bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic impact of tumor MET expression among patients with stage IV gastric cancer: A Danish cohort study.
Authors: Erichsen Rune , Oliner Kelly S. , Kelsh Michael A. , Nielsen Karsten B. , Frøslev Trine , Lænkholm Anne-Vibeke , Vyberg Mogens , Acquavella John F. , Sørensen Henrik Toft
Published: February 2017

43

Background: Recent clinical trial data indicate poor prognosis for patients with late-stage gastric cancer and positive tumor mesenchymal epithelial transition factor (MET) protein expression. However, there is limited information about the real-world prevalence of MET-positive (-pos) cancers and the associated prognosis. Methods: Using medical registries, we identified a cohort of patients with stage IV gastric cancer in a single institution in Northern Denmark from 2003-2010. From these patients, we collected archived (paraffin-embedded) cancer specimens and analyzed MET protein expression by immunohistochemistry (MET-pos if ≥25% of tumor cells showed membrane staining). We calculated the prevalence of patients with MET-pos tumors. We estimated survival using the Kaplan-Meier method and computed mortality rate ratios comparing MET-pos to MET-negative (-neg) patients using Cox proportional hazards models adjusted for age, gender, and Charlson’s Comorbidity Index (score of 0, 1-2, and 3+). Results: 101 patients with stage IV gastric cancer were included in the study of which 55% had MET-pos tumors. The group of patients with MET-pos tumors were younger at diagnosis than patients with MET-neg tumors (median age 65 vs 68 years), included more men, showed higher comorbidity levels, included more poorly differentiated cancers, and were less likely to undergo surgery or chemotherapy. In patients with MET-pos tumors, one-year survival was 18% compared to 39% in patients with MET-neg tumors (mortality rate ratio=2.3, 95% CI: 1.4-3.9). Conclusions: A large proportion of patients with stage IV gastric cancer had tumors demonstrating MET protein expression, and these patients had poor survival compared with patients without tumor MET expression. [Table: see text]
Determinants of anemia in screen-detected colorectal cancer.
Authors: Mansouri David , McMillan Donald , Crighton Emilia M. , Horgan Paul G.
Published: February 2017

430

Background: Anaemia is an important clinical feature in colorectal cancer, since it may result in blood transfusion that may in turn compromise long term survival. The aim of the present study was to examine the relationship between tumour and host features, and anaemia in patients undergoing surgery for screen detected colorectal cancer. Methods: A prospectively maintained database of patients with cancer detected through a population based faecal occult blood test (FOBt) screening programme was analysed. Preoperative anaemia was defined as Hb<115 g/l in females and Hb<130 g/l in males. The amount of blood in the stool was classified on the degree of positivity of the FOBt (strong/weak) and the SIR was measured by the preoperative neutrophil to lymphocyte ratio (NLR>5/NLR<5). Results: A total of 263 patients were included: 174 (66%) males, 49 (19%) rectal, 177 (67%) node negative. Preoperative anaemia was present in 61 (23%) patients. The presence of anaemia was associated with more advanced T-stage (5% T1 vs. 42% T4, p<0.001), advanced N-stage (18% N0 vs. 45% N2, p=0.001), and the presence of a right-sided tumour (44% vs. 14%, p<0.001). In addition, anaemia was more likely to be present in patients with a strongly positive FOBt (30% strong vs. 19% weak, p=0.034), and in patients with an elevated SIR (44% vs 22%, p=0.045). Right-sided tumours were more likely to be strongly positive on FOBt compared to left-sided tumours (43% vs. 34%, p=0.053). Furthermore, strong FOBt positivity was associated with advanced T-stage (p=0.015), however was not associated with the presence of an elevated SIR (p=0.604). When T-stage, FOBt positivity and the SIR were examined in binary logistic regression analysis, only advanced T-stage (O.R. 2.82, 95% C.I. 1.32 – 6.02, p=0.008) remained significant in predicting those more likely to be anaemic. Conclusions: In this predominantly early stage cohort of screen-detected colorectal cancer, anaemia was uncommon. Its presence was related to both a greater amount of enteric blood loss and an elevated SIR, however these appear to be driven by the stage of the tumour itself. Further work, exploring in more detail the mechanism by which anaemia develops in early stage colorectal cancer is required.
Targeted therapy in gastrointestinal stromal tumor (GIST): A nationwide database analysis from Taiwan.
Authors: Chiang I-Jen , Shau Wen-Yi , Fang Wei-Tse , Fang Chi-Hui , Chen Yen-Yang
Published: February 2017

437

Background: Gastrointestinal stromal tumor (GIST) is a visceral sarcoma that arises from the gastrointestinal tract. Currently, imatinib (first-line) and sunitinib (second-line) are two reimbursed targeted therapies for GIST in Taiwan. This study aimed to evaluate the real world data of targeted therapies in GIST treatment among Taiwanese population. Methods: We conducted a nationwide retrospective cohort study based on data from the National Health Insurance Research Database (NHIRD) between January 2005 and December 2010. NHIRD is a comprehensive database of administrative and claim data which covers over 99% of entire population in Taiwan. Patients were selected with ICD codes and targeted therapy utilization, imatinib (IMA) or sunitinib (SUN). Time to treatment discontinuation (DC) due to any reasons (such as death, intolerance and disease progression) was estimated using Kaplan-Meier analysis. Results: From 2005 to 2010, the incidence rate of GIST in Taiwan was between 20 and 30 cases per million. A total of 3,436 GIST patients were identified; the mean age was 63.2 years and 57 % were male. Most patients (94.7%) received standard dose IMA (…400mg/day). Among these patients, 136 patients (4.0%) required IMA dose escalation and 44 (1.3%) patients switched to SUN after IMA. The probability of the 1st-line treatment DC was 20%, 30.7%, 38.9%, 43.2%, and 47.1% for years 1 to 5, respectively. The probability of a change in treatment pattern (defined as either IMA dose escalation or switch to SUN) was 4% 6.8%, 9.6%, 10.5% and 11.7% for years 1 to 5. Lastly, the probability of the 2nd-line treatment DC was 20.5%, 33.7%, 41.1%, 44.8%, 51.7% for years 1 to 5, respectively. Conclusions: First-line IMA plus other treatment modalities may provide additional benefits to progression-free survival. Taiwanese GIST patients who failed first-line treatment still gained benefit from either IMA dose escalation or a switch to SUN. Additional analysis is required for the detailed comparison in different treatment patterns.
Smoking and the risk of anal cancer recurrence: The Addenbrookes Hospital experience.
Authors: Bowzyk Al-Naeeb Anna , Barnett Gill , Wilson Charles
Published: February 2017

