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4038 Background: The incidence of GEJC is increasing in North America and Europe, especially among white men. Many pts present with metastatic disease or relapse locally or systemically after resection of early-stage disease. The global phase 3 study TAGS (NCT02500043) demonstrated the efficacy and safety of FTD/TPI in previously treated pts with metastatic gastric cancer (mGC)/mGEJC. Here we report results in the mGEJC subgroup from TAGS. Methods: Pts with mGC/mGEJC treated with ≥2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 of each 28-day cycle) or placebo, plus best supportive care. A preplanned efficacy and safety analysis was performed in pts with mGEJC. Results: Of 507 randomized pts, 145 (29%) had GEJC as the sole primary disease site (FTD/TPI, 98/337; placebo, 47/170). Of pts with mGEJC, 85% were male and 83% were white (overall population, 73% and 70%). Baseline characteristics were generally balanced for pts with mGEJC across treatment groups, except for fewer pts having prior gastrectomy (40% vs 55%) and more pts having received ≥3 prior regimens (74% vs 66%) in the FTD/TPI group than in the placebo group. FTD/TPI had an efficacy benefit in pts with mGEJC, and the FTD/TPI safety profile was similar in this subgroup and the overall population (table). Conclusions: FTD/TPI showed a manageable safety profile and efficacy benefit in pts with mGEJC in the TAGS trial, despite heavier pretreatment of the FTD/TPI than the placebo group. Clinical trial information: NCT02500043. [Table: see text]

3610 Background: Although being the standard-of-care for stage III colon cancer, no biomarkers can identify patients (pts) who benefit from adjuvant chemotherapy. In metastatic pts, the lack of metabolic response (mR) in FDG-PET/CT after 1 chemotherapy cycle predicts the absence of treatment benefit. The PePiTA study aims to evaluate if the absence of mR after 1 cycle of pre-operative chemotherapy is predictive of recurrence in non-metastatic colon cancer pts. Herein, we report a preliminary analysis on surgical outcomes, adverse events and mR assessment after 1 cycle of pre-operative chemotherapy after completing the study accrual objective. Methods: Colon cancer pts eligible for curative resection and ECOG ≤1 received 1 cycle of mFOLFOX followed by surgery in this prospective, multicentre, non-randomized trial. FDG-PET/CT was performed at baseline and after 1 cycle of mFOLFOX. Adjuvant mFOLFOX was administered for up to 12 cycles for stage III pts, whereas for stage II pts the decision to pursue adjuvant chemotherapy was at investigator’s discretion. A decrease ≥15% in SUVmax after 1 cycle of chemotherapy was defined as mR (EORTC criteria) at central review. Results: mR was assessable on the primary tumor in 204/240 pts (85%). In 11 pts (4.6%), staging was modified by the baseline FDG-PET/CT, which detected metastatic disease or other tumors. Pre-operative mFOLFOX was administered to 218 pts, of which 14 (6%) had a grade ≥3 adverse event. Surgery was performed in 218 pts, with a median delay of 20 days (6 to 59) after chemotherapy. Surgical complications occurred in 28 (13%) pts, however no deaths occurred. The median SUVmax decrease between baseline and 2nd FDG-PET/CT was 24%. A mR was observed in 65.2% of the pts, whereas 34.8% showed no mR, including 3% who had progressive disease. Conclusions: One cycle of pre-operative mFOLFOX followed by a mR assessment has shown to be a feasible and safe strategy, raising interest on the potential of neoadjuvant chemotherapy in colon cancer. The early mR assessment identified pts that may not benefit from chemotherapy and might have a worse prognosis. The substantiation of this hypothesis is expected with the study’s long-term results. Clinical trial information: NCT00994864.

2628 Background: We investigated whether an adaptation to rectal biopsies of the recently validated consensus Immunoscore, could predict the response to neoadjuvant treatment and delineate clinical responders that could benefit from a “Watch and Wait” (W&W) strategy with acceptable outcomes. Methods: Initial biopsies from 273 patients with locally advanced rectal cancer (LARC) treated by neoadjuvant chemoradiotherapy (nCRT) followed by Total Mesorectal Excision (TME), were immunostained for CD3+ and cytotoxic CD8+ T cells and quantified by digital pathology to determine the Immunoscore within pre-treatment Biopsy (ISB). Expression level of 44 immune related genes post-neoadjuvant treatment was investigated by Nanostring technology (n = 64 patients). Results were correlated with response to neoadjuvant treatment, disease free survival (DFS) and time to recurrence (TTR). Prognostic performance of ISB was finally assessed in 73 LARC treated by W&W strategy. Results: ISB Low, Intermediate and High were respectively observed in 23.3, 50.4 and 26.3 % of the cohort. ISB was positively and significantly correlated with the response to nCRT, as evaluated by Dworak classification (P = .0034), ypTNM (P = .0003), down-staging (P = .0014), and neoadjuvant rectal (NAR) score, (P < .0001). ISB status was also positively associated with the degree of local immune activation post-neoadjuvant treatment. ISB High patients were at low risk of relapse, with 5-year DFS rates of 81.1 % (CI, 71.3-92.1 %) as compared to 57.8 % (CI, 45.9-72.9 %) in ISB low patients. In multivariate analysis, ISB was the only significant parameter at presentation associated with DFS (High vs Low: P = .001). Among W&W patients, significant difference was observed for TTR according to ISB status (High vs Low: P = .025). Conclusions: ISB could provide a reliable estimate of the response to nCRT and risk of recurrence in LARC patients' treated by TME or W&W strategy.

