith F.
Published: February 2017

427

Background: Appendiceal adenocarcinoma (AA) is a rare disease with a prognosis related to tumor histology. Distant metastases, including those to the lung or pleura, are considered rare. We investigated the clinical characteristics and survival in patients with AA and intra-thoracic metastases.

Methods: All patients with a pathologic diagnosis of AA who were evaluated at a single institution between September 1993 and July 2009 were retrospectively reviewed to identify patients with intra-thoracic metastasis. Parameters evaluated included demographics, histologic subtype and location of thoracic metastasis (parenchyma vs. pleural). Survival was calculated using the Kaplan-Meier method.

Results: We evaluated 626 AA patients. Forty-two (6.7%) had intra-thoracic metastases: 24% pleural, 52 % parenchymal and 24% had both. Of those with intra-thoracic metastasis, the mean age at diagnosis was 54 years. Sixty percent were male. Histologic grade was: 19 (45%) low, 13 (31%) moderate and 9 (21%) grade high. Mean follow-up was 6.6 years. Median overall survival from diagnosis of the entire cohort was 5.2 years. Median overall survival by tumor grade: high 1.87 years, moderate 4.1 years, and not reached in low grade tumors (p=0.0001). The median overall survival from time of diagnosis of intra-thoracic metastasis is 1.44 years with survival by grade as follows: high-0.2 years, moderate-1.2 years, and low grade not reached (p=0.0003). Survival was not dependent on intra-thoracic location.

Conclusions: Intra-thoracic metastasis in patients with AA occurs at a higher rate than previously thought, even in low grade tumors. This suggests that thoracic imaging should be considered in patients with AA. Overall survival depends heavily on tumor histology.
EORTC QLQ CR-29 evaluation in 500 patients with colorectal cancer.
Authors: Silva José Pedro Carvalho Moreira da
Published: February 2017

429

Background: Colorectal cancer represents the 4th most frequent cancer in the world and is the 2nd leading cause of death due to cancer. This disease has a negative impact in the Quality of Life (QoL), due to its associated symptoms and due to the used treatments (surgery, chemotherapy and radiotherapy). Therefore it is fundamental to evaluate and assure a good quality of life of this patients and define the best QoL instrument in Colorectal cancer.

Methods: Type of study: Transversal study The main objective was: validate for Portuguese population CR29 instrument. The QLQ-CR29 was administered with the QLQ-C30, core questionnaire, to 500 portuguese patients. Questionnaire scaling and reliability were established and clinical and psychometric validity examined. Patient acceptability and understanding were assessed with a debriefing questionnaire.

Results: 57.4% (287) are male with a median of age of 66,67 years (Min.: 34 e Máx.: 88), 55.2% had rectal cancer (35.7% were Stage III disease at diagnosis. 46.4% had adjuvant and 27.4% had neoadjuvant treatment. The mean value of the QLQ-C30 Global Health Status was 58,75. The CR29 Multi-trait scaling analyses and face validity refined the module to four scales assessing urinary frequency, faecal seepage, stool consistency and body image and single items assessing other common problems following treatment for colorectal cancer identifying different groups of patients. High scores of cognitive and social functioning scales (QLQ C30), Subscale Corporal Image and the functional item Female Sexual function (QLQ-CR29) were related with good QoL. Low scores of Emotional Functioning subscales (QLQ C30) and Anxiety (QLQ-CR29), were related with poor QoL. A multivariable analysis reveals that sex, scholarship, marital status, distance between home and hospital and disease recurrence affect significantly the global health score.

Conclusions: QLQ-CR29 Scale did not correlate with QLQ-C30 scales, demonstrating construct validity and it is a good instruments to identify a poor QoL in patients with colorectal cancer.
Physician’s awareness and practices toward colorectal cancer screening guidelines.
Authors: Kanna Sowjanya , Ali Asif , Anna Kiran , Ganapathi Thimmaiah Theethira , Sappati Biyyani Raja Shekhar Reddy , Mullen Kevin D
Published: February 2017

431

Background: Colorectal cancer (CRC) is the second most common cancer with an estimated incidence of 72,090 men and 70,480 women and a cause specific mortality of 51,370 in 2010. Despite promotion of CRC screening by various professional societies ACG /AGA and USPSTF, there seems to be an under utilization of screening colonoscopy for unclear reasons. We aimed to study the awareness of physicians towards CRC screening across various levels of training in different specialities.

Methods: A survey questionnaire of 16 questions, assessing awareness of CRC screening guidelines was provided to 100 physicians in our academic medical center who are at various levels of training in Primary Care Group (PCG comprising residents, attending physicians in Internal Medicine and Family Medicine) and Specialty Group (SG comprising fellows, attending physicians in Gastroenterology).