439

Background: Anal cancer, a tumour induced by the human papilloma virus (HPV) is highly responsive to chemoradiation. Smoking appears to be an important cofactor in its development, possibly through immunomodulatory mechanism and has been reported to have a negative effect on prognosis. Objective is to evaluate the relation between smoking and the outcome in patients receiving radical chemoradiotherapy (50.4 Gy/ 28f with concomitant 5FU/Mitomycin) for squamous carcinoma of the anus. Methods: 109 patients treated with radical intent from January 2009- Feb 2013 were retrospectively analysed. Details of staging, smoking history, HIV status, response to treatment, follow up time and recording of persistent or recurrence were collected. High risk disease (HR) was defined as any T3/T4 disease or TxN2+, standard risk (SR) as T1/2 N0-1. Results: 68 females and 41 males with an age range 38-83 (median 61).Data about smoking status was available in 74 patients: 28 smokers, 8 ex-smokers, and 38 non-smokers. 54/109 (49%) had high risk disease (HR), and the distribution was balanced across the groups. 4 patients were HIV positive. Median follow up time was 23 months. Complete clinical response was achieved in 101/109 (93%), 1 patient died (cause unknown), and 7 had persistent disease. Of these 6 were smokers (2 SR, 3HR, 1 HR and HIV+) 1 was a non-smoker (1 HR). 9 patients developed recurrent disease: 5 smokers (2 SR, 3 HR), 1 ex-smoker (HR), 3 unknown (2HR, 1SR). 11/16 patients who had a local failure were persistent smokers. Using ordinal logistic regression, smoking increases the risk of recurrence with an Odds ratio of 17.4 (p=0.008). Conclusions: This retrospective series suggest that smoking is associated with a higher risk of local recurrence following chemoradiotherapy. One of the hypothesis is that tissue hypoxia may impact on the oxygen dependent effect of chemoradiation. Patients should be encouraged to stop smoking and smoking may need to be considered as a factor defining a higher risk category which may benefit from dose escalation.
Are the survival benefits associated with primary resection in de novo metastatic colorectal cancer (mCRC) mediated by reversal of systemic inflammation?
Authors: Tran Phillip V. , Samanthaby Mathu , Wong Hui-li , Desai Jayesh , Tie Jeanne , Field Kathryn M. , Kosmider Suzanne , Bae Susie , Gibbs Peter , Tran Ben
Published: February 2017

464

Background: Despite reported survival benefits for primary tumor resection in de novo mCRC, its use remains controversial, particularly as the biological explanation remains unclear. We explored whether reversal of systemic inflammation, a marker of a tumor-promoting immune response and poor prognosis, is associated with improved survival in pts undergoing primary resection. Methods: We identified pts who underwent primary resection for de novo mCRC from a prospective CRC database, excluding pts who had metastatectomy. Neutrophil-lymphocyte ratio (NLR) was used to represent systemic inflammation. Survival differences associated with reversal of systemic inflammation, as defined by NLR falling from an elevated level (> 5) at diagnosis to ≤ 5 postoperatively, were examined. Associations between falling NLR and primary tumor bulk (maximal length assessed by pathologist) as well as metastatic burden (maximal axial diameter of largest metastasis assessed by radiologist) were explored. Results: Baseline and postoperative NLR were examined in 156 pts with median age 69y and median overall survival (OS) 18.3 mo. Baseline NLR was elevated in 66 (42%) pts; primary resection resulted in falling NLR in 37 of these pts (56%). Compared to pts with persistent NLR >5, a falling NLR was significantly associated with improved OS (HR 0.53, p = 0.012). Falling NLR was also associated with larger primary tumors, although this was not significant (median length 55mm vs. 45mm, p = 0.059). In a preliminary analysis of 26 pts with retrievable radiology, falling NLR was associated with lower metastatic burden compared to an unchanged NLR (median diameter 29mm vs. 41mm, p = 0.046). Conclusions: Our data demonstrates improved OS in pts who have reversal of systemic inflammation following primary resection in de novo mCRC. The possible associations between reversed systemic inflammation with larger primary tumors or a lower metastatic burden suggest an immune mediated response to reduced tumour bulk as an explanation for the reported survival advantage associated with primary resection. If confirmed, this might define a subgroup of pts who might benefit most from primary resection.
Detection of potential actionable targets in appendiceal cancer detected by immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and mutational analysis.
Authors: Borazanci Erkut , Kimbrough Jeffery , Sachdev Jasgit C. , Millis Sherri Z. , Ejadi Samuel , Burnett Ken , Ratliff Stephanie , Von Hoff Daniel D. , Ramanathan Ramesh K.
Published: February 2017