O1 Combinatorial CD8+ and PD-L1+ cell densities correlate with response and improved survival in non-small cell lung cancer (NSCLC) patients treated with durvalumab #### Sonja Althammer1, Keith Steele2, Marlon Rebelatto2, Tze Heng Tan1, Tobias Wiestler1, Guenter Schmidt1, Brandon Higgs2, Xia

487 Background: Immunoscore Colon is an IVD test predicting the risk of relapse in early-stage colon cancer (CC) patients, by measuring the host immune response at the tumor site. It is a risk-assessment tool providing independent and superior prognostic value than the usual tumor risk parameters and is intended to be used as an adjunct to the TNM classification. Risk assessment is particularly important to decide when to propose an adjuvant (adj.) treatment for stage (St) II CC patients. High-risk stage II patients defined as those with poor prognostic features including T4, lymph nodes < 12, poor differentiation, VELIPI, bowel obstruction/perforation can be considered for adj. chemotherapy (CT). However, additional risk factors are needed to guide treatment decisions. Methods: A subgroup analysis was performed on the St II untreated patients (n = 1130) from the Immunoscore international validation study (Pagès The Lancet 2018). The high-risk patients (with at least 1 clinico-pathological high-risk feature) were classified in 2 categories using pre-defined cutoffs: Low Immunoscore versus High Immunoscore and their five-year time to recurrence (5Y TTR) was compared to the TTR of the low-risk patients (without any clinico-pathological high-risk feature). Results: Among the patients with high-risk features (n = 630), 438 (69.5%) had a High Immunoscore with a corresponding 5Y TTR of 87.4 (95% CI 83.9-91.0), statistically similar (logrank pv not stratified p > 0.42, wald pv stratified by center p > 0.20) to the TTR 89.1 (95% CI 86.1-92.1) observed for the 500 low-risk patients (with no clinico-pathological feature). Furthermore, 5Y TTR for these patients were statistically similar to those of St II patients with high-risk features and a High Immunoscore (n = 438), who received adj. CT (n = 162) (5Y TTR of 83.4 (95% CI 77.6-89.9). Conclusions: These data show that despite the presence of high-risk features that usually trigger adj. treatment, when not treated with CT, a significant part of these patients (69.5%) have a recurrence risk similar to the low risk patients. Therefore, the Immunoscore test could be a good tool for adj. treatment decision in St II patients.

Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. We quantified immune cell types of 603 whole-slide metastases and primary colorectal tumors from 222 patients. Primary lesions, and synchronous and metachronous metastases, had a heterogeneous immune infiltrate and mutational diversity. Small metastases had frequently a low Immunoscore and T and B cell score, while a high Immunoscore was associated with a lower number of metastases. Anti-epidermal growth factor receptor treatment modified immune gene expression and significantly increased T cell densities in the metastasis core. The predictive accuracy of the Immunoscore from a single biopsy was superior to the one of programmed cell death ligand 1 (PD-L1). The immune phenotype of the least-infiltrated metastasis had a stronger association with patient outcome than other metastases. ispartof: CANCER CELL vol:34 issue:6 pages:1012-+ ispartof: location:United States status: published

Purpose Liver dissemination is a major cause of mortality among patients with advanced colorectal cancer. Hepatic intra-arterial injection of the β-emitting isotope yttrium-90 (90Y) bound to resin microspheres (radioembolization) delivers therapeutic radiation doses to liver metastases with minimal damage to adjacent tissues. Patients and Methods We conducted a prospective, multicenter, randomized phase III trial in patients with unresectable, chemotherapy-refractory liver-limited metastatic CRC (mCRC) comparing arm A (fluorouracil [FU] protracted intravenous infusion 300 mg/m2 days 1 through 14 every 3 weeks) and arm B (radioembolization plus intravenous FU 225 mg/m2 days 1 through 14 then 300 mg/m2 days 1 through 14 every 3 weeks) until hepatic progression. The primary end point was time to liver progression (TTLP). Cross-over to radioembolization was permitted after progression in arm A. Results Forty-six patients were randomly assigned and 44 were eligible for analysis (arm A, n = 23; arm B, n = 21). Median follow-up was 24.8 months. Median TTLP was 2.1 and 5.5 months in arms A and B, respectively (hazard ratio [HR] = 0.38; 95% CI, 0.20 to 0.72; P = .003). Median time to tumor progression (TTP) was 2.1 and 4.5 months, respectively (HR = 0.51; 95% CI, 0.28 to 0.94; P = .03). Grade 3 or 4 toxicities were recorded in six patients after FU monotherapy and in one patient after radioembolization plus FU treatment (P = .10). Twenty-five of 44 patients received further treatment after progression, including 10 patients in arm A who received radioembolization. Median overall survival was 7.3 and 10.0 months in arms A and B, respectively (HR = 0.92; 95% CI, 0.47 to 1.78; P = .80). Conclusion Radioembolization with 90Y-resin microspheres plus FU is well tolerated and significantly improves TTLP and TTP compared with FU alone. This procedure is a valid therapeutic option for chemotherapy-refractory liver-limited mCRC.

Selective internal radiotherapy (SIRT) using Yttrium-90 labeled resin microspheres is increasingly used for the radioembolization of unresectable liver metastases of colorectal cancer (CRC). The treatment can be simulated by scintigraphy with Tc(99m)-labeled macroaggregates of albumin (MAA). The aim of the study was to develop a predictive dosimetric model for SIRT and to validate it by correlating results with the metabolic treatment response. The simulation of the dosimetry was performed by mathematically converting all liver voxel MAA-SPECT uptake values to the absolute Y(90) activity. The voxel values were then converted to a simulated absorbed dose (Gy) using simple MIRD formalism. The metabolic response was defined as the change in total lesion glycolysis (TLG) on FDG-PET. A total of 39 metastatic liver lesions were studied in eight evaluable patients. The mean administered Y(90) activity was 1.69 GBq (range: 1.33-2.04 GBq). The median (95% CI) simulated absorbed dose (Gy) was 29 Gy (1–98 Gy) and 66 Gy(32–159 Gy) in the poor (50% TLG change) and the good responders (TLG change50%),respectively [DOSAGE ERROR CORRECTED].Using a simple cut-off value of 1 for the MAA-tumor-to-normal uptake ratio, a significant metabolic response was predicted with a sensitivity of 89% (17/19), a specificity of 65% (13/20), a positive predictive value of 71% (17/24) and a negative predictive value of 87% (13/15). Integrated multimodality imaging allows prediction of metabolic response post radioembolization using Y(90)-resin microspheres, and should be used for patient selection.