Results: Out of 100 questionnaires, we received 59 responses (50 PCG and 9 SG) which are included in the results. About 54% of the study group followed CRC guidelines (32% USPSTF CRC screening guidelines compared to 22 % ACG/AGA guidelines) and 46% did not. All the physicians who did not follow the guidelines belonged to the PCG. Most common screening modality chosen was colonoscopy alone (46% PCG and 100% SG), followed by colonoscopy with FOBT (36% PCG), FOBT (12% PCG) and 3% PCG answered barium enema along with FOBT/ sigmoidoscopy. A 100% response from both SG and PCG was obtained for commencing screening colonoscopy at 50 years of age but only 27% of the PCG compared to 80% SG were aware of the screening cessation guidelines. Interestingly a vast majority of the study group (88%) text messaging as a better way of reminder to improve compliance compared to phone calls and postal letters. About 72% of the respondents themselves would want colonoscopy as screening modality compared to 17% for FOBT and 7% for sigmoidoscopy. An overwhelming majority of the study group (80% of both PCG and SG) felt the need for continued education in regards to guidelines for screening in didactic sessions.

Conclusions: Despite clear guidelines for screening colonoscopy, we found a significant lack of awareness amongst PCG compared to SG, and our study emphasizes the need for continued education.
Identification of imaging biomarkers using 18fluorodeoxyglucose-positron emission tomography (FDG-PET) for the prediction of pathologic response in patients receiving neoadjuvant chemoradiotherapy for locally advanced rectal cancer.
Authors: Parekh Arti , Matalon Shanna , Subramaniam Rathan , Kachnic Lisa A.
Published: February 2017

435

Background: Pre- and post-treatment FDG-PET imaging parameters may be useful for predicting pR following neoadjuvant CRT for LARC

Methods: Between 2006 and 2010, 18 patients (pts) receiving preoperative CRT (5FU or capecitabine with concurrent 50.4 Gy conformal radiation) for LARC underwent a pre- (0-14 days before) and post-CRT (4 to 6 weeks after) PET/CT. Total mesorectal excision was performed 6 weeks post CRT. pR was dichotomized into complete (pCRs) and partial responders as reference standard. Pts with pathologic microscopic disease were classified as pCRs for this analysis. Changes in FDG metabolic parameters between pre and post-CRT scans, including maximum Standardized Uptake Value (SUVmax), metabolic tumor volume (MTV) and total glycolytic activity (TGA), were investigated as predictive imaging biomarkers for pR. Fixed SUVmax percentage threshold (30%, 40% and 50%) and gradient-based segmentation (PET Edge) were used to calculate the MTV and TGA. Receiver Operator Curve analysis was performed

Results: Median pt age was 57.5 years (31-87); 67% M; 61% AJCC 2010 stage II, 33% III and 6% IV. pCR achieved in 44%. The 30% SUVmax threshold MTV best correlated with PET Edge MTV (Pearson r 0.99). Using ROC analysis, % change in SUVmax and PET edge TGA between pre and post-CRT scans were comparable and the most accurate parameters for predicting pR. SUVmax % change yielded an area under the curve (AUC) of 0.7125 (95% CI 0.4318-0.9932), while the AUC for PET Edge TGA % change was 0.7000 (95% CI 0.4209-0.9791). Based on ROC analysis, a cutoff of 78.9% change of PET Edge TGA had a likelihood ratio of 2.4, with a sensitivity of 90% and a specificity of 62.5% for predicting pCR. A cutoff of 88.7% change of PET Edge MTV yielded a likelihood ratio of 2.00 with a sensitivity of 50% and a specificity of 75%.

Conclusions: The % change pre- to post-CRT in SUVmax and PET Edge Total Glycolytic Activity appears to be the most suitable FDG metabolic parameters for predicting pR following neoadjuvant CRT for LARC. As such, these PET-FDG biomarkers of CRT response should be validated in future prospective trials.
Anti-miR-135b in colon cancer treatment: Results from a preclinical study.
Authors: Valeri Nicola , Braconi Chiara , Gasparini Pierluigi , Grivennikow Sergei , Hart Jonathan R , Paone Alessio , Lovat Francesca , Fabbri Muller , Gafa' Roberta , Nuovo Gerard , Lanza Giovanni , Frankel Wendy , Vogt Peter K , Groden Joanna , Karin Michael , Croce Carlo M.
Published: February 2017

457

Background: MicroRNAs (miRs) are small non coding RNAs involved in cell homeostasis. miRs are deregulated in colorectal cancer (CRC). Our study aimed at identifying miRs with a driver role in carcinogenesis altered by similar mechanisms in both human and mouse CRC. Goal of the study was to use CRC mouse models for the pre-clinical development of anti-miRs as therapeutic drugs.