469

Background: Appendiceal cancers are rare and there are no established guidelines for adjuvant treatment and metastatic disease. Methods: Samples were identified from > 60,000 global tumors analyzed at a referral molecular profiling CLIA certified laboratory (Caris Life Sciences) for biomarkers of drug sensitivity, under an approved protocol. 285 samples with primary tumor sites of appendix were identified (M/F ratio of 38%/62%; mean age of 55). Approximately 80% of samples were adenocarcinomas, 10% carcinoids, and 10% of indeterminate histology. IHC assays (n=273) were performed with up to 30 biomarkers; FISH (n=39) for c-Myc, cMET, EGFR, HER2 and/or TOPO2A gene copy amplifications; and sequencing done ( n= 223) for KRAS, EGFR, PIK3CA, and BRAF. Results: Targets on IHC: 97% high BCRP; 16% high KIT; 80% high COX-2; 50%high EGFR; 30% low MGMT, 81% high MRP1, 35% high PDGFR, 82% low PTEN, 27% high RRM1, 39% high SPARC; 67% high TLE3, 27% high TOPO2A ; 63% high TOPOI, and 99% negative TS. Targets on FISH: 5% amplified EGFR and 0% amplified Her2/Neu. Sequencing results: 53% mutated KRAS and 2% mutated BRAF. Conclusions: The high levels of drug resistance proteins (BCRP and MRP1) highlights the difficulty in treating these tumors. The incidence of KRAS mutations (53%) and low expression of TS (99%) is noteworthy, and points towards using 5FU/capecitabine as a backbone of therapy. Therapeutic options are varied and options include TOPO1 inhibitors (irinotecan/topotecan), EGFR inhibitors (erlotinib, cetuximab), PDGFR antagonists (regorafenib, axitinib), MGMT (temazolamide), BRAF inhibitors (vemurafenib, dabrafenib) and SPARC (nab-paclitaxel). These findings indicate the need to evaluate patient samples for patterns in marker expression and alteration, in order to better understand the molecular biology and formulate a personalized therapy approach in these difficult to treat cancers, and to pursue whole genomic sequencing. Supported by a grant from Caris Life Sciences.
Immune response and its correlation with the disease activity in patients with advanced colorectal cancer (aCRC): Results from a prospective observational study.
Authors: Ahmed Shahid , Wei Guojian , Lim June , Arnold Florence Pilar M. Plaza , Abbas Tahir , Iqbal Nayyar , Dwernychuck Lynn , Sami Amer , Haider Kamal , Yadav Sunil , Bretscher Peter
Published: February 2017

471

Background: Currently limited biomarkers are available to monitor disease status in cancer patients. Although host factors are critical in regulating cancer, the role of immune responses in aCRC is less clear. A predominant T helper 1 (Th1) response may be more effective to contain cancer than one with a substantial Th2 component. The Th1/Th2 phenotype can be inferred from relative prevalence of IgG isotypes among anti-cancer antibodies and may provide an innovative way to assess disease activity. The study aims to develop an ELISA assay to monitor IgG1:IgG2 and its utility in predicting disease status in aCRC. Methods: A validated ELISA assay (Bertech Pharma) utilizing CRC cell lines was developed to measure IgG1 (Th2) and IgG2 (Th1) levels. A sample size of 44 (24 CRC and 20 healthy control [HC]) was estimated to achieve 80% power and α error of 0.05 assuming that the assay correctly detect CRC specific antibody in > 80% cases. The IgG1:IgG2 was compared between/within groups with HC and aCRC. Results: Samples were collected from 62/66 individuals recruited at 2:1 over 1 yr. 43 CRC patients had median age of 65 yrs (39-86) and M:F 2.3:1. 25 had >1 metastatic site, 31 underwent primary tumor resection and 37 received chemotherapy. Using standard criteria, 14/43 (33%) CRC patients had elevated 1gG1 titer compared with 2/19 (10%) HCs (p = 0.06). Mean IgG1 of CRC group was 0.18±0.05 compared with 0.15±0.01 in HC (p = 0.01). Conversely, mean IgG2 level of CRC group was 0.26±0.11 compared with 0.38±0.15 in HC (p = 0.003). Mean IgG2:IgG1 of CRC group was 1.5±0.35 compared with 2.5±0.97 in HC (p < 0.001). Among 43 CRC patients, 7/12 (58%) with disease progression (DP) had elevated IgG1 compared 7/31 (23%) with stable disease (p = 0.03). Strikingly, 9/12 (75%) patients who died had elevated IgG1 compared with 5/31 (16%) who were alive during the follow up, p = 0.001. Logistic regression revealed positive association among elevated IgG1 and DP, HR:4.8 (95% CI:1.2-19.9) and mortality, HR:15 (95% CI:3.1-78.8). Conclusions: Our results revealed that patients with aCRC have abnormal IgG1:IgG2 compared with HC and elevated IgG1 (a predominant Th2 response) levels in aCRC correlate with DP and mortality.
A phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer.
Authors: Overman Michael J. , Eng Cathy , Kee Bryan K. , Fogelman David R. , Shroff Rachna T. , Fark Christine , Moinova Helen , Lutterbaugh Jim , Issa Jean-Pierre J. , Markowitz Sanford D. , Kopetz Scott
Published: February 2017

