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This study was undertaken to examine the role of prostaglandins and histamine in the hyperemic response to gastric mucosal damage followed by H+ back-diffusion. Cat stomachs were exposed to 2 mol/liter NaCl for 10 min followed by luminal perfusion at pH 1. Hypertonic saline caused extensive (microscopic) damage to the surface epithelium, increased gastric mucosal blood flow, and increased release of histamine, PGE2, and 6-keto PGF1 alpha (prostacyclin) into portal venous blood. The effect of indomethacin and histamine blockers (H1 + H2) on the hyperemic response to acid back-diffusion was related to the depth of the mucosal injury and the region of the stomach. In the corpus, indomethacin enhanced mucosal injury. In areas with superficial damage, the hyperemia was inhibited by indomethacin and antihistamines and eliminated by the combination of both. In corpus areas with indomethacin-induced deep lesions, the blood flow was very high, and this hyperemia was partly inhibited by antihistamines. In the antrum the hyperemic response was reduced by antihistamines. Indomethacin increased the release of histamine into portal venous blood (baseline recordings) and reduced basal gastric mucosal blood flow.

555 Background: Almost 50% of patients with colorectal cancer (CRC) develop liver metastases, often as multiple simultaneous metastatic deposits. Up to 25% of the patients are eligible for partial liver resection, but 70% will relapse after surgery and there are currently no good criteria to select patients who will benefit from the treatment. Genetic heterogeneity among metastatic deposits has great potential impact on disease progression, but has not been well described. Methods: Totally 134 liver metastatic deposits were collected from 45 patients undergoing partial liver resection for metastatic CRC according to a prospective study protocol. All deposits were analyzed for high-resolution DNA copy number variation using the Affymetrix SNP Array 6.0. A novel bioinformatic approach was used to measure intra-individual genetic heterogeneity among the metastatic deposits. Results: The patients showed a large variation in the level of intra-individual metastatic heterogeneity, and heterogeneity was independent of the number of liver metastases analyzed per patient. Heterogeneity was a strong and independent prognostic factor in multivariate analysis with known clinicopathological prognostic factors. Patients with a high level of heterogeneity (above the median) had a three-year overall survival rate of 18%, compared with 66% for patients with a low level (hazard ratio, HR = 3.7, P = 0.007). The corresponding survival rates for progression-free survival were 6% and 24% (HR = 2.6, P = 0.01). Conclusions: A high level of intra-individual genetic heterogeneity among liver metastatic deposits is associated with poor survival after partial liver resection in patients with metastatic CRC.

We have studied the effect of intragastric instillation of 4.5 M NaCl on cell proliferation and carcinogen penetration into the forestomach of Wistar rats at different time intervals after salt exposure. Cells in the S-phase were labelled by incorporation of bromodeoxyuridine and located after immunohistochemistry. N-[3H]Methyl-N'-nitro-N-nitrosoguanidine ([3H]MNNG) was used as the carcinogen and penetration of [3H]MNNG to proliferative cells was determined by autoradiography. The number of cells in S-phase per millimetre epithelium length 12 h and 24 h after salt exposure (32.2 +/- 11.9 and 20.6 +/- 7.4) was significantly higher than in the control animals (9.4 +/- 3.6). No increase in cell proliferation occurred during the first 2 h after salt exposure. Microscopy also revealed oedema in the lamina propia. The forestomach blood flow was not influenced by the application of hypertonic saline. [3H]MNNG at a concentration of 40 micrograms/ml did not penetrate to the proliferative cells in the forestomach and no effect of salt pretreatment on carcinogen penetration was seen. The low penetration of [3H]MNNG to proliferative cells in the forestomach epithelium may explain why this concentration of MNNG given in drinking water over several weeks usually does not induce squamous cell carcinomas in the forestomach. The previously observed cocarcinogenic effect of salt on squamous cell cercinogenesis in the upper gastrointestinal tract could be due to the observed increase in cell proliferation after salt exposure.

Background/Aims: The hyperemic response after superficial gastric mucosal damage is essential for repair of the mucosa. Only indirect evidence suggests that this is caused by supply of bicarbonate. Therefore, this study tested the effect of maintaining the availability of bicarbonate after prevention of the hyperemic response after damage by 2 mol/L NaCl. Methods: Celiac artery flow was reduced, as monitored by Doppler ultrasonography, by gradual constriction of the vessel after mucosal damage. Saline (pH 1.0) was perfused through the stomach lumen and thereafter through a closed chamber with pH and Pco 2 electrodes. Results: Exposure to 2 mol/L NaCl produced a marked increase of mucosal blood flow as measured by microspheres (P $0.025) and a high degree of mucosal restitution 90 minutes after damage as judged by microscopy, whereas prevention of the hyperemic response caused extensive erosions and much less restitution ( P ⩽ 0.001). The latter effect was completely counteracted by intravenous bicarbonate. High blood concentration of bicarbonate increased luminal release of bicarbonate, whereas high mucosal blood flow did not. Conclusions: These data show that bicarbonate is an important factor in blood flow-mediated protection and repair of damaged gastric mucosa and suggest that concentration gradients are the major determinants for transport of bicarbonate across the damaged and restituted mucosa.