Methods: Azoximetane (AOM)/Dextran-Sulfate (DSS) treated mice or CDX2-CRE/APC-/- mice were used to study inflammation-associated and sporadic APC-related CRC. Human Inflammatory Bowel Disease associated (n=30), and sporadic (n=90) CRC with their matched normal tissues were collected according to Good Clinical Practice recommendation and subjected to RNA extraction using Trizol. miR and gene expression profiling was assessed by nCounter technology (Nanostring Seattle). Anti-miR-135b and scrambled probes for in vivo studies were synthesized by Girindus.

Results: miRs profiling from AOM/DSS and CDX2-CRE/APC-/- CRC. revealed that miR-135b is one of the most up-regulated miRs in both models. In humans miR-135b over-expression was found in both IBD and sporadic CRC and was associated with reduced Progression Free Survival and Overall Survival in CRC patients. Molecular studies in Mouse Embryo Fibroblast and human CRC cell lines highlighted the role of two major pathways in the upstream activation of miR-135b: APC-β-Catenin and SRC-PI3K. MiR-135b up-regulation resulted in reduced apoptosis and increased invasion and metastasis due to the down-regulation of TGFRB2, DAPK1, APC and HIF1AN. Silencing of miR-135b in vivo reduced tumor multiplicity and tumor load in the AOM/DSS CRC model. Mice treated with anti-miR-135b showed well differentiated tumors and microacinar pattern while tumors in the control groups showed low differentiation and adenomatous pattern.

Conclusions: Our data suggest that miR-135b is a key molecule whose activation is downstream of oncogenes and oncosuppressor genes frequently altered in CRC. Our study defines specific pathways that converge on the activation of the same microrna. The “in vivo” silencing of miR-135 shows preclinical efficacy with low toxicity and represents the first in vivo study for the use of antimiRs in CRC treatment.
A phase I trial of a recombinant CEA yeast-based vaccine targeting CEA-expressing cancers.
Authors: Bilusic Marijo , Gulley James L. , Hodge James W. , Tsang Kwong , Arlen Philip M. , Heery Christopher Ryan , Rauckhorst Myrna , McMahon Sheri , Intrivici Chiara , Ferrara Theresa A. , Cohn Allen , Apelian David , Franzusoff Alex , Guo Zhimin , Schlom Jeffrey , Madan Ravi A.
Published: February 2017

458

Background: Saccharomyces cerevisiae (yeast) has been genetically modified to express CEA protein and employed as a heat-killed immune-stimulating, vector-based vaccine. Preclinical studies have shown that yeast CEA vaccine can induce a strong CEA-specific T-cell immune response (IR) and anti-tumor activity.

Methods: Patients (Pts) were enrolled in this phase I trial at 3 dose levels: 4, 16, and 40 yeast units (each unit =107 yeast particles). The vaccine was administered equally at 4 sites subcutaneously in bilateral inguinal and anterior chest wall regions. Vaccine was administered at 2 week intervals for 3 months, then monthly. Eligible pts were required to have a serum CEA > 5 ng/ml or > 20% CEA+ positive tumor block and no autoimmune history. An expansion cohort of 10 pts was enrolled to focus on IR. Pts had re-staging scans at 3 months, then bimonthly. Peripheral blood was collected for analysis of IR including the Effector/Regulatory T-cell ratio, ELISPOT assay, changes in the myeloid-derived suppressor cells (MDSC) and natural killer cells (NK).

Results: 25 pts with progressive metastatic CEA-expressing carcinoma were enrolled; 22 had colorectal adenocarcinoma. Vaccine was well tolerated with no dose limiting toxicities. The most common adverse event was grade 1/2 injection site reaction. Overall, 7 patients had stabilization or declines in serum CEA after treatment. Of them, 5 pts (3 with colorectal cancer) had stable disease beyond 3 months and 1 is still on-going (14 +, 8, 8, 4.5 and 4 months). No anti-CEA antibodies were detected. Post vs. pre-vaccination: a) five out of 9 evaluable pts showed evidence by ELISPOT of CEA-specific T-cell IRs b) 8/16 pts had increased and 8/16 pts had decreased CD4 Effector/Treg ratio and c) 6/13 pts had increased and 2/13pts had decreased NK frequency.

Conclusions: Saccharomyces cerevisiae-CEA demonstrated an acceptable safety profile. Although this is an advanced disease population of pts which is not ideal for immune-based therapy, CEA serum stabilizations and CEA-specific IRs were seen in some pts. Randomized studies are required to determine the clinical benefit of this vaccine in a more appropriate patient population for vaccine therapy.
Target-based therapeutic matching in early-phase clinical trials in patients with advanced colorectal cancer and PIK3CA mutations.
Authors: Janku Filip , Naing Aung , Falchook Gerald Steven , Tsimberidou Apostolia Maria , Stepanek Vanda M. T. , Fu Siqing , Piha-Paul Sarina Anne , Luthra Rajyalakshmi , Hong David S. , Kurzrock Razelle
Published: February 2017

459

Background: Therapeutic matching based on underlying molecular abnormalities showed promising results in patients with diverse advanced cancers in early phase clinical trials. PIK3CA mutations may predict response to therapies with PI3K/AKT/mTOR inhibitors.