488

Background: Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and both clinical and preclinical studies have shown the ability to restore platinum sensitivity with the reversal of hypermethylation. CIMP is implicated in the pathogenesis of a subset of colorectal cancers termed CIMP-high. Methods: The primary objectives were as follows: phase I—MTD and DLTs; phase II—RECIST response rate. Prior progression on fluoropyrimidine/oxaliplatin-based treatment was required (RECIST criteria progression in 21 pts). The phase II portion was restricted to patients with CIMP-high (≥ 2/6 methylation-specific PCR markers: hMLH1, P16, P14, MINT1, MINT2, and MINT31). Pre-treatment, C1D5, C2D1, C2D5, and at restaging blood samples were collected. Results: 26 pts [M/F 15/11, median age: 66 yrs (range: 34-75), ECOG PS 0/1: 1/25, median number of prior therapies: 4.5] were enrolled from 8/2010 to 12/2012. The phase I portion enrolled 15 pts (12 treated at MTD), of which 3 were CIMP-high. No DLTs were observed with the MTD determined to be azacitidine (75 mg/m2, SQ D1-5), oxaliplatin (110 mg/m2 IV D2), and capecitabine (1500 mg/m2/d, PO divided BID, D1-14) q21 days. The phase II portion enrolled 11 CIMP-high pts and closed due to lack of an objective response. Common grade 3-4 treatment-related toxicities were neutropenia in 10 pts (38%) and diarrhea in 3 pts (12%). Grade 2 fatigue occurred in 14 pts (54%). No responses were seen. Stable disease (SD) occurred in 7 of 15 phase I pts and 10 of 11 phase II pts (p=0.04) with median PFS of 2.5 and 4.5m (p=0.04), respectively. SD >6 months was seen in 2 phase II pts (6.8m and 8.5m). Median OS and median post-study OS were 9.4m and 5.3m, respectively, and were similar between phase I and phase II portions. Post-study therapy was given to 14 patients: 12 progressed, 1 on active treatment, 1 lost to f/u. Conclusions: Azacitidine and CAPOX were well tolerated with high rates of stable disease in CIMP-high pts, but no objective responses. Improved activity from post-study treatment was not seen. Ongoing correlative work evaluating quantitative changes in methylation from circulating free tumor DNA will be presented. Clinical trial information: NCT01193517.
Plasma cell-free DNA and fraction of circulating KRAS mutations as prognostic in patients with metastatic colorectal cancer.
Authors: Sefrioui David , Vasseur Nasrin , Sesboüé Richard , Blanchard France , Oden-Gangloff Alice , Sabourin Jean-Christophe , Frébourg Thierry , Michel Pierre , Di Fiore Frédéric
Published: February 2017

490

Background: It has been suggested that detection of circulating tumor DNA may be relevant in patients with metastatic colorectal cancer (mCRC). The main objective of the present study was to evaluate a method based on the TaqMan Mutation Detection Assay (TMDA) for the detection of circulating KRAS mutations in mCRC patients. Moreover, we also investigated the prognostic impact of the plasma cell-free DNA and the fraction of circulating KRAS mutations. Methods: The study was conducted from April to July 2013 and plasma samples were prospectively collected in a series of 35 mCRC patients treated with chemotherapy (CT). QIAamp Circulating Nucleic Acid kit was used for DNA extraction and Quant-iT High Sensitivity dsDNA Assay for cf-DNA quantification. Detection of circulating tumor DNA was based on the KRAS mutations detected in tumour and was performed in plasma by the castPCR Technology TMDA. Response to CT was assessed according to RECIST criteria. The results of plasma cf-DNA and level of mutant DNA fragments were correlated with response and 3-months survival. Results: We isolated and quantified plasma cf-DNA in all patients with a mean concentration of 106 ng/mL. Among them, 18 were wild-type and 17 mutated for KRAS in the tumour. Detection of circulating KRAS mutations was performed with TMDA in 23 patients (10 KRAS wild-type and 13 KRAS mutated). The sensitivity was 62% (8/13) and specificity 100% (0/10) with a level of circulating mutant DNA fragments ranging from 0 to 29%. Plasma cf-DNA and level of circulating mutant DNA were both significantly correlated with the 3-months survival (mean 36 versus 524 ng/mL, p=0.0015 and 2% versus 29%, p<0.0001). There was a non significant trend for response to CT (respectively p=0.14 and p=0.12). Conclusions: TMDA method is a simple, accurate and non-invasive tool for the detection of circulating tumor DNA. Our preliminary results also suggest that plasma cf-DNA and fraction of mutant DNA fragments could be prognostic markers in mCRC patients.
Correlation of lymphovascular invasion and staging in patients undergoing lymphatic mapping for colon cancer.
Authors: Korant Alpesh K. , Dhar Vikrom K. , Johnston Gregory , Saha Supriya Kumar , Shaik Mohammed , Wiese David , Saha Sukamal
Published: February 2017

498

Background: Lymphovascular invasion (LVI) is known as a negative prognostic factor in colon cancer (CCa) patients (pts). Sentinel lymph node mapping (SLNM) is known to upstage more pts than conventional surgery. A retrospective study was undertaken to determine the relationship between LVI and other known prognostic factors in CCa pts undergoing SLNM. Methods: Pts with CCa underwent SLNM. Data was collected for tumor (T) and node (N) stage, distant metastasis (M), size, grade, recurrence, and 5-year overall survival (5yrOS). Chi-square analysis was used to calculate the association between categorical variables with a p value of 0.05 as significant. Kaplan-Meier method was used to calculate 5yrOS. Results: We studied 310 CCa pts undergoing SLNM. Success rate was 100%. Nodal positivity was 46%. LVI was present in 34% of pts overall, in 66% node +ve pts versus only 7% in node -ve pts (p<0.001). Pts with LVI were proportionately of higher grade, larger size, higher T-stage, node +ve and higher AJCC stage. Pts with LVI had significantly higher recurrence and lower 5yrOS (Table). Conclusions: Presence of LVI positively correlated with all known prognostic factors in CCa pts undergoing SLNM, with higher recurrence and significantly lower 5yrOS. [Table: see text]
Concordance of ColoPrint and MSI-print classification in paired endoscopic-surgical specimens of stage I-III colorectal cancer (CRC).
Authors: Garcia-Carbonero Rocio , Sanchez-Simon Inmaculada , Bozada Juan M. , Araujo Miguez Angela , De la Portilla Fernando , Nieboer Frank , Stork Lisette , Simon Iris M.
Published: February 2017

