Background: Reliable and modern information on primary evaluation, treatment, and long-term survival rates for patients with colorectal cancer (CRC) metastases are needed. Whether synchronous CRC metastases carry a worse prognosis than metachronous is still debated. Methods: Population-based study on 7,950 CRC patients from Central Norway, 2001– 2015. Of these, 1,843 (23.2%) had synchronous metastases and of radically operated patients with stage I–III disease 1,117 (20.1%) developed metachronous metastases. The treatment strategies and outcomes for patients with metastases were analyzed, stratified by three consecutive 5-year periods. Results: Median and 3-year survival for patients with synchronous metastases were 11 months and 16.4%, compared to 17 months and 29.4% with metachronous metastases, p < 0.001 and p < 0.001, respectively. The subsets receiving supportive care only, had a median survival of 3–4 months. Patients with synchronous metastases and primary palliative chemotherapy had a median survival of 15 months compared to 18 months with metachronous metastases, p < 0.001. Neither groups improved survival across the study period. The 5-year survival for the 342/1,843 (18.6%) patients with synchronous metastases and curative intent treatment was 41.8% compared to 43.6% for the corresponding 422/1,117 (37.8%) patients with metachronous metastases, log-rank p = 0.281. Survival significantly improved for both these groups across the study period. Interpretation: A key determinant of better survival for patients with metachronous CRC metastases compared to synchronous was a significantly higher proportion treated with curative intent. Survival for both patients with synchronous and metachronous metastases taken collectively steadily improved during the study period, driven by the increased proportions and improved survival for the subsets with curative intent treatment.

Background In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma. Methods NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), and fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m(2) over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m(2) twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m(2), irinotecan 150 mg/m(2), leucovorin 400 mg/m(2), and fluorouracil 2400 mg/m(2) over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing. Findings Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49-71) in the neoadjuvant FOLFIRINOX group versus 73% (62-84) in the upfront surgery group (p=0 center dot 032), and median overall survival by ITT was 25 center dot 1 months (95% CI 17 center dot 2-34 center dot 9) versus 38 center dot 5 months (27 center dot 6-not reached; hazard ratio [HR] 1 center dot 52 [95% CI 1 center dot 00-2 center dot 33], log-rank p=0 center dot 050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46-67) in the neoadjuvant FOLFIRINOX group versus 70% (55-83) in the upfront surgery group (p=0 center dot 14), and median overall survival in per-protocol population was 23 center dot 0 months (95% CI 16 center dot 2-34 center dot 9) versus 34 center dot 4 months (19 center dot 4-not reached; HR 1 center dot 46 [95% CI 0 center dot 99-2 center dot 17], log-rank p=0 center dot 058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0 center dot 24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0 center dot 56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event. Interpretation This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven. Copyright (c) 2024 Elsevier Ltd. All rights reserved.

Biomarkers associated with the progression from gastric intestinal metaplasia (GIM) to gastric adenocarcinoma (GA), i.e., GA-related GIM, could provide valuable insights into identifying patients with increased risk for GA. The aim of this study was to utilize multi-bioinformatics to reveal potential biomarkers for the GA-related GIM and predict potential drug repurposing for GA prevention in patients. The multi-bioinformatics included gene expression matrix (GEM) by microarray gene expression (MGE), ScType (a fully automated and ultra-fast cell-type identification based solely on a given scRNA-seq data), Ingenuity Pathway Analysis, PageRank centrality, GO and MSigDB enrichments, Cytoscape, Human Protein Atlas and molecular docking analysis in combination with immunohistochemistry. To identify GA-related GIM, paired surgical biopsies were collected from 16 GIM-GA patients who underwent gastrectomy, yielding 64 samples (4 biopsies per stomach x 16 patients) for MGE. Co-analysis was performed by including scRNAseq and immunohistochemistry datasets of endoscopic biopsies of 37 patients. The results of the present study showed potential biomarkers for GA-related GIM, including GEM of individual patients, individual genes (such as RBP2 and CD44), signaling pathways, network of molecules, and network of signaling pathways with key topological nodes. Accordingly, potential treatment targets with repurposed drugs were identified including epidermal growth factor receptor, proto-oncogene tyrosine-protein kinase Src, paxillin, transcription factor Jun, breast cancer type 1 susceptibility protein, cellular tumor antigen p53, mouse double minute 2, and CD44.