A 1-ml dose of 4.5 M NaCl was given intragastrically to male Wistar rats at 10 min, 1 h, 4 h, 12 h, 24 h or 48 h before a single intragastric dose of 250 mg/kg N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). After 52 weeks the incidence of forestomach squamous cell carcinoma was 21% in control animals receiving MNNG alone. The cancer incidence in the forestomach varied with the time elapsed between application of NaCl and MNNG, and was significantly increased in animals pretreated with NaCl 4 h (43%), 12 h (54%) and 24 h (41%) before MNNG. These results show that salt has a cocarcinogenic effect on initiation of forestomach carcinogenesis in rats, and that this effect depends on the time interval between pretreatment with NaCl and application of MNNG. Gastric adenocarcinomas occurred more frequently in the antrum (78%) than in the corpus (22%). The incidence of gastric adenocarcinoma in animals pretreated with salt before application of MNNG (11%-22%) was not significantly influenced by the time elapsed between pretreatment with salt and application of MNNG, and did not differ from animals receiving MNNG alone (18%). The lack of a cocarcinogenic effect of NaCl on glandular gastric carcinogenesis might be due to the use of dimethyl/sulfoxide as solvent for MNNG.

Dimethyl sulfoxide applied intragastrically for 10 min in rats caused extensive mucosal damage. In concentrations of 5%, 10%, or 100%, dimethyl sulfoxide caused superficial damage to 33%, 36%, and 97%, respectively, of the corpus mucosa, and 28%, 44%, and 96%, respectively, of the antral mucosa. Concentrated dimethyl sulfoxide also caused damage to the pits and glands in some areas of the mucosa. The amount of fluid in the stomach increased by 0.24 ml, 0.48 ml, and 2.07 ml during application of 5%, 10%, and 100% dimethyl sulfoxide. The 10% dimethyl sulfoxide increased mucosal blood flow by 0.57 ml/min/g in the antrum, and 100% dimethyl sulfoxide increased mucosal blood flow by 2.21 ml/min/g in the antrum and by 1.17 ml/min/g in the corpus. We conclude that dimethyl sulfoxide is a gastric irritant, which should be considered when it is used as an oxygen radical scavenger, as a drug or carcinogen vehicle, or as oral medication in patients. The protective effect of intragastric dimethyl sulfoxide against stress and various drug-induced gastric injury may be due to "adaptive cytoprotection" rather than an oxyradical scavenger effect.

Patients with metastatic poorly differentiated endocrine carcinoma (PDEC) usually have a short survival. The chemotherapy combination of cisplatin and etoposide is frequently used as first-line palliative chemotherapy. There are, however, no published studies concerning second-line treatment of the disease. Temozolomide has shown clinical effect in well-differentiated endocrine carcinomas. This study was performed to evaluate the effect of temozolomide in PDEC patients who had progressed on first-line treatment.Twenty-five patients with PDEC (mainly gastrointestinal) were treated with temozolomide alone or in combination with capecitabine. A subset of patient also received bevacizumab. MGMT methylation was analyzed in tissue specimens. Data were collected retrospectively.One patient had a complete response, and 7 patients had partial response (33% response rate). Median duration of response was 19 months. Another 9 (38%) patients had a stable disease, after progression at inclusion, with a median duration of 18 months. Median progression-free survival for all patients was 6 months, and median overall survival was 22 months. Only 1 patient had a MGMT methylation.Treatment with temozolomide alone or in combination with capecitabine and bevacizumab resulted in objective response or stabilization in 71% of PDEC patients who failed on first-line chemotherapy. These results indicated that temozolomide may be used as second-line treatment in PDEC.

Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P0.001), and less often responded to treatment (P0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).

Udgivelsesdato: 2009-Oct-15 BACKGROUND: Trial accrual patterns were examined to determine whether metastatic colorectal cancer (mCRC) patients enrolled in trials are representative of a general cancer population concerning patient characteristics and survival. METHODS: A total of 760 mCRC patients referred for their first oncological consideration at 3 hospitals in Scandinavia covering defined populations were registered consecutively during 2003 to 2006. Clinical trial enrollment, patient characteristics, and treatment were recorded prospectively, and the follow-up was complete. RESULTS: Palliative chemotherapy was initiated in 61% of the patients. Approximately one-third (36%) of patients receiving chemotherapy were included in a trial. The main reason for nonparticipation was failed eligibility criteria (69%). The median survival after chemotherapy was 15.8 months for all patients, and 18 months after combination chemotherapy. Trial patients had better prognostic characteristics and significantly longer survival than nontrial patients: 21.3 months versus 15.2 months when receiving combination chemotherapy. Poor performance status was the main reason for giving best supportive care only, and the median survival was then only 2.1 months. The median survival for all 760 nonresectable mCRC patients was 10.7 months. CONCLUSIONS: mCRC patients enrolled into clinical trials differ in characteristics from patients receiving chemotherapy outside protocol and have better survival, even when given the same treatment. Although trial patients have a median survival close to 2 years, survival is lower for all patients receiving chemotherapy and much lower for all patients diagnosed with mCRC. Studies that better accept the heterogeneity of the population with mCRC are needed.

Two consecutive studies have evaluated the efficacy of oxaliplatin combined with the Nordic bolus schedule of 5-fluorouracil and folinic acid as first-line treatment in metastatic non-resectable colorectal cancer. One hundred and twelve patients were followed after end of first-line treatment and any secondary therapy registered. Fifty-three patients (47%) did not receive second-line irinotecan-based chemotherapy. The main reason was too poor performance status (59%). These patients had a median survival of only 1.7 months after progression of first-line therapy. The best predictive factors at start of first-line chemotherapy for receiving later second-line chemotherapy were performance status and alkaline phosphatase level. Fifty-nine patients (53%) received irinotecan-based second-line therapy. Four (7%) patients had a partial response, and 28 (52%) had stable disease. Median progression-free survival after second-line chemotherapy was 4.1 months and median survival 9.5 months. Median survival after first-line chemotherapy and secondary liver surgery was 34 months and five-year disease-free survival 8%. Survival among patients receiving both first- and second-line chemotherapy was 20.8 months, but only 8.9 months in patients not receiving second-line irinotecan-based chemotherapy. Poor performance status or elevated alkaline phosphatase level at start of first-line chemotherapy predicts whether second-line chemotherapy will be given or not.