501

Background: ColoPrint is a gene expression classifier that has demonstrated improved prognostic accuracy over conventional clinical and pathological factors in patients with stage II-III CRC (Salazar et al, JCO 2011). MSI-Print is a gene classifier that identifies patients with deficient mismatch repair system and MSI-H status (Tian et al. J Pathol 2012). The gene signatures have been validated in several independent patient cohorts. The aim of this study was to assess the performance of ColoPrint and MSI-Print in fresh-frozen endoscopic samples obtained by colonoscopy. Methods: A pilot study was initiated to address the concordance of gene signatures in paired endoscopic-surgical fresh-frozen samples from patients with stage I-III CRC. RNA was isolated from samples with > 30% tumor cells. Nineteen paired samples passed quality control and were hybridized to the diagnostic microarrays. Results: Patient characteristics–median age: 74 years (range:49-84); male/ female: 58/42(%); ECOG 0-1/2-3: 84/16(%); stage I/II/III: 21/47/32(%). ColoPrint risk classification was highly concordant between paired endoscopic and surgical specimens from the same patient. 14 cases were equally classified as low risk; 3 cases were equally classified as high risk; 2 cases were not concordant but the risk score was close to the cut-off value between low and high risk for both matched pairs (borderline samples). A similar high concordance was observed for the MSI signature in paired endoscopic-surgical samples (13 cases were equally classified as MSS, 5 equally classified as MSI, and 1 case had borderline results (both samples close to the cut-off between MSS/MSI). Conclusions: These encouraging preliminary results suggest endoscopic procedures may be valuable, non-invasive and widely available tools to obtain adequate tumor tissue for molecular assays, and can allow for easy implementation of genomic signatures in patients not amenable to surgical resection (i.e., advanced disease) and/or in less complex community sites for routine clinical practice.
A proprietary multianalyte test for predicting extreme resistance to neoadjuvant 5-FU based chemoradiation (CTRT) in esophageal adenocarcinoma (EC).
Authors: Shan Weiwei , Lassen Natalie , Johnson Clare , Biermann-Harrar Yaeli , Oelschlager Kristen M. , Cook Robert W. , Rosen Daniel , Badve Sunil S. , Kessler Kenneth , Saxena Romil
Published: February 2017

51

Background: Standard of care for localized EC is neoadjuvant CTRT followed by surgery. Although 5-FU based regimens are still commonly used, other regimens (CROSS) are also prescribed. Published EC studies report 20-25% of patients exhibit extreme resistance (exCTRT) to 5-FU based neoadjuvant treatment (NT); these patients may benefit from alternative treatment regimens. We have developed a proprietary assay using a training set of 167 patients to accurately identify patients with exCTRT (ROC 0.96). The results presented herein constitute an independent clinical validation. Methods: Biopsy samples from 71 pts diagnosed to have EC and who had undergone surgical excision following NT were obtained. IHC detection of NF-kB, SHH, and Gli-1 proteins in FFPE sections was performed in a CLIA approved lab. A GI pathologist and an expert clinical scientist blindly evaluated resection specimens and assigned a labeling index (LI) score. The LI for each case was compared to the established training set and the predicted response determined using a logistic regression algorithm. Blinded pathology scoring for exCTRT vs. non-exCTRT was performed for all samples using both CAP Tumor Response Grade (TRG) and the Rohatgi research scale. Results: Of the 71 EC cases in the clinical validation cohort, 24 had an outcome of exCTRT (<50% reduction in tumor following neoadjuvant treatment; TRG 3) and 47 had an outcome of non-exCTRT (>50% reduction in tumor; TRG 0-2). ROC for the validation cohort was 0.85. The positive predictive value for the validation study was 83%, reflecting an assay that can accurately predict those likely to have some degree of response to chemotherapy / radiation. Conversely, a negative predictive value of 83% with specificity of 94% was achieved indicating accurate identification of those not likely to benefit from neoadjuvant treatment. Conclusions: The analysis of NF-kB, SHH, and Gli-1 in EC tissue can accurately identify patients unlikely to respond to 5-FU based NT. These results are now confirmed using a CLIA accredited lab and a multicenter independent validation cohort of esophageal adenocarcinoma biopsies.
TRP genes family expression in colorectal cancer and its relationship with prognostic factors.
Authors: Kalender Mehmet Emin , Sozucan Yilmaz , Sari Ibrahim , Suner Ali , Oztuzcu Serdar , Bozgeyik Ibrahim , Cengiz Beyhan , Igci Yusuf Z , Balakan Ozan , Camci Celaletdin
Published: February 2017