Methods: Tumors from patients with colorectal cancer referred to the Clinical Center for Targeted Therapy (Phase I Program) were analyzed for PIK3CA mutations. Patients with PIK3CA mutations were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway.

Results: Of 194 patients analyzed, 31 (16%) had PIK3CA mutations. Of 194 patients 175 (90%) were assessed for the presence of KRAS mutation. Patients with PIK3CA mutations had higher prevalence of simultaneous KRAS mutations than patients with wild-type (wt) PIK3CA (21/30, 70% vs. 63/145, 43%; p=0.009). Of the 31 patients with PIK3CA mutations, 17 (55%) were treated in clinical trials containing a PI3K/AKT/mTOR pathway inhibitor (median age, 57; median number of prior therapies, 4). Of these 17 patients, none achieved a partial or complete response (PR/CR) and only 1 (6%, 95% CI 0.01-0.27) patient had stable disease for more than 6 months (SD>6), which was not significantly different from the SD>6/PR/CR rate of 16% (11/67; 95% CI 0.09-0.27) in colorectal cancer patients without PIK3CA mutations treated on the same protocols targeting the PI3K/AKT/mTOR pathway (p=0.44). The median progression-free survival was only 1.9 months (95% CI 1.5-2.3).

Conclusions: Heavily pretreated patients with PIK3CA-mutant advanced colorectal cancer do not seem to benefit from protocols incorporating PI3K/AKT/mTOR inhibitors. PIK3CA mutations are associated with simultaneous KRAS mutations, which might account for therapeutic resistance.
Comparative effectiveness of chemotherapy in elderly patients with metastatic colorectal cancer.
Authors: Satram-Hoang Sacha , Ramanan Devi , Lee Luen F. , Yu Shui , Reyes Carolina M. , McKenna Edward
Published: February 2017

463

Background: The management of metastatic colorectal cancer (mCRC) has evolved considerably with advances in chemotherapeutic agents that have led to improved outcomes. Less is known about the benefits of newer agents in the real-world setting. The objective of this study was to evaluate treatment patterns and survival in older, demographically diverse mCRC patients.

Methods: Using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we conducted a retrospective cohort analysis of 5931 stage IIIB, IIIC and IV CRC patients diagnosed between 1/1/ 2000 – 12/31/2007, who were >66 years, enrolled in Medicare Parts A and B, and received first-line treatment with 5FU/LV (n=2907), CAP (capecitabine; n=963), FOLFOX (n=1856) or CAPOX (CAP + oxaliplatin; n=205). Date of last follow-up was 12/31/2009. Statistical comparisons were made between 5FU/LV vs. CAP and FOLFOX vs. CAPOX. Cox regression with backward elimination estimated the relative risk of death, adjusting for demographic and clinical factors.

Results: Compared to 5FU/LV, patients treated with CAP were older (>80 years) at diagnosis (36% vs. 22%; p<.0001) and more likely female (59% vs. 53%; p=.0025), while patients receiving CAPOX were older (>80 years: 12% vs 8%; p<0.05) compared to FOLFOX. The mean time to chemotherapy initiation after diagnosis was similar between CAP and 5FU/LV (76 vs. 71 days) and between FOLFOX and CAPOX (75 vs. 70 days). The mean duration of treatment was longer for 5FU/LV (144 days) vs. CAP (122 days; p<.0001) and comparable between CAPOX (144 days) and FOLFOX (150 days; p=0.2139). The incidence of adverse events (AE) within 180 days after initiation of treatment were higher in patients treated with 5FU/LV (37%) vs. CAP (9%); p<.0001 and in FOLFOX (58%) vs. CAPOX (44%); p<0.0001. In multivariate analysis there were no significant differences in risk of death between CAP and 5FU/LV, and between CAPOX and FOLFOX ( table ).

Conclusions: Overall survival was comparable between CAP and 5FU/LV and between CAPOX and FOLFOX with fewer AEs associated with CAP and CAPOX. This provides real-world confirmation of clinical trial data.

[Table: see text]
TOP1 gene copy number in stage III colorectal cancer (CRC) samples: Association to prognosis.
Authors: Nygaard Sune Boris , Rømer Maria Unni , Christensen Ib Jarle , Nielsen Signe Lykke , Smith David Hersi , Nielsen Kirsten Vang , Müller Sven , Vainer Ben , Nielsen Hans J. , Brünner Nils
Published: February 2017

475

Background: TOP1 inhibitor treatment is frequently being used in combination therapy of metastatic CRC. This study aims to reveal whether TOP1 gene copy number associates with patient prognosis, since such a relationship may have significant implications for future studies aiming at validating the predictive value of TOP1 gene copy number.