BACKGROUND Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Beside classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. MATERIAL AND METHODS Patients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P 3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity. RESULTS Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T9>10 (rs3832043)) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy. CONCLUSION This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of a close liver tests monitoring during regorafenib treatment. This article is protected by copyright. All rights reserved.

The aim of this study is to investigate the role of Octreotide LAR in secondary prevention in patients with chemotherapy-induced diarrhea.In this study, patients experiencing CID ≥ grade 2 received 30 mg long-acting octreotide as a monthly injection and the next chemotherapy dose was administrated with a 25% dose decrease. If no CID ≥ grade 2 occurred, subsequent chemotherapy doses were increased to the initial 100% values. The primary endpoint of the study was the diarrhea control rate (grade 2) for patients receiving the optimal dose of chemotherapy for a minimum of 2 cycles.Twenty-nine patients were included. Ten patients experienced no improvement or ended the study very early after the first injection of octreotide LAR. Nineteen patients had a reduction in the grade of diarrhea after the first administration of Octreotide LAR and a reduced chemotherapy dose. Seven of them (24%) did not reach the end of the study because of disease progression (6) or lost in follow-up (1). Ultimately 12 patients (41%) continued the study till the end. In ten of these twelve patients, there was a significant and persisting reduction of diarrhea while receiving full dose chemotherapy.This study suggests that monthly injections with long-acting octreotide might be used as a secondary prevention of chemotherapy-induced diarrhea. Its usefulness and optimal dosage in secondary prevention in combination with antidiarrheal agents needs further research.

OBJECTIVE: To identify imaging markers predicting clinical outcomes to regorafenib in metastatic colorectal carcinoma (mCRC). METHODS: The RadioCORRECT study is a post hoc analysis of a cohort of patients with mCRC treated within the phase III placebo-controlled CORRECT trial of regorafenib. Baseline and week 8 contrast-enhanced CT were used to assess response by RECIST 1.1, changes in the sum of target lesion diameters (ΔSTL), lung metastases cavitation and liver metastases density. Primary and secondary objectives were to develop ex novo univariable and multivariable models to predict overall survival (OS) and progression-free survival (PFS), respectively. RESULTS: 202 patients were enrolled, 134 (66.3%) treated with regorafenib and 68 (33.7%) with placebo. In the univariate analysis, PFS predictors were lung metastases cavitation at baseline (HR 0.50, 95% CI 0.27 to 0.92, p=0.03) and at week 8 (HR 0.58, 95% CI 0.36 to 0.93, p=0.02). Baseline cavitation (HR 0.23, 95% CI 0.08 to 0.66, p=0.007), RECIST 1.1 (HR 0.23, 95% CI 0.14 to 0.4, p

Introduction: The introduction of targeted drugs has had a significant impact on the approach to assessing tumour response. These drugs often induce a rapid cytostatic effect associated with a less pronounced and slower tumoural volume reduction, thereby impairing the correlation between the absence of tumour shrinkage and the patient’s unlikelihood of benefit. The aim of the study was to assess the predictive value of early metabolic response (mR) evaluation after one cycle, and its interlesional heterogeneity to a later metabolic and morphological response assessment performed after three cycles in metastatic colorectal cancer (mCRC) patients treated with combined sorafenib and capecitabine. Methods: This substudy was performed within the framework of a wider prospective multicenter study on the predictive value of early FDG PET-CT response assessment (SoMore study). A lesion-based response analysis was performed, including all measurable lesions identified on the baseline PET. On a per-patient basis, a descriptive 4-class response categorization was applied based upon the presence and proportion of non-responding lesions. For dichotomic response comparison, all patients with at least one resistant lesion were classified as non-responding. Results: On baseline FDG PET-CT, 124 measurable “target” lesions were identified in 38 patients. Early mR assessments showed 18 patients (47 %) without treatment resistant lesions and 12 patients (32 %) with interlesional response heterogeneity. The NPV and PPV of early mR were 85 % (35/41) and 84 % (70/83), respectively, on a per-lesion basis and 95 % (19/20) and 72 % (13/18), respectively, on a dichotomized per-patient basis. Conclusions: Early mR assessment performed after one cycle of sorafenib-capecitabine in mCRC is highly predictive of non-response at a standard response assessment time. The high NPV (95 %) of early mR could be useful as the basis for early treatment discontinuation or adaptation to spare patients from exposure to non-effective drugs., SCOPUS: ar.j, info:eu-repo/semantics/published