LBA4005 Background: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) has shown improved survival in metastatic pancreatic cancer, and promising results as downstaging chemotherapy in locally advanced pancreatic cancer. The efficacy of neoadjuvant FOLFIRINOX in patients with resectable pancreatic cancer is unknown. Methods: This is a randomized phase II trial with patients included from 12 Nordic centers in the period 2017-2021. Patients with resectable pancreatic head cancer were randomly assigned to receive either four neoadjuvant cycles of FOLFIRINOX followed by surgery and eight adjuvant cycles mFOLFIRINOX, or upfront surgery and adjuvant mFOLFIRINOX (12 cycles). The primary endpoint was overall survival at 18 months after date of randomization (intention-to-treat [ITT]). Overall survival was estimated with the Kaplan-Meier method, and differences between the respective treatment arms were analyzed with log rank tests. Results: In NORPACT-1, 140 patients were randomly assigned (neoadjuvant chemotherapy, n=77;upfront surgery, n=63). Median age was 66.5 years (IQR 59, 72), while 115 (82.1%) and 25 (17.9%) patients were ECOG 0 and 1, respectively. Median OS by ITT was 25.1 months [95% CI 17.2-34.9] with neoadjuvant chemotherapy and 38.5 months [95% CI 27.6-not reached] with upfront surgery (p=0.096). The proportion of patients alive at 18 months by ITT was 59.7 % [95% CI 48.9-70.7] and 73.0 % [95% CI 62.0-84.0], respectively (p=0.100). Resection rates were 81.8% (63/77) in the neoadjuvant group and 88.9% (56/63) in the upfront surgery group (p=0.342). In the neoadjuvant group 61 (79.2%) patients initiated neoadjuvant FOLFIRINOX. Completion of the four planned cycles was 60%, with dose reductions and delays in 70% and 28.3%. Per-protocol (PP) analysis of 60 patients with pancreatic ductal adenocarcinoma (PDAC) who received minimum one cycle neoadjuvant FOLFIRINOX compared with 55 patients in the upfront surgery arm who were explored showed median OS of 23.0 months [95% CI 16.2-34.9] and 34.4 months [95% CI 19.4-not reached] (p=0.158). Adjuvant chemotherapy initiation rate was 66.2% and 74.6% (p=0.282) by ITT. In resected PDAC patients the rate was 86.4% and 89.8% (p=0.593). Of 120 patients receiving at least one dose of neoadjuvant and/or adjuvant chemotherapy (safety population), 57.5% (42/73) in the neoadjuvant group and 40.4% (19/47) in the upfront surgery group experienced at least one grade ≥3 adverse event (p=0.067). In PP analysis neoadjuvant FOLFIRINOX was associated with significantly higher rate of N0 (p=0.002) and R0 resection (p=0.011). Conclusions: Neoadjuvant FOLFIRINOX did not improve OS compared with upfront surgery in resectable pancreatic head cancer. Our results do not support neoadjuvant chemotherapy as standard of care for these patients. Future trials should incorporate a biomarker-based design. Clinical trial information: NCT02919787 .

BackgroundFollowing neoadjuvant chemotherapy (NAC) for resectable gastric cancer, the prognostic adequacy of the UICC staging system needs to be investigated. In particular to explore whether the ypTNM curves for radically resected gastric cancer patients receiving NAC follow the stage-matched survival curves of radically resected chemo-naive patients (pTNM). Further, to disclose any interaction between the TNM-response mode to NAC and stage-specific survival rates, i.e., whether survival for a particular pathological disease stage was dependent on whether this was reached through a downstaging or as stable disease following NAC.Material and methodsRetrospective study on radically resected patients <= 75 years of age with gastric adenocarcinoma stages I-III diagnosed during 2001-2016. The patients constitute two population-based cohorts; the SURG-group with n = 121 patients treated before 2007 when NAC was introduced, and the NAC-group with n = 126 patients diagnosed since early 2007, receiving NAC and subsequent radical resection.ResultsLong-term survival rates were similar when specific ypTNM-stages were compared to their corresponding pTNM chemo-naive counterparts. The dichotomised N0 vs. N + had a substantial impact on the long-term survival rates in both groups, however, no discrepancy in long-term survival rates between pN0 vs. ypN0, and pN + vs. ypN + was found. The pathological stage determined long-term survival rates irrespective of the baseline disease stage, as no interaction between the response mode and stage-specific survival rates was found.ConclusionsSurvival curves for specific ypTNM-stages following NAC did not differ from the corresponding survival curves of their chemo-naive pTNM counterparts. The interpretation is that NAC affected the gastric cancer, lymph nodes, and micrometastases, in such a way that the final ypTNM-stage provided similar prognostic information as the chemo-naive pTNM-stages. Survival rates were contingent on the final ypTNM-stages alone, and not influenced by the response mode to reach that particular disease stage, or predetermined by the original clinical TNM-stage.