Background: A systemic inflammatory response (SIR) affects prognosis and treatment outcome in metastatic colorectal cancer (mCRC). The aim of the study was to explore the prognostic significance of several SIR-derived markers and the correlation between the best marker of SIR and plasma interleukin-6 (IL-6). Methods: The study was based on data from the randomized phase III NORDIC-VII study (Nordic FLOX +/cetuximab as first line treatment of mCRC). The effect of different markers of SIR, including modified Glasgow Prognostic Score (mGPS), derived Neutrophil Lymphocyte Ratio (dNLR), levels of platelets and levels of C-reactive protein (CRP) on survival were analyzed by Kaplan-Meier plots, logrank test, and Cox Proportional Hazards model. Further, the relationship between CRP, IL-6 and RAS and BRAF mutation status was examined. Results: 374 patients were eligible for the comparison of markers of SIR and 393 were eligible for the final analysis related to CRP, IL-6 and RAF and BRAF mutation status. The prognostic significance of CRP was at least as good as the other markers of SIR. CRP together with IL-6 were selected for further investigation. Logtrans-formed CRP and IL-6 were highly correlated (r = 0.661, p 60 mg/L, the different groups showed a median overall survival (OS) of 24.3, 20.6,17.1 and 12.3 months, respectively (HR = 1.34, 95% CI 1.22-1.48, p

In general a rising carcinoembryonic antigen (CEA) level means tumor progression. We observed a transient increase in CEA level despite objective response among patients receiving chemotherapy for metastatic colorectal cancer. This surge phenomenon has not previously been described for patients with metastatic colorectal disease. CEA was measured every second week in 27 patients receiving oxaliplatin, 5-fluororuracil, and folinic acid as first-line therapy against metastatic colorectal cancer. Four patients (15%, 95% CI 5-31%) met the criteria for therapy-induced CEA surge. The time of reaching maximum CEA level varied from 13 to 56 days. Median rise in CEA from baseline was 263% (range 24-632%). An initial rise of CEA during chemotherapy in colorectal cancer patients may therefore not always indicate progression of disease but may be a transient CEA surge in patients responding to chemotherapy.

This study combined oxaliplatin with the Nordic bolus schedule of 5-fluorouracil (5-FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer. Twenty-seven patients were treated every second week with oxaliplatin 85 mg/m2 as a 2-h infusion on day 1, followed by a 3-min bolus injection with 5-FU 500 mg/m2 and 30 min later a bolus injection with FA 60 mg/m2 given on days 1 and 2. Seventeen patients achieved a complete (n = 2) or partial (n = 15) response, leading to a confirmed response rate of 63% (95% CI 45-81%). The estimated median times to progression and survival were 8.9 and 18.7 months, respectively. Neutropenia grade 3-4 toxicity was seen in 63% of patients, neuropathy grade 3 in one patient and grade 2 in 12 patients. Oxaliplatin combined with the bolus Nordic schedule of 5-FU/ FA (Nordic FLOX) appears to be well tolerated, effective and feasible as first-line treatment of metastatic colorectal cancer yielding results comparable with those obtained by more complex schedules.

Background. Duodenogastric reflux predisposes to gastric cancer. This study investigates whether ulceration induced by duodenogastric reflux is associated with the development of neoplasms in the stomach. Materials and methods. In a rat experiment, duodenal fluid was directed into the corpus (jejunal reflux) or through the pylorus into the antrum (pyloric reflux). Sham-operated animals served as controls. The animals were sacrificed after 24, 36, or 52 weeks. Results. Ulcerations and neoplasms occurred more frequently in the corpus than in the antrum. In the corpus, ulceration was observed significantly more often in animals with jejunal reflux (62, 55, and 53% at 24, 36, and 52 weeks, respectively) than in animals with pyloric reflux (15, 21, and 30%). The incidence of neoplasm in the corpus increased significantly with time from 38% at 24 weeks to 89% at 52 weeks in animals with jejunal reflux and from 12 to 33% in animals with pyloric reflux. Ulceration and neoplasms shared location in the corpus adjacent to the gastrojejunostomy and by 24 weeks, all but one neoplasm in the jejunal reflux and one in pyloric reflux groups occurred adjacent to ulceration. In the antrum, 37% of the animals had a prepyloric ulceration after 24 weeks of pyloric reflux and only one of these animals had a neoplasm. By 52 weeks 20% of animals with pyloric reflux had a neoplasm that appeared in the prepyloric area. Conclusions. Ulceration and neoplasm occurred at the same sites in the stomach, and ulcerations preceded the development of neoplasms in the antrum and very likely in the corpus. The results suggest that ulceration plays an important role in the genesis of neoplasms in the stomach and that the vulnerability to duodenogastric reflux is more pronounced in the corpus than in the antrum mucosa.

e14525 Background: Tumor progression and metastasis are regulated by the tumor stroma (TS), suggesting a largely unexplored prognostic significance of its features. The aim of this study was to per...

D routine follow-up of patients with testicular cancer in Western Norway from January 1985 to December 1995, the following 4 patients with presumed recurrent retroperitoneal malignant disease were referred back to our Department. All patients had a history of a retroperitoneal lymph node dissection performed 2 months to 6 years previously. At presentation the mass was initially considered a possible recurrence. Further investigations, including ultrasound-guided aspiration of clear or milky fluid without malignant cells, confirmed a retroperitoneal lymphocele. Lymphoceles are well-documented complications of surgical operations involving pelvic and retroperitoneal lymph node excision (RLNE), renal transplantation, and abdominal aortic surgery. Lymphoceles after RLNE for testicular cancer seem less common. We have identified sporadic reports of 13 previous cases described in the literature. Our finding of 4 lymphoceles among 120 cases after RLNE indicates a frequency of 3.3% (95% CI, 2.8% to 10.3%). Thus lymphoceles may be one of the most common complications of RLNE. We have adopted a conservative treatment policy. In case 4 the lymphocele regressed spontaneously, whereas in cases 1 and 2 the lymphocele continued to increase. Provided the lymphocele becomes symptomatic, percutaneous puncture and aspiration or surgical drainage of the lymphocele are recommended. FIGURE 1. Case 1: a 41-year-old man, with a partly cystic tumor of 6 3 4 3 5 cm situated between the inferior caval vein and the aorta. Computed tomography scan taken 6 years after RLNE during follow-up for a retroperitoneal nonseminomatous germ cell tumor.