820 Background: Prognosis in pts with mCRC is affected by PTL; PTL may also affect the activity of the epidermal growth factor receptor inhibitor Pmab (+ FOLFIRI). Methods: In this phase II, single-arm study (NCT00508404), pts received first-line Pmab+FOLFIRI Q2W until disease progression (PD); primary endpoint: objective response rate (ORR). Analyses included pts with RAS wild-type (WT) mCRC (no mutations in KRAS/ NRAS exons 2, 3 and 4). Baseline demographics/disease characteristics were summarised by PTL and the effect of PTL on outcome was analysed. Early tumour shrinkage (ETS) was defined as a ≥30% reduction in the sum of the longest diameters of measurable target lesions at week 8. Depth of response (DpR) was the maximum % change from baseline to nadir in pts with shrinkage, or the change at PD in pts with no shrinkage. DpR was positive for shrinkage, negative for growth and zero for no change. Progression-free survival (PFS) was analysed by PTL and ETS status. There was no long-term follow-up of overall survival in this study. Results: PTL could be determined in 52/69 (75%) RAS WT pts; 45/52 (87%) had left (L)-sided disease. Pts with L- vs right (R)-sided disease were more likely to have BRAF WT mCRC (91% vs 71%), an ECOG performance status of 0 (56% vs 43%) and liver+other metastases (53% vs 29%). Pts with L- vs R-sided disease had longer median (95% CI) PFS (11.2 [7.6,17.0] vs 7.2 [1.1,19.1] months) and were more likely to experience ETS ≥30% (53% vs 29%). ORR (60% vs 57%), median (95% CI) duration of response (DoR; 13.2 [9.3,47.7] vs 14.3 [3.5,17.3] months), median DpR (61% vs 60%), and resection rates (any: 13% vs 14%; R0: 7% vs 14%) were similar for L- and R-sided pts. ETS ≥30% was associated with improved PFS irrespective of PTL (HR [95% CI] vs ETS < 30%: 0.53 [0.22,1.29] on L; 0.35 [0.03,3.54] on R). Conclusions: These post-hoc data are in line with larger previous studies suggesting improved ETS/PFS with Pmab treatment in RAS WT left-sided mCRC; ORR, DoR and DpR were similar regardless of PTL. No formal conclusions can be drawn regarding the activity of Pmab+FOLFIRI in right-sided mCRC due to the small pt numbers, but ETS may also predict PFS benefit in right-sided disease. Clinical trial information: NCT00508404.

3599 Background: Pre-operative CRT followed by total mesorectal excision (TME) is nowadays the standard of care for patient with LARC (cT3-T4N0 or cTxN+). Currently, pathologic complete response occurs in +/- 15% after CRT. Colorectal cancer T-cell infiltration is a strong prognostic factor for survival after primary tumor resection. Our aim was to determine whether T-cell infiltration in PTB could be predictive of tumor response and relapse after CRT + TME. Methods: Between 1999 and 2012, patients with LARC who underwent CRT + TME and with available clinical follow-up and PTB (with sufficient tumor cells density) were identified at the Cliniques universitaires St-Luc. The density of CD3 (T cells) and CD8 (cytotoxic) was quantified on immunostained PTB slides and analyzed with a dedicated image analysis software on whole-slide imaging. Comparisons were made using the Wilcoxon-Mann-Whitney test. Cumulative disease-free survival (DFS) was performed using the Kaplan-Meier estimator and compared by log-rank tests. Cox regression we used for uni- and multi-variate analysis. P value of less than 0.05 was considered statistically significant. Results: 154 patients (sex ratio M/F 1.8; mean age 65 years-old; upper (20%), mid (29%) and low rectum (51%), synchronous metastases (11%)) were analyzed. High CD3 and CD8 PTB densities were significantly associated with a higher pathological response (Dworak 3-4) and lower ypTNM stage after CRT +TME (p < 0,05). Higher CD3 and CD8 PTB densities were associated with higher patient DFS (CD3: HR = 2,30 (CI95%:1,15-4,59) p = 0,02; CD8: HR = 1,95 (CI95%: 1,01-3,75) p = 0,04). These results were confirmed in uni and multivariate analysis. CD3 and CD8 PTB densities added to pathological response (ypTNM/Dworak) but also clinical response (ycTNM) after CRT + TME increases significantly the accuracy prediction of tumor relapse. Conclusions: Pretherapeutic T-cell infiltration of LARC is predictive of tumor response and relapse after CRT +TME. This biomarker could be helpful for patient treatment decision. It must be validated in larger patient cohorts.

Liver metastases represent the principal cause of death for patients with advanced colorectal cancer. Resection remains the only potentially curative treatment. Selective internal radiation therapy by means of the administration of yttrium-90 labeled resin microspheres (SIR-Spheres; Sirtex Medical Limited, Sydney, Australia) into the arterial supply of the liver is a local treatment option for patients with unresectable malignant liver tumors. We report the case of a patient with an unresectable liver colorectal metastasis refractory to chemotherapy downstaged to allow resectability after selective internal radiation therapy. © 2008 by Lippincott Williams & Wilkins.

Our goal was to optimize the radiosensitizing potential of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, when given concomitantly with preoperative radiotherapy in KRAS wild-type locally advanced rectal cancer (LARC). Based on pre-clinical studies conducted by our group, we designed a phase II trial in which panitumumab (6 mg/kg/q2 weeks) was combined with preoperative radiotherapy (45 Gy in 25 fractions) to treat cT3-4/N + KRAS wild-type LARC. The primary endpoint was complete pathologic response (pCR) (H0 = 5 %, H1 = 17 %, α = 0.05, β = 0.2). From 19 enrolled patients, 17 (89 %) were evaluable for pathology assessment. Although no pCR was observed, seven patients (41 %) had grade 3 Dworak pathological tumor regression. The regimen was safe and was associated with 95 % of sphincter-preservation rate. No NRAS, BRAF, or PI3KCA mutation was found in this study, but one patient (5 %) showed loss of PTEN expression. The quantification of plasma EGFR ligands during treatment showed significant upregulation of plasma TGF-α and EGF following panitumumab administration (p

3618Background: Pre-operative CRT followed by total mesorectal excision (TME) is nowadays the standard for LARC (cT3-T4N0 or cTxN+). TME could be avoided for patients with pathologic complete respo...