Methods: The study included TOP1 and CEN-20 FISH analyses (DAKO A/S Denmark) on FFPE tissue sections from 154 stage III CRC patients who did not receive adjuvant chemotherapy. TOP1 gene copy number, CEN-20 copy number and the TOP1/CEN-20 ratios were analyzed and correlated to overall survival (OS), to time to recurrence (TTR) of patients with CRC and to local recurrence (LR) in patients with rectal cancer (RC).

Results: TOP1 copy number counts and the TOP1/CEN-20 ratios, age, gender and primary tumor location were separately added into a multivariate analysis as continuous variables. For OS and LR, TOP1 copy number was significant and the ratio was borderline significant with higher copy number associated with longer OS or longer time to LR. When the patients were dichotomized using the TOP1 median copy number, we found that patients with high TOP1 copy number in their tumor cells had a significant longer OS (HR: 0.68; 95% CI: 0.47-0.98; p = 0.04) compared to patients with low TOP1 copy number. Using the median TOP1/CEN-20 ratio to dichotomize, no significant differences were observed between patients with levels above or below the median ratio number for OS (HR: 0.76; 95% CI: 0.53-1.10; p = 0.14). TOP1 copy number divided the RC patients into two groups with a trend towards a significant difference in time to LR (HR: 0.56; 95% CI: 0.27-1.16; p = 0.11) with higher copy number. If the median ratio was used, a significant association with longer time to LR (HR: 0.43; 95% CI: 0.20-0.92; p = 0.03) was found. No significant associations between TOP1 copy number or ratio and TTR were observed.

Conclusions: Increased TOP1 copy number is associated with longer OS in CRC patients and fewer LR in RC patients. Thus, future studies analyzing the association between TOP1 copy number and response to therapy in CRC patients should be planned in such a way that a prognostic and a predictive value of TOP1 can be separated.
A novel and simple KRAS mutation detection method, FRET-Based Preferential Homoduplex Formation Assay (f-PHFA): Results from a multicenter, clinical evaluation trial.
Authors: Yamaguchi Kensei , Akagi Kiwamu , Kakuta Miho , Kurosumi Masafumi , Nishimura Yoji , Saito Norio , Kojima Motohiro , Ochiai Atsushi , Ohtsu Atsushi , Yoshino Takayuki
Published: February 2017

476

Background: KRAS gene mutation in colorectal tumors is predictive of nonresponse to anti-epidermal growth factor receptor (EGFR) antibodies in patients with metastatic colorectal cancer (CRC). The F-PHFA has been developed as a simple and accurate mutation detection assay especially for somatic mutations. In this study, we evaluated KRAS mutation detection by F-PHFA which detects 7 common mutations in codon 12 and 13. This study was a multicenter, clinical evaluation trial designed to evaluate the efficacy of the F-PHFA method forKRAS testing in patients with CRC. Primary endpoint was the concordance rate of KRAS mutation between F-PHFA and direct sequencing with manual micro-dissection (MMD) to enrich the tumor concentration. Secondary endpoints included the concordance rate between F-PHFA and direct sequencing without MMD.

Methods: The key eligibility criteria included histologically confirmed colorectal adenocarcinoma with adequate tumor samples. The materials were formalin-fixed paraffin-embedded (FFPE) 8 unstained slides at 10 um and 2 matching hematoxylin-eosin (HE)-stained slide, which were sent to the central pathology review to confirm the tumor content and to mark the tumor area. Genomic DNA was extracted using QIAamp DNA FFPE Tissue from both whole tissue of slide and tissue with MMD. F-PHFA and direct sequencing were conducted independently in two laboratories.

Results: FFPE specimens from 165 patients with colorectal adenocaricinoma were registered. Success rates on KRAS tests of F-PHFA both of with or without MMD were 100% (165/165). However, those of direct sequencing were 99.4% (164/165). The concordance rate between F-PHFA and direct sequencing were 99.4% (163/164) for both of with MMD and without MMD. Only one discordant sample had a rare mutation other than the 7 common mutations. Total assay time was about 3.5 hrs. Also 20 ng of DNA was enough to examine 7 types of KRAS mutations.

Conclusions: We confirmed that F-PHFA and direct sequencing shows high concordance rate regardless of MMD. F-PHFA for KRAS mutation detection method is very suitable for clinical use in terms of easiness and accuracy.
Effect of stents on radiation dosimetry for esophageal cancer.
Authors: Francis Samual Roberts , Anker Christopher James , Wang Brian , Williams Greg V. , Adler Douglas G. , Salter Bill J.
Published: February 2017

48

Background: To evaluate how self-expanding metal stents (SEMS) affect esophageal cancer radiation planning target volumes (PTVs) and dose delivered to surrounding organs-at-risk (OARs).