3571 Background: New vessel formation is an essential factor for tumor growth and metastasis. Tumor vessels show reduced and variable pericyte coverage. Several pericyte markers have been identified, including platelet-derived growth factor receptor beta (PDGFbR), smooth muscle α-actin (ASMA) and desmin. Variability in pericyte status and its prognostic significance remains largely uncharacterized in colorectal cancer (CRC). The aim of the present study was to perform a preliminary analysis of the variability in expression of the three pericyte markers and to investigate the potential prognostic significance of perivascular PDGFbR (PV-PDGFbR). Methods: A population-based cohort was used for double-staining, performed on 100 tumors with CD34 and above-named pericyte markers. For the rest of the study a metastatic CRC (mCRC) collection from the phase III NORDIC-VII study was used. Analyses were performed on a tissue microarray with tumor material from 328 out of the 566 patients in the intention to treat population. All tumors and corresponding normal tissue were scored by immunohistochemistry (IHC) with regard to PV-PDGFbR. 255 and 97 cases were analyzed by IHC with regard to perivascular ASMA and microvessel density (MVD), respectively. Results: Analyses of the double-staining revealed independent and variable expressions of all three pericyte markers. Analyses of the NORDIC-VII cohort revealed two prognostic groups with low and high PV-PDGFbR expression. Median OS was 14.3 mo for PV-PDGFbR-low tumors (N=22) vs. 22.9 mo for PV-PDGFbR-high (N=306) tumors (HR=1.95; 95% CI 1.20-3.16; log-rank p=0.007). Multivariate analysis, including WHO performance status, alkaline phosphatase level and BRAF mutation status confirmed PV-PDGFbR as an independent prognostic factor of OS (HR=1.75; 95% CI 1.07-2.84; p=0.025). PV-PDGFbR was not significantly linked to perivascular ASMA or MVD. PV-PDGFbR in normal tissue was not associated with survival. Conclusions: CRC display a previously un-recognized variability in pericyte characteristics. Low tumor PV-PDGFbR level is associated with worse prognosis in patients with mCRC, in a manner independent of performance status, alkaline phosphatase levels and BRAF status.

3597 Background: Tight junctions (TJ) are the most apical epithelial cell–cell adhesions. Claudin super-family trans-membrane proteins, including claudin 2 (cl2), are important components of TJs. Expression of cl2 has been reported to be elevated in colorectal cancer (CRC) and its up-regulation increases tumorigenicity of CRC cells in vitro. The aim of this study was to analyze the prognostic significance of cl2 in CRC. Methods: A tissue microarray (TMA) from the stage IV CRC patients of the phase III NORDIC-VII study was used. Cl2 IHC staining was evaluated in a semi-quantitative manner in cancer cells (cl2-C) and in the tumor stroma (cl2-S). Primary fibroblasts were established from human CRC tumor tissue and non-tumor colon tissue, and evaluated by immunoblotting. Results: Analyses of the TMA derived from the NORDIC-VII cohort revealed that cancer cell expression and tumor stroma expression of cl2 was associated with shorter OS in a Log-Rank test for trend (cl2-C, n=315, p=0.018; cl2-S, n=319, p=0.020). Expression of cl2-S, but not cl2-C was prognostic in multivariate analysis including WHO performance status, alkaline phosphatase level and BRAF mutation status (HR=1.30; 95% CI 1.08-1.56; p=0.006). When cl2-C and cl2-S expression was combined the prognostic significance was increased. The group with high cl2-C and high cl2-S (N=182), when compared with the rest of the cases (n=129), displayed a worse prognosis in terms of OS (19.1 mo vs 27.2 mo; p=0.003) in univariate analyses (HR=1.55, 95% CI 1.16-2.08, p=0.003) and in multivariate analyses (HR=1.52, 95% CI 1.13-2.05, p=0.006). Immunoblotting analysis of primary cultures of fibroblasts confirmed cl2 expression in fibroblasts from CRC tissue and from non-tumor tissue, with higher expression observed in the tumor fibroblasts. Conclusions: CRC display a previously un-reported stromal expression of cl2 of prognostic significance. High cl2-S is associated with worse prognosis in patients with metastatic CRC, in a manner independent of WHO status, alkaline phosphatase levels and BRAF status. Furthermore, high expression of cl2 in both cancer cells and the tumor stroma is also associated with poor prognosis.