BACKGROUND: Endoscopic resection and radiofrequency ablation are now established therapies for high-grade intraepithelial neoplasia and mucosal cancer complicating Barrett's esophagus. These techniques may be more challenging in patients with previous antireflux surgery, because of poor visibility and accessibility. OBJECTIVE: To assess the results of endoscopic resection for early neoplasia complicating Barrett's esophagus after antireflux surgery. DESIGN: Case series, retrospective review. SETTING: Single tertiary-care referral center. PATIENTS: This study involved 7 patients treated for Barrett's neoplasia by endoscopic resection between 2001 and 2009. INTERVENTIONS: Endoscopic resection was performed by using the EMR cap technique or by endoscopic submucosal dissection. MAIN OUTCOME MEASUREMENTS: The curative resection rate, complications, follow-up, and complete remission status were determined. RESULTS: Seven patients underwent endoscopic resection (mean number of sessions, 3.1; range, 1-6): endoscopic submucosal dissection in 3 patients and EMR in 4 patients. Two patients needed additional argon plasma coagulation. Pathology examination disclosed invasive adenocarcinoma in 3 patients and high-grade intraepithelial neoplasia in 4 patients. At the last follow-up examination, all patients were in complete remission. Major procedure-related complications were not encountered. LIMITATIONS: Small number of patients, single center, retrospective study. CONCLUSIONS: We demonstrated that full endoscopic resection by using EMR or endoscopic submucosal dissection in patients with previous antireflux surgery can be achieved successfully and safely. These patients can be treated endoscopically, similarly to patients without previous surgery.

High-risk stage II and stage III colon cancers are associated with significant recurrence rates after surgical resection. Adjuvant chemotherapy has demonstrated a significant disease-free and overall survival benefit for patients, even if not helpful for all. Currently, there are limited clinical and molecular markers that can predict response to chemotherapy and clinical outcome in advanced colon cancer. Herein, we review and discuss recent data about the most promising clinicopathologic and molecular factors described thus far and that are of interest in the management of patients with colon cancer.

(90)Y-labelled compounds used in targeted radiotherapy are usually imaged with SPECT by recording the bremsstrahlung X-rays of the beta decay. The continuous shape of the X-ray spectrum induces the presence of a significant fraction of scatter rays in the acquisition energy window, reducing the accuracy of biodistribution and of dosimetry assessments.The aim of this paper is to use instead the low branch of e(-) e(+) pair production in the (90)Y decay. After administration of (90)Y-labelled SIR-Spheres by catheterization of both liver lobes, the activity distribution is obtained by (90)Y time-of-flight (TOF) PET imaging. The activity distribution is convolved with a dose irradiation kernel in order to derive the regional dosimetry distribution.Evaluation on an anatomical phantom showed that the method provided an accurate dosimetry assessment. Preliminary results on a patient demonstrated a high-resolution absorbed dose distribution with a clear correlation with tumour response.This supports the implementation of (90)Y PET in selective internal radiation therapy of the liver.

Liver metastases from colorectal cancer (CRC) have a poor prognosis. Despite recent advances in the management of advanced disease with chemotherapy, liver resection remains the only hope for cure for patients with colorectal liver metastases. Approximately 15% of patients with stage IV CRC referred to specialist centers have metastatic liver disease deemed to be resectable at presentation. Over the last five years, combination chemotherapeutic regimens, namely 5-fluorouracil/folinic acid with irinotecan or oxaliplatin and, more recently, integrating targeted monoclonal antibodies, have been shown to downsize the tumour burden to an extent that sometimes allows initially unresectable metastases to be excised. Five-year survival rates following liver resection range between 25% and 55% compared with 0% and 5% for non-operated patients. Beyond liver resection, the rationale for "pseudo-adjuvant" chemotherapy lacks scientific evidence, despite some promising data. However, perioperative chemotherapy for resectable lesions is gaining ground in current practice. In this article we review the state of the art treatment for CRC liver metastases and, considering the results of recent trials, try to determine the appropriate role of chemotherapy.

We report the case of a 40 year-old Turkish woman with severe ileal Crohn's disease associated with palmoplantar pustulosis and aseptic spondylitis, also known as the SAPHO syndrome. However, in the present case, the syndrome developed three months after starting infliximab (Remicade) therapy, which is generally used to treat the SAPHO syndrome. This case-report discusses the unclear relationship between Crohn's disease, the appearance of a SAPHO syndrome and treatment with infliximab.

Le cas d'une malade turque de 40 ans est rapporté pour illustrer une association de maladie de Crohn iléale sévère avec une pustulose palmoplantaire et une spondylite aseptique, dans le cadre d'un syndrome SAPHO. La particularité du cas est le déclenchement du syndrome trois mois après instauration d'un traitement à l'infliximab (Remicade®), plutôt préconisé comme traitement du syndrome SAPHO. La relation mal précisée entre maladie de Crohn, syndrome SAPHO et infliximab est discutée. [Crohn's disease and the SAPHO syndrome during treatment with infliximab: a case report and review of literature] We report the case of a 40 year-old Turkish woman with severe ileal Crohn's disease associated with palmoplantar pustulosis and aseptic spondylitis, also known as the SAPHO syndrome. However, in the present case, the syndrome developed three months after starting infliximab (Remicade) therapy, which is generally used to treat the SAPHO syndrome. This case-report discusses the unclear relationship between Crohn's disease, the appearance of a SAPHO syndrome and treatment with infliximab.

e14643 Background: The adaptive Th1 immune response (CD3/CD8/CD45RO T-cells) is a strong prognostic factor for the survival of the patients after colorectal primary tumor and metastases resection. ...

3610 Background: The adaptive Th1 immune response (CD3, CD8, CD45RO T cells) observed in resected primary colorectal tumor (PCT) and liver colorectal metastases (LCM) is an important prognostic fac...