Methods: Ten patients were evaluated for whom a SEMS was placed before radiation. A CT scan obtained before stent placement was fused to the post-stent CT simulation scan. Three methods were used to represent pre-stent PTVs: 1) Image Fusion (IF) - PTVs were contoured based on the pre-stent CT, 2) Volume Approximation (VA) - the post-stent PTV was altered to approximate the pre-stent PTV based on differences in esophageal volumes between scans, and 3) Diameter Approximation (DA) - the post-stent PTV was altered based on differences in esophageal diameters. PTVs and OARs were contoured per RTOG 1010 protocol using Eclipse Treatment Planning software. Post-stent dosimetry for each patient was compared to approximated pre-stent dosimetry.

Results: For the IF, VA, and DA methods, the post-stent PTVs were larger than pre-stent PTVs by an average of 155, 68, and 67 cm3, respectively. Pre-stent heart and lung doses were less than post-stent using VA and DA; however, IF only yielded a significantly lower heart V40 (Table). Liver, spinal cord, and kidney doses were not significantly different between planning methods.

Conclusions: Placement of an esophageal SEMS increased the PTV size for radiation planning, causing a statistically significant increase in heart and lung radiation doses, although the absolute dose increase was relatively small. Most patients receiving stents will have no increased risk of radiation-induced toxicity. In patients where one anticipates difficulty meeting crucial dose constraints, it may be preferable to consider avoidance of stenting before radiotherapy.

[Table: see text]
Use of colorectal cancer subtypes identified through iterative clustering to predict response to therapy.
Authors: Schlicker Andreas , Beran Garry , Chresta Christine M , McWalter Gael , Pritchard Alison , Weston Susie , Runswick Sarah , Davenport Sara , Heathcote Kerry , Alferez Castro Denis , Orphanides George , French Tim , Wessels Lodewyk F A
Published: February 2017

482

Background: Colorectal cancer (CRC) is generally stratified based on genetic and epigenetic features, such as KRAS mutation and microsatellite instability status. In order to facilitate the development of new targeted drugs and treatment regimens, it is important to redefine CRC at the molecular level by identifying subtypes that are relevant for response to targeted therapy.

Methods: We applied a new unsupervised approach for iteratively stratifying tumor samples using genome-wide mRNA expression data. The resulting gene expression signatures were used to subtype CRC cell line panels and publicly available CRC tumor datasets. We employed pharmacological data on the cell line panels to link the subtypes to therapy response.

Results: Starting from a gene expression dataset of 63 CRC tumor samples, we employed non-negative matrix factorization (NMF) and identified two dominant CRC subtypes. In agreement with previously published results, one of the types showed a mesenchymal and the other an epithelial-like gene expression pattern. In a second step, we applied NMF on these two dominant subtypes and further stratified them into two and three subtypes, respectively. The resulting five CRC subtypes show many differences, most notably activation of specific signaling pathways. Importantly, we recovered these five subtypes in several independent, publicly available CRC datasets. This strongly suggests that the signatures capture disease-relevant features of CRC. Furthermore, we found that the different subtypes corresponded to different cell lines in a panel of CRC cell lines. The clustered CRC cell lines displayed differential responses to a number of targeted compounds, indicating that the new CRC clusters may represent disease subtypes that of differential drug sensitivity.

Conclusions: The CRC subtypes discovered using our new method offer new insights into the functional and molecular processes driving CRC. Furthermore, the evidence suggests that these subtypes may differ in activated pathway status and the response to some targeted inhibitors, indicating that targeting pathways conserved in these subtypes may provide new drug discovery opportunities.
Characterization of serum proteome in patients with metastatic colorectal cancer responsive and nonresponsive to bevacizumab using 2 d-DIGE.
Authors: Martin Petra , Noonan Sinead , Nolan Blathnaid , Scaife Caitriona , Elia Giuliano , O'Donoghue Diarmuid , Fennelly David William , O'Sullivan Jacintha
Published: February 2017

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Background: Treatment of patients with metastatic colorectal cancer includes chemotherapy and a monoclonal antibody (cetuximab or bevacizumab). Patients who have k-ras mutated tumors are given bevacizumab. However, no biomarker exists to determine those patients who will respond to this targeted treatment. The objective of this study was to investigate the differential protein expression between patients who do and do not respond to bevacizumab and also compare this with normal controls.

Methods: Serum from 24 patients diagnosed with metastatic colorectal cancer and 11 normal controls were collected pre-treatment. All patients received bevacizumab along with chemotherapy. Progression free and overall survival data was collected on all patients. Serum was depleted of high abundant proteins and protein expression analysed using fluorescence two-dimensional differential in-gel electrophoresis (2 D-DIGE). Gels were scanned using a Typhoon 9410 Variable Mode Imager (GE Healthcare) and exported into Progenesis SameSpots v3.3 (Nonlinear Dynamics, UK) for quantitative analysis. Selected differentially expressed were excised, digested with trypsin and analysed using the LTQ-Orbitrap XL mass spectrometer.