Background Updated knowledge about the rates of recurrence and time to recurrence following curative treatment of colorectal cancer is essential to secure better patient information on prognosis, to serve as a premise in the discussion on adjuvant chemotherapy, and help to properly scale the intensity and length of follow-up.Methods This is a population-based study investigating aspects on first recurrence after radical treatment of clinical stages I-III of colorectal cancer in Central-Norway during 2001-2015. To reveal any time-trends, data were stratified by the time periods 2001-2005, 2006-2010 and 2011-2015. The cumulative incidence of first recurrence was calculated, treating death of unrelated causes as a competing event. Multivariable Cox analyses were done to calculate cause specific hazard ratios (HR) for risk of recurrence.Results At a minimum follow-up of six years, a first recurrence was detected in 1,113/5,556 patients at risk (20.0%). The recurrence rate was reduced from 23.6% in the first time period, through 20.0% in the second, and to 17.2% in the last, p < 0.001. The reduction applied to all tumor locations, to pathological disease stages II and III, to both gender, across different tumor differentiations, and to both elective and emergency surgery. In multivariable analyses time period, gender, disease stage, and tumor differentiation were significant determinants for risk of recurrence.Conclusions The rate of first recurrence after curative surgery for colorectal cancer was substantially reduced from 2001 to 2015. The reason for the reduction could not be attributed to a single factor only. A combined effect of several incremental improvements, such as an increased use of preoperative radiation for rectal cancers, improved adjuvant chemotherapy for colon cancer, and a reduced proportion of emergency surgery, is suggested.

Background: The method of response evaluation following neoadjuvant chemotherapy (NAC) in resectable gastric cancer has been widely debated. An essential prerequisite is the ability to stratify patients into subsets of different long-term survival rates based on the response mode. Histopathological measures of regression have their limitations, and interest resides in CT-based methods that can be used in everyday settings. Methods: We conducted a population-based study (2007–2016) on 171 consecutive patients with gastric adenocarcinoma who were receiving NAC. Two methods of response evaluation were investigated: a strict radiological procedure using RECIST (downsizing), and a composite radiological/pathological procedure comparing the initial radiological TNM stage to the pathological ypTNM stage (downstaging). Clinicopathological variables that could predict the response were searched for, and correlations between the response mode and long-term survival rates were assessed. Results: RECIST failed to identify half of the patients progressing to metastatic disease, and it was unable to assign patients to subsets with different long-term survival rates based on the response mode. However, the TNM stage response mode did achieve this objective. Following re-staging, 48% (78/164) were downstaged, 15% (25/164) had an unchanged stage, and 37% (61/164) were upstaged. A total of 9% (15/164) showed a histopathological complete response. The 5-year overall survival rate was 65.3% (95% CI 54.7–75.9%) for TNM downstaged cases, 40.0% (95% CI 20.8–59.2%) for stable disease, and 14.8% (95% CI 6.0–23.6%) for patients with TNM progression, p < 0.001. In a multivariable ordinal regression model, the Lauren classification and tumor site were the only significant determinants of the response mode. Conclusions: Downsizing, as a method for evaluating the response to NAC in gastric cancer, is discouraged. TNM re-staging by comparing the baseline radiological CT stage to the pathological stage following NAC is suggested as a useful method that may be used in everyday situations.

This brief communication presented a dissertation of PhD thesis on translational research using state-of-the-art methods of multi-disciplinary integrations between basic and clinical research and between dry- (computational) and wet- (experimental and clinical) investigations. The findings showed possible causal association between neural innervation and tumorigenesis of gastric cancer via Wnt signaling and metabolic reprogramming within the tumor microenvironment. Accordingly, selective vagotomy, Botulinum neurotoxin type A (injection into the tumor areas), RAD001 (also known as Everolimus), CPI-613 (devimistat) and ivermectin were found to be potential for treatment of gastric cancer. The assessment showed that this translational research approach guaranteed the efficient development of novel knowledge in fundamental medical sciences, and that the identification of the role of vagal innervation and the possibilities of its modulation during gastric tumorigenesis represented valuable contributions to the fields of gastroenterology and cancer research. Possible roles of angiogenesis vs neurogenesis and brain-gut axis would be worth exploring in further research.