602 Background: We previously reported that an adaptive Th1 immune response (CD3/CD8/CD45RO T-cells) observed in resected primary colorectal tumor and liver colorectal metastases (LCM) is an important prognostic factor. B and FoxP3 regulatory lymphocytes participate to the modulation of this response. We aimed to investigate whether the preoperative treatments influenced the quality and the density of the immune infiltrates previously reported in the LCM. Methods: We used a cohort of metastatic colorectal patients (n=107) engaged for curative liver surgery with available FFPE blocks for all resected LCM to confirm the prognostic impact of the immune response. Among this cohort of 338 LCMs, 46 were completely resected after chemotherapy (CT) alone, 130 after CT + anti-VEGF, 118 after CT + anti-EGFR and 44 after surgery alone. LCMs were analyzed for histological response according the Tumor Regression Grade (TRG) and regrouped as Response (R, TRG1-3) or No Response (NR, TRG4-5). The density of CD3+ (T-cells), CD8+ (cytotoxic), CD45RO+ (memory), CD20+ (B-cells) and FoxP3+ (regulatory) in the core (CT) and invasive margin (IM) of all LCM was quantified on immunostained slides. The mean density value (CT/IM) was calculated for each marker with a dedicated image analysis software on whole-slide imaging. Comparisons were made using the Wilcoxon-Mann-Whitney test. Results: LCMs showing R (compared to NR and untreated LCM) were more frequently associated with a high immune infiltrate for CD3+ (CT: p

TPS795 Background: Even if the use of targeted therapies combined with chemotherapy has demonstrated increase response rate and survival benefit in non resectable metastatic colorectal cancer (mCRC), the administration of these combinations in frontline resectable disease is source of debate and optimal association is still unclear. Based on a retrospective analysis, we previously reported thatthe chemotherapy partner combined with VEGF or EGFR inhibitors influenced pathological responses (pR) on the resected colorectal cancer metastases (CRCM) with a significant advantage for oxaliplatin with anti-VEGF or irinotecan with anti-EGFR combinations. We aimed to design 2 parallel studies (BEV-ONCO, CET-ONCO) to prospectively precise optimal combination between oxaliplatin and irinotecan with bevacizumab or cetuximab before CRCM resection. Methods: The 2 studies are open label randomized multi-centric trials and concern mCRC patients with resectable disease in whom a preoperative treatment is considered. The primary objective is to assess the CRCM pR rate according the Tumor Regression Grade classification (Rubbia-Brandt) after allocated preoperative treatment (bevacizumab combined with FOLFOX vs. FOLFIRI without consideration of RAS/BRAF for BEV-ONCO trial (EUDRACT 2012-005376-34) and cetuximab associated with FOLFOX or FOLFIRI only for RAS/BRAF wild type tumor for CET-ONCO trial (EUDRACT 2012-005249-19)). According investigator’s choice, patient will received 3 to 6 treatment cycles before CRCM resection. Patient’s survival, safety, surgical complications and treatment associated liver-toxicity are secondary end-points. Up to 60 patients (30 per treatment group) will be randomised in each study (power: 80%, type I error of 5% to detect a difference in proportion of pR rate between FOLFOX or FOLFIRI association of 0.40). Formal comparison will not be done across studies. Translational research projects are ongoing (CRCM immune response, tumour specific genetic rearrangements as new specific biomarkers). Clinical trial information: NCT01858649 (BEV-ONCO); NCT01858662 (CET-ONCO). Clinical trial information: NCT01858649 (BEVONCO) NCT01858662 (CETONCO).

e14602 Background: p53IHC RO was previously described as a distinct pattern from the negative or diffuse p53 IHC expression. p53IHC RO is characterized by a limited number of homogenously scattered strongly positive CRC cells and is associated with some clinico-pathologic CRC feature. The prognostic impact of p53IHC RO remains unknown. Methods: p53 and MMR (MLH1, MSH2, MSH6 and PMS2) proteins IHC expression were performed on CRC primary tumors from an unselected cohort of patients who underwent surgery at the Cliniques St-Luc between 1995 and 2000. p53 IHC results were defined as negative, diffuse or restricted expression. Clinico-pathologic CRC characteristics and patients follow-up were available for this analysis. Comparisons of numerical and categorical clinico-pathological data were evaluated respectively by ANOVA and Fisher exact tests between p53 expression groups. Progression-Free Survival (PFS) and Overall Survival (OS) analyses were performed using Kaplan-Meier method and compared with the log-r...

4041 Background: Activating MAPK pathway mutations (predominantly RAS) occur with a high incidence in metastatic pancreatic adenocarcinoma (mPaCa). Pimasertib is a MEK1/2 inhibitor with potent activity in cell lines and xenografts with an activated MAPK pathway. This two-part trial in patients (pts) with mPaCa comprises a dose-escalation safety run-in and a randomized phase II part (EudraCT 2009-011992-61). We defined the maximum tolerated dose (MTD), safety, pharmacokinetics (PK) and antitumor activity of two pimasertib dosing schedules (S), and the recommended phase II dose (RP2D). Methods: Dose-escalation (3+3 design) in two dosing S of oral pimasertib: once-daily (qd) - 5 days on, 2 days off (S1); and twice-daily (bid) - continuous (S2) combined with the standard dose of gemcitabine (gem). Results: 53 pts (median age 61 years and ECOG performance status 0-1) have been treated at six dose levels in S1 (15 to 120 mg qd) and at 60 and 75 mg bid in S2. MTDs were defined as 120 mg qd and 75 mg bid. Two pts had a dose-limiting toxicity (DLT) in the DLT observation period: a grade (G) 3 confusion with ataxia and disorientation at 60 mg bid and a G4 suicidal ideation at 75 mg bid. G3-4 adverse events (AEs) in >5% of pts were: neutropenia (32%), thrombocytopenia (25%), asthenia (19%), dyspnea (9%), transaminitis (9%), anemia (8%), and diarrhea, pulmonary embolism, pulmonary sepsis (6% each). Most common AEs were asthenia (70%), ocular AEs (68%), skin rash (62%), nausea (58%), diarrhea (58%), peripheral edema (51%), thrombocytopenia (49%), vomiting (45%), mucositis (43%), neutropenia (38%), decreased appetite (36%) and anemia (34%). The main ocular AE was serous retinal detachment (58%); manageable retinal vein occlusion occurred in five pts. PK data were comparable to pimasertib monotherapy and published gem data. Partial responses were noted in 10 pts and stabilisation ≥3 months in 13 pts. Hot spot mutations in genes activating the MAPK and PI3K/AKT pathway and correlation with clinical outcome are being investigated. Conclusions: Pimasertib MTDs were reached. The RP2D was defined as 60 mg bid. PK was dose proportional and associated with target inhibition. Sustained responses were seen in both dosing schedules. Clinical trial information: 2009-011992-61.