513

Background: Different factors are effective in the development of colorectal cancer (CC). With the discovery of that TRP (transient receptor potential) genes family is an important component of calcium channel, about 30 members of the family of TRP ion channel in mammals have been determined up to the present. TRP channels are associated with many pathological conditions like cancer and cardiovascular diseases as well as the physiological significance of them.. The aim of this study is to investigate TRPM, TRPV and TRPC gene expression levels in tumor tissues of CC patients and to analyze the relationship of expression in tumor tissue of colorectal cancer with other known prognostic factors. Methods: In this study, 93 CC patients whose follow-up and treatment realized in Medical Oncology Department of Gaziantep University Medical Faculty Hospital were analyzed retrospectively. Level of TRP gene expression in paraffin blocks of normal and cancerous colorectal tissue samples of 93 patients were studied at the level of mRNA with real-time PCR. Results: From normal and cancerous colorectal tissues of 37 female and 56 male patients diagnosed with colorectal cancer, expressions of TRPV3, TRPV4, TRPV5, TRPM4, and TRPC6 genes in tumor tissue were detected lower when compared to normal tissue (p < 0.05). When expression levels of other TRP genes in tissues were compared, any significant difference was not found (p > 0.05). There was no meaningful difference between prognostic factors and gene expressions of tumor tissues statistically (p > 0.05). Conclusions: Expression of many proteins in cancer cells compared to normal cells increases or decreases. In CC, TRPV3, TRPV4, TRPV5, TRPM4, and TRPC6 genes of which expression in cancerous tissue decreases may be thought as potential genes contributing to tumorigenesis. To verify this hypothesis, it should be supported with further studies.
The 12-gene colon cancer assay validation and utility: Summary of clinical evidence.
Authors: Burke Emily , Tezcan Haluk , Lopatin Margarita , Clark-Langone Kim Michelle , Lee Mark , Shak Steven , Sing Amy Pratt
Published: February 2017

523

Background: The 12-gene colon cancer assay is the first commercially available molecular assay to predict the risk of recurrence in stage II/III colon and rectal cancer. Rigorous evidence for clinical validity and utility of an assay is imperative since the result is used for treatment decision-making. This summary outlines the studies that meet an established definition of clinical validation and additional studies that support the utility of the assay. Methods: Prospectively designed studies using archival tissue with pre-specified methods, clinical outcomes, and analysis plan were considered clinical validation studies (Simon et al. JNCI 2009). Additional studies that demonstrated the utility of the assay in a clinical setting were considered supportive. Results: The assay has been clinically validated in four independent studies with 3315 patients (2390 stage II/628 stage III colon and 130 stage II/167 stage III rectal). All four studies demonstrated a significant association (p<0.05) between the result and outcome (e.g. recurrence risk and cancer specific survival). The score was examined in the context of other variables, including T and N stage, MMR status, number of nodes examined, lymphovascular invasion, and tumor grade; across all studies, the result consistently contributed to risk stratification beyond these variables. Three clinical utility studies with 502 patients showed that 29-45% of initial treatment recommendations in stage IIA colon cancer were changed, with a net reduction in use of adjuvant chemotherapy. Conclusions: Clinical validation of the 12-gene assay followed a now-standard approach of using archived tissue from multiple large, prospectively-designed studies with documented long-term outcomes; the 12-gene colon assay meets level IB evidence criteria. Subsequent studies showed the assay has impact on clinical practice. The underlying tumor biology assessed by the score is relevant in both colon (stage II and III) and rectal cancer, providing information beyond conventional features, and can help guide treatment decisions regarding adjuvant chemotherapy.
Updated patient reported outcomes and survivorship care plan use by survivors of colorectal cancer (CRC).
Authors: Metz James M. , Hampshire Margaret K. , Vachani Carolyn , Di Lullo Gloria A. , Hill-Kayser Christine
Published: February 2017

527

Background: Colorectal cancer patients may be at risk for late effects after treatment, the impact of which may difficult to evaluate using conventional methods. Here, we described patient reported outcomes after CRC, as well as use of survivorship care plans. Methods: Patient-reported data were gathered via a convenience sample frame from CRC survivors voluntarily utilizing a publically available, free, Internet-based tool for creation of survivorship care plans. Available at www.livestrongcareplan.com and through the OncoLinkwebsite, the tool allows survivors to enter data regarding diagnosis, demographics, and treatments, and provides customized guidelines for future care. During use of the tool, CRC survivors are queried regarding late effects associated with specific treatments, and asked to answer “yes,” “no,” or “I don’t know.” They are also asked to score GI toxicity using WHO criteria. All data have been maintained with IRB approval. Results: 657 CRC survivors utilized the care plan and answered queries regarding late effects; 64% were female and 82% Caucasian. Median diagnosis age was 50 (24 – 76) and median current age 54 (24 – 77). Many reported having had multimodality therapy - 97% surgery, 89% chemotherapy, and 37% radiation. Overall, 63% reported chronic changes in bowel patterns, 38% chronic diarrhea, 9% bowel obstruction, 18% hernia development, 8% radiation colitis, and 2% fistula formation. Of 249 survivors who graded GI toxicity, 23% reported 4-6 stools per day, and 18% > 6 stools per day or incontinence. When queried regarding sexual function, 35% of men reported worse erectile function than pre-treatment, and 42% of women reported sexual changes such as vaginal dryness. A follow-up survey was completed by 31 (5%) of users, who reported that care plans improved knowledge about late effects (90%) and potential related treatments and tests (83%). Conclusions: Survivors using this tool report significant toxicity after cancer treatment, mainly related to GI and sexual function. Survivors appear to gain knowledge from survivorship care plans. The data reported here may be of significant impact in future study of quality of life, as well as patient counseling and survivor care.
Association of radiation therapy with overall survival in patients undergoing surgery for T3N0M0 adenocarcinoma of the rectum.
Authors: Marcus David Mitchell , Nickleach Dana , El-Rayes Bassel F. , Landry Jerome Carl
Published: February 2017