Abstract Purpose: Hypergastrinemia increases the risk of developing proximal gastric adenocarcinoma. However, it is unclear if hypergastrinemia affects the survival in patients with gastric adenocarcinoma. This study aimed to examine the hypothesis that hypergastrinemia is associated with increased risk of mortality in patients with gastric adenocarcinoma. Materials and methods: This prospective population-based cohort study based on the Trøndelag Health Study (HUNT) included 78,962 adult individuals (≥20 years). During the baseline assessment period (1995–2008) of these participants, serum samples were collected and frozen. All participants with a newly diagnosed gastric adenocarcinoma in the cohort in 1995–2015 were identified and their gastrin levels were measured in the pre-diagnostic serum samples. Gastrin levels were analysed in relation to all-cause mortality until year 2020 using multivariable Cox regression providing hazard ratios (HRs) with 95% confidence intervals (CIs), adjusted for sex, age, body mass index (BMI), tobacco smoking, tumour stage, completeness of surgical resection, and peri-operative chemotherapy. Results: Among 172 patients with gastric adenocarcinoma, 81 (47%) had hypergastrinemia (serum gastrin >60 pmol/L) and 91 (53%) had normal gastrin level. The tumour location was proximal in 83 patients (43%) and distal in 78 (41%). Hypergastrinemia was not associated with any increased risk of all-cause mortality in all patients (adjusted HR 0.8, 95% CI 0.5–1.1), or in sub-groups of patients with proximal tumour location (HR 0.9, 95% CI 0.4–2.2) or distal tumour location (HR 0.9, 95% CI 0.5–1.7). Conclusion: This population-based cohort study indicates that hypergastrinemia may not increase the risk of mortality in patients with gastric adenocarcinoma.

BACKGROUND:The method of response evaluation following neoadjuvant chemotherapy (NAC) in resectable gastric cancer has been widely debated. An essential prerequisite is the ability to stratify patients into subsets of different long-term survival rates based on the response mode. Histopathological measures of regression have their limitations, and interest resides in CT-based methods that can be used in everyday settings.METHODS:We conducted a population-based study (2007-2016) on 171 consecutive patients with gastric adenocarcinoma who were receiving NAC. Two methods of response evaluation were investigated: a strict radiological procedure using RECIST (downsizing), and a composite radiological/pathological procedure comparing the initial radiological TNM stage to the pathological ypTNM stage (downstaging). Clinicopathological variables that could predict the response were searched for, and correlations between the response mode and long-term survival rates were assessed.RESULTS:RECIST failed to identify half of the patients progressing to metastatic disease, and it was unable to assign patients to subsets with different long-term survival rates based on the response mode. However, the TNM stage response mode did achieve this objective. Following re-staging, 48% (78/164) were downstaged, 15% (25/164) had an unchanged stage, and 37% (61/164) were upstaged. A total of 9% (15/164) showed a histopathological complete response. The 5-year overall survival rate was 65.3% (95% CI 54.7-75.9%) for TNM downstaged cases, 40.0% (95% CI 20.8-59.2%) for stable disease, and 14.8% (95% CI 6.0-23.6%) for patients with TNM progression, p < 0.001. In a multivariable ordinal regression model, the Lauren classification and tumor site were the only significant determinants of the response mode.CONCLUSIONS:Downsizing, as a method for evaluating the response to NAC in gastric cancer, is discouraged. TNM re-staging by comparing the baseline radiological CT stage to the pathological stage following NAC is suggested as a useful method that may be used in everyday situations.