e14060 Background: The addition of anti Epidermal Growth Factor Receptor (EGFR) monoclonal antibodies (mabs) to preoperative chemoradiation in RC has produced low pathological complete response (pCR) rate. The postulated reasons for the poor outcome are: lack of patient selection, suboptimal treatment sequencing, and potential negative interaction between anti EGFR mabs and chemotherapy (CT) when used concurrently as radiosensitizers. Given these issues, we conducted a phase II trial of PAN in combination with preoperative RT in Kras wt RC. Methods: We studied several treatment sequences in murine models of Kras wt human colorectal cancer. Next, we used our preclinical results to design the treatment schedule of the phase II trial. PAN (6mg/kg/q2w) was combined with RT (45 Gy) to treat T3-4, Kras wt RC. Surgery was done 6-8 weeks after the end of RT. The primary endpoint, the pCR rate on surgical specimen, was assessed centrally (Simon: H0=5%, H1=17%, α=0.05, β=0.2). Results: In our murine models, the addition of anti EGFR mabs to RT significantly improved response when anti EGFR mabs were started during RT and extended after the end of RT (p50% pathological tumour regression (grade 3 Dworak) and 12 (70%) showed >2mm of tumour-free circumferential resection margin. Conclusions: Preclinical data confirm the need of optimal treatment sequencing to potentiate synergism between anti EGFR mabs and RT. However, the pCR rate in our phase II trial remains low despite adequate patient selection and optimized study design. Thus, we do not recommend the concurrent use of anti EGFR mabs and RT in the neoadjuvant treatment of RC.

Background Anemia is usually not taken into account in internal radiotherapy. We investigated whether the hemoglobin (Hb) level could have an impact on the tumor response, as observed in external beam radiotherapy (EBRT). Methods Absorbed doses of 25 hepatic metastatic sites in eight patients who underwent a liver selective internal radiotherapy (SIRT) were computed by a 3D convolution of a dose deposition kernel with the 90Y time-of-flight positron emission tomography (TOF-PET) images acquired following therapy. Early tumor response was assessed by comparing a follow-up FDG TOF-PET scan with a baseline scan. Hb level was measured on the day of the SIRT procedure. Results All patients displayed early tumor response increasing with the tumor-absorbed dose. Significant differences between patients were noted, the response slope correlating with the Hb level. After applying a global fit on all metastases using a tumor radiosensitivity modulated by a Hb enhancement factor (HEF) linearly dependent on the Hb level, a strong correlation (R = 0.96) was observed between the early response and the absorbed dose. Hb level had a major impact on tumor response by modulating HEF by a factor 6. Conclusions These results prove the significant impact of Hb level on the tumor response and support the study of methods for correcting tumor hypoxia, such as intensively performed in EBRT. The quantitative analysis of the relationship between tumor doses and early response has the power to allow fast screening of such correction methods in limited patient series. Internal radiotherapy could be more efficient if performed earlier in the therapy line, when the disease- and treatment-related anemia remains limited.

The decay of Y has a minor branch to the 0 excited state [1], followed by an internal ee creation which happens in 32 out of one million decays [2]. Consequently, Y PET scan was proposed in order to assess the biodistribution [3] of Y-labelled therapeutic agents. A 61-year-old woman was referred for treatment of chemorefractory colorectal liver metastasis. Based on the pretreatment evaluation (including a diagnostic FDG PET/CT scan on day 1, and a prophylactic embolization of the right gastric and gastroduodenal arteries followed by a Tc-MAA SPECT/CT scan on day 8), 1.3 GBq of Y-labelled SIR-Spheres were administered by sequential catheterization of both liver lobes (day 15). Subsequently, a 30-min Y TOF PET/CT scan was performed using a Philips GEMINI TF camera. In order to prevent saturation of the detectors, a copper ring of 2.5 mm thickness was inserted into the gantry to absorb the bremsstrahlung x-rays. The TOF data were reconstructed with attenuation and scatter correction using Philips RAMLA software (eight iterations, three subsets). An additional 20 min bremsstrahlung Y-SPECT was acquired using a Trionix XLT20 triple head camera (medium energy collimator, 30% window centred on 90 keV). Data were reconstructed using OSEM (four iterations, six subsets). As illustrated, despite the differences in their respective uptake mechanism, Y-PET better reflects the tumour heterogeneity assessed by FDG PET/CT (a necrotic core surrounded by active tumour margins) than traditional bremsstrahlung Y-SPECT. This gain in resolution should therefore contribute to increasing the accuracy of the dose distribution into the tumours and their surrounding healthy tissues.