Results: 66 proteins were identified to be statistically expressed between the responders and non-responding group (p<0.05). 30 proteins were differentially expressed between the cancer and normal group (p<0.05).

Conclusions: There is a significant difference in protein expression patterns between responders and non responders to bevacizumab. Further screening required to assess for instability proteins that may have functional importance in governing treatment resistance.
Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors.
Authors: Rangwala Fatima A. , Bendell Johanna C. , Kozloff Mark , Arrowood Christy , Meadows Jennifer , Tourt-Uhlig Sandra Ellen , Murphy Jennifer , Meadows Kellen , Morse Michael , Uronis Hope Elizabeth , Hsu Shiaowen David , Zafar Yousuf , Hurwitz Herbert
Published: February 2017

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Background: Everolimus (E), an oral rapamycin analogue, is a potent mTOR inhibitor. Combined inhibition of VEGF and mTOR pathways may increase anti-angiogenic and anti-tumor activity. We evaluated E in combination with capecitabine (C), oxaliplatin (O), and bevacizumab (B) in a phase I dose escalation study.

Methods: Eligible patients (pts) had advanced solid tumors, adequate organ function and no increased risk for class-related toxicities. B and O were given intravenously; C and E were orally administered. Cycle length was 21 days. Doses for level 1: C 850 mg/m2 on days 1-14; O 130 mg/m2 on day one; B 7.5 mg/kg on day one; and E 5 mg three times a week. Doses for level -1: C 680 mg/m2, O100mg/m2. An intermediate dose level (-1b) of E escalated to 5 mg five times weekly was added to maximize dose intensity. Dose limiting toxicity (DLT) was assessed in cycle 1. Concomitant administration of CYP3A4 substrates, inhibitors or inducers was prohibited.

Results: Dose escalation is complete with 27 pts evaluable for toxicity and 24 evaluable for efficacy. Two DLTs (grade 2 intolerable fatigue, anorexia, vomiting and grade 3 diarrhea) were observed in 6 pts in cohort 1. No DLTs were observed in cohort -1; one DLT (rectovaginal fistula) was observed in the -1b cohort. Possible grade ≥3 treatment-related adverse events any time on study (n=1 except as indicated) included diarrhea (n=2), intestinal perforation/fistula, rectovaginal fistula, hypertriglyceridemia (n=3), hyperglycemia, hypoalbuminemia, hyponatremia, peripheral neuropathy, neutropenia (n=2), lymphopenia, thrombocytopenia, hypertension (n=3), deep vein thrombosis, and arterial thrombosis. Adverse events were consistent with known class-related toxicities. For efficacy, 10 pts had a partial response (PR); 10 had stable disease as best response. Of 13 pts with chemorefractory metastatic colorectal cancer (mCRC), 5 had a PR. Of 8 pts with chemonaive mCRC, 5 had a PR.

Conclusions: E in combination with full dose C, O and B was associated with unacceptable toxicity, primarily GI toxicity. E at 5mg five times weekly, C at 680 mg/m2 on days 1-14, O at 100 mg/m2 and B at 7.5 mg/kg on day one appears well tolerated. Activity was noted in chemorefractory and chemonaive mCRC patients.
Survival analysis according to disease subtype in AVAGAST: First-line capecitabine and cisplatin plus bevacizumab (bev) or placebo in patients (pts) with advanced gastric cancer.
Authors: Shah Manish A. , Van Cutsem Eric , Kang Yoon-Koo , Dakhil Shaker R. , Satoh Taroh , Chin Keisho , Bang Yung-Jue , Bu Lilian , Bilic Grozdana , Ohtsu Atsushi
Published: February 2017

5

Background: Gastric cancer (GC) is a heterogeneous disease that may be divided into distinct subtypes with different epidemiology, risk factors, and molecular expression profiles: proximal non-diffuse GC (type 1), diffuse GC (type 2), and distal non-diffuse GC (type 3). In clinical practice, GC subtypes are treated as a single disease. Regional efficacy differences were seen in AVAGAST: pts in Americas and Europe showed more evidence of benefit than Asia-Pacific pts. We analyzed outcomes in the phase III AVAGAST study according to GC subtype and region in order to test if GC subtype was prognostic of outcome and predictive of bev benefit.

Methods: Pts were randomized and treated as previously described. The effect of treatment on overall survival (OS), measured by hazard ratio, was examined in an unplanned exploratory analysis using Cox proportional hazards models. Median OS was estimated using the Kaplan-Meier method.

Results: 733 of 774 AVAGAST pts were included. Type 2 GC (52.1%) was more common than type 1 (9.5%) or type 3 (38.3%). Irrespective of treatment, pts with type 2 GC had worse outcome than type 3 GC (median OS 10.3 vs 11.7 mo; HR=0.82; 95% CI 0.68–1.00); non-Asian pts had the most dismal prognosis (8.0 vs 11.1 mo; HR=0.68; 95% CI 0.53–0.89). The table below describes the bev effect according to subtype. Non-Asian pts with GC type 2 and 3 appear to benefit from bev.