528

Background: The standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiation followed by surgery, but many physicians question the benefit of multimodality therapy in patients with stage T3N0M0 disease. We aimed to determine the impact of radiation therapy (RT) on overall survival (OS) in this group of patients. Methods: We used the Surveillance, Epidemiology, and End Results database to identify patients undergoing surgery for T3N0M0 adenocarcinoma of the rectum from 2004 to 2010. The Kaplan-Meier method was used to compare OS for patients receiving RT vs. no RT, along with for pre-op vs. post-op RT among patients that received RT. Multivariable analysis (MVA) using a Cox proportional hazards model was performed to assess the association of RT with OS after adjusting for patient age, gender, race, tumor grade, carcinoembryonic antigen, type of surgery, and circumferential margin status. The analysis was repeated separately on patients that underwent total colectomy (TC) vs. sphincter-sparing surgery. Results: The cohort included 8,679 patients, including 4,705 who received RT and 3,974 who did not. Median age was 66 years. Five year OS was 76.5% in patients who received RT, compared to 60.0% in patients who did not receive RT (p <0.001). Five year OS was 76.9% for patients receiving pre-op RT vs. 75.7% in patients receiving post-op RT (p = 0.247). In patients undergoing TC, five year OS was 74.7% for patients receiving RT, compared to 47.5% in patients not receiving RT (p <0.001). In patients undergoing sphincter-sparing surgery, five year OS was 77.7% in patients receiving RT, compared to 62.9% in patients not receiving RT (p <0.001). Use of RT was significantly associated with OS on MVA, both in the entire cohort (HR 0.70 [95% CI 0.60-0.81]; p<0.001) and in subsets of patients undergoing TC (HR 0.55 [95% CI 0.38-0.79]; p=0.001) and sphincter-sparing surgery (HR 0.70 [95% CI 0.59-0.84]; p<0.001). Conclusions: The use of RT is associated with superior OS in patients undergoing surgery for T3N0M0 adenocarcinoma of the rectum. This benefit is demonstrated in both the pre-op and post-op settings and applies to patients undergoing both TC and sphincter-sparing surgery.
Correlation of tumor-associated macrophages with clinicopathologic factors and angiogenesis in gastric cancer.
Authors: Lim Sung-Jig , Choi Sung Il , Park Jae
Published: February 2017

54

Background: Tumor associated macrophages (TAMs) are major components of tumor environment, and polarized into M1 and M2 type. M1 has been known as antitumorigenic, whereas M2 as protumorigenic. M2 have a significant role in tumor progression by promoting tumor cell invasion, migration and angiogenesis. We evaluated the M2 macrophages to investigate its importance in predicting clinical outcome or prognosis, and the relationship between M2 and angiogenesis in patients with gastric cancer. Methods: Formalin-fixed, paraffin-embedded blocks were obtained from the 88 patients with gastric cancer. CD163+ TAMs and CD105+ vessels were evaluated by immunohistochemical staining and the extent of CD163+ TAMs in tumor were divided into three groups: (A) infiltrated TAMs in cancer cell nest (nest TAMs); (B) infiltrated TAMs in tumor stroma (stroma TAMs); and (C) infiltrated TAMs along the invasive margin of a tumor (margin TAMs). Results: The increased stroma and margin TAMs (>72 and >102, respectively) were closely correlated with lymph node metastasis, TNM stage and lymphatic invasion (p<0.05 in 3 factors) and positive correlation existed between the stroma and margin TAMs (p<0.001). Disease-free survival rate analyzed using the Kaplan– Meier method was significantly lower in patient with high stroma and margin TMAs than patient with low stroma and margin TAMs (p=0.0039 and 0.0499, respectively). CD105+ vessels showed significant correlation with lymph node metastasis and lymphatic invasion.(p=0.006 and p<0.0001, respectively) Stromal, marginal and nest TAMs were positively correlated with CD105+ vessels (p=0.001). Conclusions: M2 infiltration in tumor stroma and tumor margin in gastric cancer showed relationship with aggressive phenotypes such as lymph node metastasis, TNM stage and lymphatic invasion and was correlated with angiogenesis. This study supports the view that the adverse prognostic impact of M2 involves tumor angiogenesis in gastric cancer.
Phase II study of capecitabine in substitution of 5-FU in the chemoradiotherapy regimen for patients with squamous cell carcinoma of the anal canal.
Authors: Ribeiro Suilane Coelho , Moniz Camila Motta Venchiarutti , Riechelmann Rachel , Bariani Giovanni Mendonca , Braghiroli Maria Ignez , Nahas Caio , Coudry Renata , Alex Alexandra Khichfy , Carneiro Allyne Q. , Nebuloni Daniela R. , Glasberg Joao , Hoff Paulo
Published: February 2017

560

Background: Squamous cell carcinoma (SCC) of the anal canal is an uncommon malignancy accounting for 1-5% of intestinal tumors; however, its incidence has been increasing. Treatment for stage II and III anal canal SCC is infusional 5-fluorouracil associated with mitomycin and radiotherapy, since 1974. More convenient treatments for patients are needed. Methods:Patients with SCC of anal cancer T2-4N0M0 or T (any) N1-3M0, with good performance status, normal blood, and renal function were treated with capecitabine 825 mg/m2 12/12hs during radiotherapy associated with a single dose of mitomycin 15 mg/m2 on day 1. Primary objective was local control rate at 6 months determined by clinical examination and radiological assessment. Sample size was calculated using Fleming single stage design. Results: From November/2010 to August/2013 42 patients were initially included, however 36 patients were assessed. Fifteen patients (41.7%) were stage II, 8 patients (22.2%) stage IIIA, and 13 patients (36.1%) stage IIIB. Four patients (11.1%) were HIV-positive, while 32 (88.9%) were HIV-negative. Thirty-two patients finished the treatment, 4 patients are still in treatment. Median follow-up was 18.7 months. Among patients who finished the treatment and were reevaluated at 6 months 4 patients (13.3%) presented partial response, 25 patients (83.3%) had complete response, and 1 patient developed liver metastasis (3.3%). Regarding grade 3-4 toxicities, 7 patients (21.8%) had grade 3 radiodermitis, 1 patient (3.1%) had grade 3 diarrhea, 2 patients (6.2%) had grade 3-4 thrombocytopenia, 3 (9.3%) had lymphopenia and one patient had grade 3 leukopenia. One HIV+ patient had septic shock, pneumonia, herpetic encephalitis and macrophage activation syndrome. Colostomy was required in 2 patients before the beginning of the treatment and 2 patients after the treatment because of local failure, corresponding to a colostomy rate of 12.5%. Conclusions: Capecitabine and mytomicin with radiotherapy seem to be a safe treatment for SCC of the anal cancer.
A UGT1A1 genotype-guided dosing study of irinotecan in metastatic colorectal cancer (mCRC) patients (pts) treated with FOLFIRI plus bevacizumab (BEV).
Authors: Sharma Manish , Toffoli Giuseppe , Buonadonna Angela , Marangon Elena , Polite Blase N. , Frustaci Sergio , Innocenti Federico
Published: February 2017