Objective: The aim of the present study was repositioning of ivermectin in treatment of gastric cancer (GC) by computational prediction based on gene expression profiles of human and mouse model of GC and validations with in silico, in vitro and in vivo approaches. Methods: Computational drug repositioning was performed using connectivity map (cMap) and data/pathway mining with the Ingenuity Knowledge Base. Tissue samples of GC were collected from 16 patients and 57 mice for gene expression profiling. Additional seven independent datasets of gene expression of human GC from the TCGA database were used for validation. In silico testing was performed by constructing interaction networks of ivermectin and the downstream effects in targeted signaling pathways. In vitro testing was carried out in human GC cell lines (MKN74 and KATO-III). In vivo testing was performed in a transgenic mouse model of GC (INS-GAS mice). Results: GC gene expression “signature” and data/pathway mining but not cMAP revealed nine molecular targets of ivermectin in both human and mouse GC associated with WNT/β-catenin signaling as well as cell proliferation pathways. In silico inhibition of the targets of ivermectin and concomitant activation of ivermectin led to the inhibition of WNT/β-catenin signaling pathway in “dose-depended” manner. In vitro, ivermectin inhibited cell proliferation in time- and concentration-depended manners, and cells were arrested in the G1 phase at IC50 and shifted to S phase arrest at >IC50. In vivo, ivermectin reduced the tumor size which was associated with inactivation of WNT/β-catenin signaling and cell proliferation pathways and activation of cell death signaling pathways. Conclusion: Ivermectin could be recognized as a repositioning candidate in treatment of gastric cancer.

Tumors comprise cancer cells and the associated stromal and immune/inflammatory cells, i.e., tumor microenvironment (TME). Here, we identify a metabolic signature of human and mouse model of gastric cancer and show that vagotomy in the mouse model reverses the metabolic reprogramming, reflected by metabolic switch from glutaminolysis to OXPHOS/glycolysis and normalization of the energy metabolism in cancer cells and TME. We next identify and validate SNAP25, mTOR, PDP1/α-KGDH, and glutaminolysis as drug targets and accordingly propose a therapeutic strategy to target the nerve-cancer metabolism. We demonstrate the efficacy of nerve-cancer metabolism therapy by intratumoral injection of BoNT-A (SNAP25 inhibitor) with systemic administration of RAD001 and CPI-613 but not cytotoxic drugs on overall survival in mice and show the feasibility in patients. These findings point to the importance of neural signaling in modulating the tumor metabolism and provide a rational basis for clinical translation of the potential strategy for gastric cancer.

The incidence of proximal gastric adenocarcinoma is increasing among younger adults. Rodent models have shown that hypergastrinemia causes carcinogenesis in the proximal stomach. The aim of our study was therefore to assess if hypergastrinemia was associated with an increased risk of developing gastric adenocarcinoma also in humans. A prospective population-based nested case-control study within the Nord-Trondelag Health Study (HUNT) cohort, Norway, was used to assess this association. Serum was collected from 78 962 participants in 1995 to 1997 and 2006 to 2008. In the cohort, 181 incident gastric adenocarcinoma cases were identified from the Norwegian Cancer and Patient Registries through 2015 and matched with 359 controls. The risk of gastric adenocarcinoma was compared between participants with prediagnostic hypergastrinemia (>60 pmol/L) and normal serum gastrin (<= 60 pmol/L). Logistic regression provided odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for body mass index, tobacco smoking and comorbidity. Hypergastrinemia was associated with increased risk of gastric adenocarcinoma overall (OR 2.2, 95% CI 1.4-3.4) and in particular for gastric adenocarcinoma with proximal location (OR 6.1, 95% CI 2.7-13.8), but not with gastric adenocarcinoma with distal location (OR 1.7, 95% CI 0.9-3.4). Moreover, hypergastrinemia was associated with an increased risk of gastric adenocarcinoma of intestinal histological type (OR 3.8, 95% CI 1.8-7.9), but not for diffuse histological type (OR 1.6, 95% CI 0.7-3.7). In conclusion, hypergastrinemia was associated with an increased risk of proximal and intestinal type gastric adenocarcinoma.

Background: Neuroendocrine tumours (NETs) in the ileum grow slowly but metastasise to the liver at an early stage. After resection of the primary tumour and mesenteric lymph nodes, selected patients with liver metastases have been operated with curative intention. Recurrence-free survival seems low, suggesting that micrometastases are present in the liver at the time of surgery. We have therefore examined whether NET metastases could be detected in perceived normal liver tissue at the time of liver resection. Material and methods: Liver tissue outside the macrometastases from patients (n = 10) operated by liver resection due to metastases from ileal NETs G1/2, were examined for NE cells by immunohistochemistry. Liver tissue from patients operated for metastatic colon cancer was used as control (n = 6). Groups of >= 3 NE cells >= 3 mm from macrometastases were considered micrometastases. Clinical course was recorded retrospectively. Results: Ten of 10 patients had micrometastases, consisting of multiple groups of NE cells. None of the control patients had NE cells in the liver tissue. After median follow-up time of 5.5 (0.8-18.7) years 6 of 10 patients had developed recurrent NET metastases detected by cross-sectional imaging. The follow-up time of the four patients without detectable metastases was 4.8 (0.8-7.5) years vs. with detectable metastases 7.9 (3.2-18.7) years. Conclusions: All patient had micrometastases outside macrometastases at the time of liver resection, suggesting that subsequently recurrent liver metastases develop from NET depositions in the liver already present at the time of surgery. The likelihood of curation by hepatic resection appears very low.