e14710 Background: Plasma Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) is a biomarker in patients with metastatic colorectal cancer (mCRC). TIMP-1 inhibits matrix metalloproteinases and has tumor promoting functions. High levels of TIMP-1 associate with reduced sensitivity to irinotecan-based but not oxaliplatin-based treatment in patients with mCRC. Based on our prior studies, we here tested the hypothesis that high pretreatment plasma TIMP-1 correlate with short overall survival (OS) and short progression-free survival (PFS) but not response rate (RR) in patients with mCRC included in the NORDIC VII Study in which patients received oxaliplatin-based therapy. Methods: In the NORDIC VII Study patients were randomized to: A) Nordic FLOX; B) Nordic FLOX + cetuximab or C) Nordic FLOX intermittently + cetuximab continuously. Plasma samples for TIMP-1 analysis were available from 426 patients. Plasma TIMP-1 was determined using the MAC15 antibody in-house validated kinetic ELISA. Results: The three study populations were comparable and not different from the total intention to treat population. The median pretreatment plasma TIMP-1 was 269 ng/mL (58-1318 ng/mL). KRAS mutated in 149 patients (35%). There was no interaction between treatment arms and pretreatment plasma TIMP-1 either for PFS (p = 0.16) or OS (p = 0.64). High pretreatment plasma TIMP-1 was associated with shorter PFS (HR=1.22, 1.07-1.39, p=0.003) and shorter OS (HR=1.55, 1.36-1.80, p

392 Background: KRAS status is presently the best known biomarker to select patients with metastatic colorectal cancer (mCRC) for therapy with EGFR inhibition. However, in NORDIC VII a survival benefit of adding cetuximab to the Nordic FLOX regimen could not be confirmed. Plasma Tissue Inhibitor of MetalloProteinases-1 (TIMP-1) is a promising biomarker in patients with mCRC, and has multiple actions including regulation of apoptosis, angiogenesis, cell growth and differentiation. High levels of TIMP-1 associate with reduced sensitivity to irinotecan-based treatment in patients with mCRC. We investigated whether high plasma TIMP-1 also correlates with response rate, progression-free survival (PFS) and overall survival (OS) in patients with mCRC treated in NORDIC VII. Methods: In NORCIC VII 571 patients with mCRC were randomized to: (A) Nordic FLOX; (B) Nordic FLOX + cetuximab or (C) Nordic FLOX intermittently + cetuximab continuously. Baseline plasma samples for TIMP-1 analysis were available from 426 patients (79%). Plasma TIMP-1 was determined using the MAC15 antibody in-house validated kinetic Enzyme Linked Immunosorbent Assay. Results: Median plasma TIMP-1 was 296 ng/mL. The tumor was KRAS mutated in 149 patients (35%). Best response did not correlate to TIMP-1 values (OR=1.16, 0.91-1.49, p=0.22). High plasma TIMP-1 was associated with short PFS (HR=1.22, 1.07-1.39, p=0.003) and OS (HR=1.55, 1.36-1.80, p

This study was undertaken to examine the role of adenosine and nitric oxide (NO) in the hyperemic response to H+ back-diffusion into superficially or deeply injured gastric mucosa, and the role of adenosine in mucosa when blood flow was reduced with indomethacin.Cat stomachs were exposed to 2 M NaCl for 10 min followed by luminal perfusion at pH 1. Gastric mucosal blood flow was determined by radioactive microspheres, portal vein blood flow by transit-time flowmetry, and H+ back-diffusion/secretion by pH-stat titration, and concentrations of histamine in aortic and portal vein blood were measured.In the antrum pretreatment with the adenosine blocker 8-phenyltheophylline (8-PT) or with NG-methyl-L-arginine (L-NMMA), a specific inhibitor of NO formation, had no effect on the hyperemic response or mucosal injury. However, pretreatment with 8-PT in addition to indomethacin produced extensive deep lesions in the antrum. In the corpus/fundus 8-PT had no effect on the hyperemic response and did not increase indomethacin-induced lesions. L-NMMA significantly reduced the hyperemic response in corpus/fundus. In areas with deep lesions very high blood flow was observed in the vital part of the mucosa below the necrotic tissue. This hyperemia was reduced by L-NMMA but not by 8-PT. Indomethacin increased the release of histamine during base-line conditions, whereas 8-PT reduced histamine release after damage.This study indicates that usually adenosine is not involved in the hyperemic response to mucosal damage, but it appears to have important protective functions in the antral mucosa under marginal circulatory conditions. NO is one of the mediators of the hyperemic response to mucosal injury in the corpus/fundus.

In this study we tested the influence of blood flow and the mucoid cap on the penetration of carcinogens to the proliferative cells in the injures rat gastric mucosa. Ten minutes after mucosal exposure to 4.5 mol/liter NaCl, N-[3H]methyl-N'-nitro-N-nitrosoguanidine was instilled intragastrically. Hypertonic saline caused superficial mucosal damage, formation of a mucoid cap, high gastric mucosal blood flow, and a large flux of fluid into the gastric lumen. The mean percentage of S-phase cells labeled with carcinogen (the cell population at risk for N-methyl-N'nitro-N-nitrosoguanidine-induced carcinogenesis) in the antrum and corpus was 0.2 and 0.2, respectively, in the injury control group, 10.1 and 2.0 after removal of the mucoid cap, 1.5 and 9.8 after celiac artery ligation, and 28.2 and 21.9 after removal of the mucoid cap and celiac artery ligation. These results show that both the mucoid cap and gastric mucosal blood flow protect against penetration of carcinogens into the superficially injured gastric mucosa.

Age dependent increase in median and long-term survival in 29 628 metastatic colorectal cancer (mcrc) scandinavian patients during the past two decades

Long term survival data from EORTC study 40983 : Perioperative chemotherapy for resectable liver metastases from colorectal cancer

3548 Background: KRAS status is presently the best biomarker to select patients with metastatic colorectal cancer (mCRC) for therapy with EGFR inhibition even though not confirmed in all phase III studies. In the NORDIC VII study a survival benefit of adding cetuximab to the Nordic FLOX regimen could not be confirmed. Identification of new predictive and prognostic biomarkers is essential. Plasma concentration of YKL-40 is emerging as a new biomarker in patients with cancer and inflammatory diseases. We tested the hypothesis that high plasma YKL-40 associates with short progression free survival (PFS) and short overall survival (OS) in patients included in the NORDIC VII Study. Methods: 566 patients with mCRC were randomized to: A) Nordic FLOX; B) FLOX + cetuximab; and C) FLOX for 16 weeks + cetuximab continuously. Plasma samples were available from 510 patients (90%). Pretreatment plasma YKL-40 was determined by ELISA (Quidel), and the plasma YKL-40 concentration was dichotomized according to the age-corrected 95% YKL-40 level in 3130 healthy subjects. Results: Plasma YKL-40 was elevated in 204 patients (40%) and the median plasma YKL-40 was higher in the study group compared to healthy subjects (120 mg/l vs. 40 mg/l, p