This study assesses how the metastatic immune landscape is impacting the response to treatment and the outcome of colorectal cancer (CRC) patients.Complete curative resection of metastases (n = 441) was performed for two patient cohorts (n = 153). Immune densities were quantified in the center and invasive margin of all metastases. Immunoscore and T and B cell (TB) score were analyzed in relation to radiological and pathological responses and patient's disease-free (DFS) and overall survival (OS) using multivariable Cox proportional hazards models. All statistical tests were two-sided.The spatial distribution of immune cells within metastases was nonuniform. Patients, as well as metastases of the same patient, had variable immune infiltrates and response to therapy. A beneficial response was statistically significantly associated with increased immune densities. Among all metastases, Immunoscore (I) and TB score evaluated in the least immune-infiltrated metastases were the strongest predictors for DFS and OS (five-year follow-up, Immunoscore: I 3-4: DFS rate = 27.9%, 95% CI = 15.2 to 51.3; vs I 0-1-2: DFS rate = 12.3%, 95% CI = 4.9 to 30.6; HR = 0.45, 95% CI = 0.28 to 0.70, P = .02; I 3-4: OS rate = 64.6%, 95% CI = 46.6 to 89.6; vs I 0-1-2: OS rate = 32.5%, 95% CI = 17.2 to 61.4; HR = 0.32, 95% CI = 0.15 to 0.66, P = .001, C-index = 65.9%; five-year follow-up, TB score: TB 3-4: DFS rate = 25.7%, 95% CI = 14.2 to 46.6; vs TB 0-1-2: DFS rate = 5.0%, 95% CI = 0.8 to 32.4; HR = 0.36, 95% CI = 0.22 to 0.57, P.001; TB 3-4: OS rate = 63.7%, 95% CI = 46.4 to 87.5; vs TB 0-1-2: OS rate: 21.4%, 95% CI = 9.2 to 49.8; HR = 0.25, 95% CI = 0.12 to 0.51, P.001, C-index = 67.8%). High TB score and Immunoscore patients had a median survival of 70.5 months, while low patients survived only 25.1 to 38.3 months. Nonresponding patients with high-immune infiltrates had prolonged DFS (HR = 0.28, 95% CI = 0.15 to 0.52, P = .001) and OS (HR = 0.25, 95% CI = 0.1 to 0.62, P = .001). The immune parameters remained the only statistically significant prognostic factor associated with DFS and OS in multivariable analysis (P.001), while response to treatment was not.Response to treatment and prolonged survival of metastatic CRC patients were statistically significantly associated with high-immune densities quantified into the least immune-infiltrated metastasis.

524 Background: The SOR-CAP combination has shown clinical activity in several phase I-II trials involving metastatic breast cancer and mCRC patients (pts). SoMore aims to substantiate the combination’s effects in mCRC refractory to all medications and the predictive value of early metabolic response (MR) on survival. Methods: SoMore (EUDRACT 2010-023695-91) has 2 coprimary objectives: 1) to demonstrate an overall survival (OS) rate at 6 months (mths) > 30%, and 2) to compare OS between pts with and without MR. CAP was given at 1700 mg/m²/day (D), 2 weeks out of 3. SOR was administered at 600mg/D for the first cycle, then at 800mg/D until progression or unacceptable toxicity. FDGPET-CT was performed at baseline and before the 2nd cycle. MR analysis was centralized and blinded for the investigators. Results: From February to October 2011, 92 eligible pts were prospectively recruited in 6 Belgian centers: M/F: 54%/46%; ECOG PS 0/1: 55%/45%; median age: 61. A median of 5 treatment cycles were given (0-28+). Grade 3-4 toxic reactions were reported in 61.2%, mainly fatigue (18%), hand-foot skin reaction (14%) and diarrhea (11%), but no toxic death. 6.9% of the pts stopped therapy due to toxicity. 6 mths OS was 71% (95% CI: 61%-79%), significantly >30% (p

Background: Regorafenib, an oral multi-tyrosine kinase inhibitor that shares with sorafenib several targets on tumor angiogenesis, oncogenesis, and tumor microenvironment, was recently approved for patients (pts) with pretreated advanced colorectal cancer (aCRC). The drug improves the pts’ outcome, but with significant toxicities, underscoring the need to identify those who will not benefit. A previous study (SoMore trial) showed that early FDGPET-based metabolic response assessment (MRA) may adequately discriminate pts with chemorefractory aCRC unlikely to benefit from a sorafenib-capecitabine combination. RegARd-C aims to explore early MRA in pts treated with regorafenib as a clinical tool to spare pts from needless toxicity from a drug that gives them little or no benefit and as a translational tool to guide comprehensive genomic and epigenetic research on the determinants of drug resistance. Methods: RegARd-C’s (EUDRACT 2012-005655-16) is a multi-centric prospective study. Its primary objective is to identify in a population of pts with pretreated aCRC, those who will not benefit from regorafenib given at 160 mg/day, three weeks/4. Baseline PET is repeated at D14 of the first treatment course. MRA results are blinded for the investigators. Tumor tissues, optionally obtained from a PET-measurable lesion, and blood samples (at baseline; after the first chemotherapy course; and every two months) are collected. Overall survival (OS) is the primary endpoint and will be correlated with metabolic parameters, and genetic, epigenetic and molecular aberrations assessed from tumor biopsies and blood samples using gene expression and methylation profiling, RNA and exome sequencing. As the study is exploratory, no formal hypothesis was formulated. We arbitrarily decided to have a sample size of 105 evaluable pts with 70 pts as a derivation set and 35 pts as a validation set. Taking into account an expected 20-25% drop-out rate, between 124 and 140 pts will be accrued.This sample size is, however, sufficient to validate the hypothesis generated by the SoMore study, which found a prognostic impact of homogeneous metabolic response on OS, with an estimated HR of 0.59. RegARd-C has accrued 76 pts since August 2013. Clinical trial information: NCT01929616.