Background and aims: Expanded criteria for resection of colorectal liver metastases (CRLM) have led to a more aggressive surgical attitude. The aim is to evaluate any impact of expanded criteria on perioperative mortality and long-term survival. Materials and methods: A population based study from 2001 to 2015 for patients undergoing surgery for CRLM. The cohort was divided into three 5-year periods. Results: A total of 341 patients underwent resection of CRLM. Relative to the number of colorectal primaries, patients resected for CRLM increased from 82/2520 (3.3%) in 2001-2005 to 151/3071 (4.9%) in 2011-2015 (p = .007). The proportion of patients who underwent formal resections declined from 62% to 21%. There was a substantial increase in resections of synchronous liver metastases, portal vein embolizations, two-stage resections, and the share of octogenarians who underwent resection. The proportion of patients undergoing reresections of new liver recurrences increased from 6% to 24%. The 90-d postoperative mortality for 2001-2005, 2006-2010, and 2011-2015 were 7.9%, 0.8%, and 2.0%, respectively. The median overall survival was 47 months during the two first periods, for the last period not reached. The 5-year overall survival remained at 40% from 2001 to 2010, and estimated at 55.2% from 2011 to 2015. The 5-year disease-free survival was well above 30%. The 5-year overall survival following liver reresection was 52.6%. Conclusion: Postoperative mortality remained at approximately 2%, and the 5-year overall survival at 40% in the first 10 years, but increased to 55% in the last 5 years under study, despite a marked increase in resection rates.

Pancreatic cancer is the fourth leading cause of cancer-related death. While surgical resection remains the foundation for potentially curative treatment, survival benefit is achieved with adjuvant oncological treatment. Thus, completion of multimodality treatment (surgical resection and (neo)adjuvant chemotherapy) to all patients and early treatment of micrometastatic disease is the ideal goal. NorPACT–1 aims to test the hypothesis that overall mortality at one year after allocation of treatment can be reduced with neoadjuvant chemotherapy in surgically treated patients with resectable pancreatic cancer.

President Trump has closed the borders of the United States for all citizens from a selected group of Islamic countries.1Trump DJ Executive order: protecting the nation from foreign terrorist entry into the United States. The White House Office of the Press Secretary.https://www.whitehouse.gov/the-press-office/2017/01/27/executive-order-protecting-nation-foreign-terrorist-entry-united-statesDate: Jan 27, 2017Google Scholar This ban will affect a large number of our colleague surgeons and physicians in their work as clinicians and academics. We view this as unjustified and unacceptable discrimination on the basis of religion, citizenship and culture. Until this ban is lifted, we encourage our colleague hepato-pancreato-biliary and transplant surgeons to consider the ethical implications of participating at meetings and congresses held in the United States. The board of the Norwegian Association of Gastrointestinal and Hepato-pancreato-biliary (HPB) surgeons (NFGK) endorses the content of this letter. We declare no competing interests.

The UK MAGIC trial published in 2006 was the first RCT to identify improved long-term survival rates using preoperative chemotherapy for resectable gastric or gastroesophageal cancer. Overnight, the treatment regimen impacted European guidelines. However, the majority of patients underwent limited lymph node dissection, and analyses of the rates of curative resection, downsizing and downstaging were not by intention to treat, rightfully raising concerns about their validity. For the subset of true gastric cancers, meta-analyses may even question the claims of improved long-term survival rates by present-day regimens. A rhetorical question can be posed as to whether downstaging and improved survival rates by preoperative (radio)-chemotherapy for cancers of the distal esophagus or gastric cardia, has confounded our conclusions on the (lack of) effect of present-day regimens of perioperative chemotherapy for true gastric cancers, let alone in a situation with proper lymph node dissection. At present, a plea can be made to move one step back and revert to an RCT with a surgery alone arm. Inclusion criteria and analyses of future RCTs must stratify on tumor location and the Lauren type and embrace the newly developed scheme of sub-classification of gastric cancers based on extensive molecular profiling as reported in the seminal Cancer Genome Atlas Study.