3538 Background: NORDIC 7.5 is a multi-center phase II trial of Nordic FLOX plus biweekly C followed by maintenance C in first-line treatment of mCRC, KRASwild-type (KRASwt). The aim was to complement the data of the NORDIC VII trial, arm C (Tveit et al, ASCO GI 2011). Specifically, the goal was to substantiate efficacy and safety of biweekly C as maintenance therapy and to assess time to failure of strategy (TFS) as an end-point in maintenance therapy studies. Methods: Patients had KRASwt, measurable, non-resectable mCRC; no prior chemotherapy for metastases; WHO PS 0-2 and good organ function. Patients received 8 courses of FLOX (bolus 5FU/folinic acid days 1 + 2 with oxaliplatin day 1 every 2 weeks) plus biweekly C (500 mg/m2 every 2 weeks) for 16 weeks followed by biweekly C as maintenance therapy until progression (PD). After at least 2 months of maintenance therapy, patients restarted FLOX plus biweekly C at the time of RECIST PD, and continued until a second RECIST PD. The primary endpoint was response rate (RR). Eighty-six patients were planned to confirm a response rate of 60%. While awaiting the results of Nordic VII, we amended the protocol to include 150 patients. Secondary endpoints included PFS, OS, resection rate, and safety. TFS was an explorative endpoint. Results: From July 2008 to September 2010, 152 KRASwt patients were included in 11 Nordic centers. Results were updated December 2011. Median age 64 years; 94% PS 0-1. RR 62%, median PFS 8.0 months, median OS 23.2 months, median TFS 11.9 months. Ten patients (15%) had R0-resection of metastasis. FLOX + C was re-introduced in 47 of 85 patients (55%) who were candidates for re-treatment and was started median 18 days after PD. Median duration of re-introduction was 5 months (1-29), 9 patients (20%) had response. Elevated baseline platelets and neutrofiles were associated with poor OS. The most common grade 3/4 non-hematologic AEs in were diarrea (9%), skin rash (9%), infection without neutropenia (7%), and fatigue (7%) Conclusions: Maintenance therapy with biweekly cetuximab is an encouraging strategy with efficacy and toxicity comparable to weekly cetuximab.

3508 Background: This study evaluates the benefit of combining peri-operative chemotherapy and surgery for patients with liver only metastases from colorectal cancer (LM) deemed resectable on pre-operative imaging. The PFS results, the primary endpoint, were reported (ASCO 2007). We now report on the secondary endpoint overall survival (OS) results, after a median follow-up of 8.5 years. Methods: Between September 2000 and July 2004, 364 patients (pts) with up to 4 LM were randomized between peri-operative FOLFOX4 (oxaliplatin 85mg/m² and LV5FU2), 6 cycles before and 6 cycles after surgery, (CT arm), and surgery alone (S arm). OS was compared between arms using a 2-sided non-stratified log-rank test at the 0.05 level of significance (intent-to-treat analysis). Results: 182 pts were randomized in each arm (CT arm and S arm) of which 171 were eligible (CT and S) and 152 underwent resection (CT and S). In the CT arm, 171 received preop CT and 115 received postop CT. At a median follow-up of 8.5 years, 221 deaths were reported (61 % of all randomized pts). Causes of death in CT arm were cancer relapse (85 pts), complication of surgery (2 pts), other causes (16 pts) and unknown cause (4 pts), and in S arm, cancer relapse (99 pts), complication of surgery (2 pts), other causes (11 pts) and unknown cause (2 pts). Observed median OS was higher in CT arm: 61 months (CT) vs. 54 months (S) in all randomized pts and 64 months (CT) vs. 55 months (S) in eligible pts. The 5 year OS rate was 51.2% (CT) vs. 47.8% (S) (all randomized) and 52.4% (CT) vs. 48.3% (S) (eligible pts). There was no significant difference in OS between arms (HR=0.88, 95% CI 0.68-1.14, p=0.34) (all randomized). After progression, second line treatment with chemotherapy was given in 59 % (CT) and 77% (S) of the pts with cancer progression and repeat surgery in 46% (CT) and 40% (S), respectively. Conclusions: Peri-operative chemotherapy with FOLFOX4 improves PFS but does not significantly improve OS over surgery alone. A potential benefit may have been diluted by second treatment lines and by more deaths unrelated to cancer in the CT arm.