562

Background: Dosing based on UGT1A1*28 genotyping has been demonstrated to reduce irinotecan-related adverse events. Previous data (Toffoli et al. JCO, 2010) showed that mCRC pts treated with first-line FOLFIRI tolerated higher doses (310 mg/m2 for *1/*28; 370 mg/m2 for *1/*1) of irinotecan than the standard 180 mg/m2. The aims of this study (NCT01183494; supported by Eudract 2009-012227-28) were to define the maximally-tolerated dose (MTD) of irinotecan in FOLFIRI plus BEV as first-line therapy in mCRC pts and to determine whether BEV alters irinotecan pharmacokinetics (PK). Methods: Pts were accrued at 3 sites: Chicago (USA), Aviano (Italy), Rome (Italy). In *1/*28 and *1/*1 pts (*28/*28 pts were excluded), irinotecan was administered at an initial dose of 260 mg/m2 IV every 2 weeks. The dose was escalated to 310 and 370 mg/m2 if 0/3, <2/6, or <3/10 pts had a DLT (grade 3-4 non-hematologic or grade 4 hematologic toxicity during the first 28-day cycle). MTD was defined as the highest dose at which <4/10 pts had a DLT. 5-FU was administered as a 400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours, plus 200 mg/m2leucovorin. BEV was administered at 5 mg/kg IV on day 3 (2 days after irinotecan) and on day 15 (before irinotecan), then every 2 weeks. Irinotecan PK were collected on days 1-3 (in absence of BEV) and on days 15-17 (in presence of BEV). Results: 44 pts (23 *1/*28; 21 *1/*1) were enrolled and 43 were evaluable for DLTs during cycle 1 (Table). Neutropenia and diarrhea were the most common DLTs and were each observed in 5 of 11 (45%) pts with DLTs. The MTD is 260 mg/m2 in the *1/*28 cohort and at least 310 mg/m2in the *1/*1 cohort. In a preliminary analysis of 22 pts, BEV decreased the AUC of SN-38, the active metabolite of irinotecan (p = 0.026 by Wilcoxon matched pairs signed rank test). Conclusions: In first-line therapy of mCRC with FOLFIRI plus BEV, irinotecan doses higher than the standard dose can be safely administered based on UGT1A1 genotype. The impact of this genotype-guided dosing approach on survival will be established in future trials. Clinical trial information: NCT01183494. [Table: see text]
Reduced expression of DENND2D through promoter hypermethylation as an adverse prognostic factor in squamous cell carcinoma of the esophagus.
Authors: Hibino Soki , Kanda Mitsuro , Oya Hisaharu , Takami Hideki , Shimizu Dai , Nomoto Shuji , Koike Masahiko , Yamada Suguru , Nakayama Goro , Fujii Tsutomu , Sugimoto Hiroyuki , Fujiwara Michitaka , Kodera Yasuhiro
Published: February 2017

58

Background: Esophageal cancer ranks sixth in cancer mortality worldwide and patients with ESCC have a poor prognosis with a 5-year survival rate of less than 10%. Elucidation of the mechanisms of carcinogenesis and tumor progression in esophageal cancer is urgently needed to develop targets for therapy and prognostic biomarkers. In the present study, the expression and regulatory mechanism of the Differentially Expressed in Normal and Neoplastic cells Domain containing 2D (DENND2D), which is a regulator of Rab GTPases, were investigated to explore its potential as a tumor suppressor gene for esophageal squamous cell carcinoma (ESCC). Methods: The level of DENND2D mRNA expression in ESCC cell lines and surgical specimens was determined using a quantitative real-time reverse transcription-polymerase chain reaction assay, and the relationship between the expression level of DENND2D mRNA and clinicopathological factors was evaluated. The expression and distribution of DENND2D were determined using immunohistochemistry. DNA methylation analysis was performed to determine the regulatory mechanism of DENND2D expression in ESCC. Results: The level of DENND2D mRNA expression was reduced in 8/9 ESCC cell lines and in 59/65 surgical specimens, and the mean expression level was significantly lower in cancerous tissues than in corresponding normal tissues (p<0.001). The expression pattern of DENND2D protein and mRNA was consistent. Downregulation of DENND2D mRNA in ESCC tissues was identified as an independent prognostic factor in multivariate analysis (hazard ratio: 2.194; p=0.039). The DENND2D promoter was methylated in five out of nine ESCC cell lines, and DNA demethylation reactivated DENND2D mRNA expression. Hypermethylation of DENND2D was frequently detected in ESCC tissues (64.6%) and was significantly associated with downregulation of DENND2D mRNA expression (P = 0.008). Conclusions: Our data suggest that DENND2D is a candidate tumor suppressor gene that was inactivated by promoter hypermethylation in patients with ESCC and may serve as a novel biomarker of ESCC.