Conclusions: In all regions, pts with type 3 GC had a better prognosis than type 2 GC. Bev therapy appeared to improve outcomes in non-Asian pts with type 2 and 3 GC. These data suggest that GC subtypes may be important predictors of pt outcome and warrant further prospective evaluation.

[Table: see text]
Cetuximab-based or bevacizumab-based first-line treatment in patients with KRAS p.G13D mutated metastatic colorectal cancer (mCRC)? A meta-analysis of 54 cases.
Authors: Heinemann Volker , Reinacher-Schick Anke , Stintzing Sebastian , Giessen Clemens Albrecht , Tannapfel Andrea , Laubender Ruediger P. , Brodowicz Thomas , Knittelfelder Regina , Vrbanec Damir , Schmiegel Wolff , Modest Dominik Paul , Zielinski Christoph
Published: February 2017

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Background: KRAS p.G13D mutant metastatic colorectal cancer (mCRC) has been identified to represent a cetuximab-sensitive subtype of KRAS mutant mCRC. This analysis aims to answer the question whether first-line treatment of p.G13D mCRCs should contain cetuximab or bevacizumab.

Methods: Fifty-four patients with p.G13D mutant mCRC were pooled in this analysis. All patients underwent systemic 1st-line treatment with a fluoropyrimidine and oxaliplatin/irinotecan that was combined with either cetuximab or bevacizumab.

Results: Overall response rate was comparable between cetuximab- and bevacizumab-based regimens (58% vs 57%). Progression-free survival was comparable (8.0 months-cetuximab-group vs 8.7 months bevacizumab-group). Overall survival (OS) was longer in patients treated with cetuximab as first-line therapy (20.1 months vs 14.9 months). Logistic regressions modelling OS revealed oxaliplatin-based first-line treatment to correlate significantly with poor outcome (p=0.03). Moreover, a strong trend in favour of capecitabine compared to infusional 5-FU (p=0.06) was seen.. Responders among our cohort showed a benefit concerning PFS and OS undergoing cetuximab- but not bevacizumab-based regimen.

Conclusions: This retrospective pooled analysis suggests that cetuximab-based first-line therapy in p.G13D mutant mCRC shows similar activity compared to bevacizumab-containing regimen. Infusional 5-FU and oxaliplatin may represent inferior options compared to capecitabine and irinotecan in p.G13D mutant mCRC 1st-line treatment.
Pretreatment levels of serum lactate dehydrogenase (LDH) and clinical outcome in metastatic colorectal cancer patients receiving first-line chemotherapy and bevacizumab.
Authors: Maccaroni Elena , Giampieri Riccardo , Scartozzi Mario , Del Prete Michela , Faloppi Luca , Bianconi Maristella , Bittoni Alessandro , Galizia Eva , Loretelli Cristian , Belvederesi Laura , Cascinu Stefano
Published: February 2017

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Background: No predictive marker for efficacy of a Bevacizumab-based therapy has been identified in metastatic colorectal cancer. Soluble LDH levels seem to be related to increased angiogenesis. The focus of this analysis is whether high levels of LDH can be related to higher benefit of bevacizumab-based therapy in this setting.

Methods: Eligible patients were metastatic colorectal cancer patients treated in 1st line setting with a chemotherapy doublet and bevacizumab in the last year. A historical control group was also formed by collecting data of patients treated with only a chemotherapy doublet. Pre-treatment LDH serum levels were collected for all patients. Cut-off level for soluble LDH was determined via ROC curve. Primary end-point was difference in progression free survival between the two groups. Secondary end-points were overall survival and response rates.

Results: 82 patients treated with first line containing bevacizumab were eligible for our analysis. 138 patients were identified as control group. The two groups were comparable for major clinical characteristics. LDH cut-off level was stated at 588 mg/dl. In the control group PFS of 4.2 and 8 months were observed for LDH high and low levels (p=0.0003,HR:0.2973,95%CI:0.0318 to 0.3543). OS were 19.6 and 34.9 months (p=0.0014,HR:0.2484,95%CI: 0.0188 to 0.3884). No significant differences were seen for response rates (with 20% vs 39% partial responses, p=0.1671). In the group of patients treated with Bevacizumab, PFS of 8.5 and 7.3 months were observed respectively for LDH high and low levels (p=0.2,HR:0.6360,95%CI:0.2528 to 1.4185). OS were 26.6 and 22 months (p=0.7,HR:0.8480,95%CI:0.2307 to 2.9563). Improved response rate for LDH high patients could be seen (58% vs 14% partial responses, p=0.0243).

Conclusions: These data confirm the role of soluble LDH as marker of worse outcome for unselected patients and also suggest a role as potential marker of increased effectiveness of Bevacizumab based therapy.