71 Background: The Norwegian Gastrointestinal Cancer Group (NGICG) conducted a phase II randomized study comparing the efficacy and safety of FLOX and FLIRI as first line treatment in metastatic or locally advanced gastric cancer. At progression or unacceptable drug related toxicity, a crossover to the other treatment arm should be done, if second line chemotherapy was indicated. Methods: 66 patients from 6 treatment centers in Norway were randomized to FLOX (oxaliplatin 85 mg/m2 on day 1, bolus 5-FU 500 mg/m2 and FA 60 mg/m2 on day 1 and 2, or FLIRI (irinotecan 180 mg/m2 on day 1, bolus 5-FU 500 mg/m2 and FA 60 mg/m2 on day 1 and 2). Both treatments were repeated every second week. The primary endpoint was response rate (RR) and time to progression (TTP). Secondary endpoints were overall survival (OS) and safety data. Results: At the present time data from 63 patients are available for analysis. First-line treatment: FLOX (n = 32) versus (v.) FLIRI (n = 31): Complete response (CR) n = 0 in both arms, partial response (PR) n = 16 v. 9, stable disease (SD) n = 12 v. 13, progressive disease (PD) n = 3 v. 6, not assessable for evaluation n = 1 v. 3 patients. RR was 50 % in the FLOX arm v. 29 % in the FLIRI arm, p = not significant (n.s), Pearson Chi-Square test. Median TTP was 5 months (95 % CI 2.2-7.8) v. 4 months (95 % CI 2.2-5.8), p = n.s, median OS was 11 months (95 % CI 9.2-12.8 ) v. 10 months (95 % CI 5.7-14.3), p = n.s, Log Rank test. Patient characteristics were well balanced. Febrile neutropenia was present among 10 % of the patients in the FLOX arm versus 7 % in the FLIRI arm. Second line treatment: 30 patients received second line treatment with FLOX or FLIRI. Data regarding RR, TTP, OS and safety will be updated in December 2011. Conclusions: The FLOX and FLIRI regimens are well tolerated among patients with locally advanced and metastatic gastric cancer. As first line treatment the FLOX regime had a higher RR of 50% v. 29% for the FLIRI regime, longer TTP; 5 v. 4 months and longer OS 11 v. 10 months, but the difference did not reach statistical significance.

Blood flow plays an important role in protection of normal gastric mucosa and in the protection and healing of damaged mucosa. Blood flow contributes to protection by supplying the mucosa with oxygen and HCO3-, and by removing H+ and toxic agents diffusing from the lumen into the mucosa. Low mucosal blood flow predisposes to injury, whereas high blood flow protects against injurious agents. Superficial mucosal damage is followed by increased blood flow which supports the healing process and prevents superficial lesions from developing into deep ones. The hypermic response increases the supply of HCO3- to the mucosa and increases the resistance of the injured mucosa against back diffusing H+ and aggressive drugs such as ethanol (adaptive protection). Mucosal ischemia contributes to gastric ulceration in various clinical conditions such as hemorrhagic shock, stress, aorta aneurysm and after proximal gastric vagotomy. Blood vessels are damaged in gastric ulcers. During ulcer healing blood flow returns to normal. Stimulated or inhibited angiogenesis in the granulation tissue effects the healing of a gastric ulcer.

365 Background: The role of anti-EGFR therapy in first-line treatment of metastatic colorectal cancer (mCRC) is not established. In the present study pts were randomized to FLOX or FLOX + cetuximab until progression or FLOX intermittently + cetuximab continuously. Methods: Treatment arm A: Nordic FLOX (q2w): oxaliplatin 85 mg/m2day 1, 5-FU bolus 500 mg/m2 and FA 60 mg/m2 day 1-2; B: FLOX + cetuximab, initial dose 400 mg/m2, then 250 mg/m2/week; C: FLOX for 16 weeks + cetuximab continuously, with FLOX added at progression. Primary endpoint was progression-free survival (PFS). Results: Between May 05-Oct 07, 571 pts were randomized, 566 pts evaluable in intention to treat (ITT) analyses. Median age was 61 (24-74). ECOG status: 0=67%, 1=29%, 2=4%. KRAS and BRAF mutation (mut) analyses were obtained in 498 (87%) and 457 pts (81%), respectively. 40% of tumors had KRAS mut, 12% had BRAF mut. Cetuximab combined with Nordic FLOX did not significantly improve RR, PFS or OS compared to FLOX. KRAS mutation was not predictive for cetuximab effect. OS was similar for patients treated with FLOX intermittently and cetuximab continuously as for patients treated until progression. BRAF mutation was a strong negative prognostic factor (median OS 7.6 vs. 20.4 mo). Conclusions: Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC, irrespective of KRAS-mut. [Table: see text] [Table: see text]

We have studied the penetration of a labeled gastric carcinogen, N-(3H)methyl-N'-nitro-N-nitrosoguanidine (3H-MNNG), from the gastric lumen to proliferative cells in the gastric mucosa of Wistar rats. 3H-MNNG was dissolved in deionized water or dimethyl sulfoxide (DMSO) and given intragastrically through a tube in the forestomach. Cells in the S-phase were labeled by incorporation of bromodeoxy-uridine. Penetration of the carcinogen was evaluated by light microscopy after immunohistochemistry and autoradiography. Cells in S-phase labeled with 3H-MNNG (double-labeled cells) are considered to represent the cell population at risk of MNNG-induced carcinogenesis. When deionized water was used as solvent for the carcinogen, the average percentage of double-labeled cells in the pylorus was 12.0, 22.4 and 32.5 respectively, after 10, 30 and 60 min of mucosal exposure to 3H-MNNG. The corresponding percentages for the fundus mucosa were 1.7, 3.1 and 3.4, which are significantly lower than the pylorus values. When DMSO was used as solvent for the carcinogen, the percentage of double-labeled cells was 0.3 and 1.1 in the pylorus and 0.1 and 1.3 in the fundus after 10 and 30 min exposure to 3H-MNNG. Dimethyl sulfoxide caused superficial mucosal damage to the gastric mucosa and increased secretion of fluid into the stomach. Our results strongly suggest that gastric cancer develops in the pylorus because the carcinogen penetrates more easily into pyloric than fundic mucosa. The results support the view that delayed gastric emptying is a risk factor in gastric carcinogenesis, and show that DMSO counteracts the penetration of MNNG into the mucosa.

LBA5 Background: The 5-year survival after resection of colorectal cancer liver metastases is 30% but recurrence is common. This study evaluates the benefit of combining peri-operative chemotherapy and surgery for patients with initially resectable liver only metastases from colorectal cancer (LM). Methods: Between September 2000 and July 2004, 364 pts with up to 4 LM were randomized between peri-operative FOLFOX4 (oxaliplatin 85mg/m2 and LV5FU2), 6 cycles before and 6 cycles after surgery, (CT), and surgery alone (S). The primary endpoint was progression free survival (PFS) with the goal to increase median PFS by 40% (HR=0.71). Safety was a secondary endpoint (already reported at ASCO 2005). PFS results are reported at the 2-sided 0.0434 significance level (adjusting for one interim analysis). Results: Baseline characteristics were similar in both arms. Eleven of 182 pts were ineligible in each arm, mostly for more advanced disease. In the CT arm, a median of 6 pre-op cycles were delivered and 151 patients were resected. 115 pts (63%) received post-op CT, with a median number of 6 cycles and a relative dose intensity of 79% to 86%. In the S arm, 152 pts were resected. Due to the nature of the trial, evaluation of resectability (relevant for eligibility) was based on pre-op imaging, but 31/182 pts (CT arm) and 30/182 pt (S arm) could not undergo resection. There were 2 (S arm) and 1 (CT arm) deaths after surgery. At a median follow-up of 3.9 years, 254 PFS events were reported (240 in eligible pts) and the results are as shown in the table . Conclusions: Peri-operative FOLFOX4 chemotherapy improved PFS over surgery alone in patients whose metastases were actually resected. The benefit was slightly diluted when also pts considered resectable on imaging but eventually not resected were taken into account. FOLFOX4 given peri-operatively is safe and does not prevent the pts from undergoing surgery. [Table: see text] [Table: see text]

3500 Background: After resection of LM, 5y survival is 30%, but cancer recurrence is frequent. The benefit of combining surgery and CT has not yet formally been proven. Methods: This study evaluates the value of pre- and postoperative CT in patients with potentially resectable liver metastases from colorectal cancer. Between September 2000 and July 2004, 364 patients were randomized between peri-operative FOLFOX4 (oxaliplatin 85mg/m2 and LV5FU2), 6 cycles before and 6 cycles after surgery (182 patients), and surgery alone (182 patients). The primary endpoint was progression free survival. The purpose of this analysis was to evaluate tumor response to pre-operative treatment and determine if CT induces a tumor size reduction. Results: Baseline characteristics were similar in both arms: median age: 62.5 yrs, prior adjuvant CT: 41.8%, 1 to 3 metastases: 92.3%, T3 or T4: 80.8%. In the CT arm, 97.7% of the patients were documented to have completed pre-operative CT (81.5% received 6 preoperative cycles). 28.9% of the patients who started pre-operative CT required a dose reduction. Of all patients entered in the trial, 88.3% and 94.9% underwent surgery in the CT and surgery arms, respectively. Resection was achieved in 95.6% of the patients operated (84.4% of all patients) in the CT arm, and 89.2% of the patients operated (84.7% of all patients) in the surgery arm. As previously reported, preoperative chemotherapy was safely administered. From imaging data (CT scan), median sum of largest diameters of lesions was 45 mm [Q1-Q3:28.0–70.0] (both arms) before treatment and decreased to 30 mm [Q1-Q3: 15.0–55.0] after CT (median relative difference of 29.7%). At pathological examination, median sum of largest diameters of lesions was 34.5 mm [Q1-Q3:20.0–53.0] in the CT arm and 45 mm [Q1-Q3: 29.0–69.0] in the surgery arm. Conclusions: CT scan measurements were consistent with those performed at pathological examination. Pre-operative CT with 6 cycles of FOLFOX4 resulted in a decrease in diameter of lesions. Since size of metastases at time of surgery is known to have an impact on survival, it is possible that preoperative chemotherapy will improve survival. Survival data should be available at the end of 2006. No significant financial relationships to disclose.

3528 Background: After resection of LM, 5y survival is 30%, but cancer recurrence is frequent. The benefit of combining surgery and CT is not yet formally proven. Methods: This study evaluates pre- and postoperative CT. Between September 2000 and July 2004, 364 patients with potentially resectable liver metastases from colorectal cancer were randomized between peri-operative FOLFOX4 (oxaliplatin 85mg/m2 and LV5FU2), 6 cycles before and 6 cycles after surgery, and surgery alone. The primary endpoint was disease-free survival. Safety was a secondary end point. Results: We report the interim safety results of the first 346 patients with at least 3 months follow-up post surgery (174 patients in the CT arm and 172 in the surgery arm). Median follow up is 17 months. Baseline characteristics were similar in both arms. In the CT arm, 84.8% of the patients were documented to have completed CT (6 preoperative cycles). 28.2% of the patients who started CT required a dose reduction. Grade ≥3 diarrhea was reported in ...

3562 Background: Oxaliplatin (Ox) in combination with FU or Capecitabine (Xel) prolong median survival as first and second line therapy in patients with advanced colorectal cancer (ACRC). Ox induces acute, cold-induced neuropathy in most patients. The incidence is claimed to be infusion rate-dependent and therefore a 2 hour infusion is recommended, but in a prior pilot study (Pfeiffer et al, Acta Oncol 2003; 42: 832) a 30 minutes infusion could be given without additional neuropathy. Methods: For practical and economic reasons, but also for patient's convenience, we performed this phase II study to examine XELOX30 (Xel 1000 mg/m2 orally twice daily days 1–14 and Ox 130 mg/m2 as 30 minutes infusion day 1) in patients with progressive colorectal cancer after therapy with irinotecan and FU. Neuropathy was graded 0–3 using the Ox-specific scale. Other adverse events were graded using NCI-CTC. Results: From Nov 2002 to Sept 2003, 69 patients with ACRC were included and treated with XELOX30. Median age was 62 y...