Practice patterns in diagnostics, staging, and management strategies of gallbladder cancer among Nordic tertiary centers

Background and objective: Gallbladder cancer (GBC) is a rare malignancy in the Nordic countries and no common Nordic treatment guidelines exist. This study aimed to characterize the current diagnostic and treatment strategies in the Nordic countries and disclose differences in these strategies. Methods: This was a survey study with a cross-sectional questionnaire of all 19 university hospitals providing curative-intent surgery for GBC in Sweden, Norway, Denmark, and Finland. Results: In all Nordic countries except Sweden, neoadjuvant/downstaging chemotherapy was used in GBC patients. In T1b and T2, majority of the centers (15–18/19) performed extended cholecystectomy. In T3, majority of the centers (13/19) performed cholecystectomy with resection of segments 4b and 5. In T4, majority of the centers (12–14/19) chose palliative/oncological care. The centers in Sweden extended lymphadenectomy beyond the hepatoduodenal ligament, whereas all other Nordic centers usually limited lymphadenectomy to the hepatoduodenal ligament. All Nordic centers except those in Norway used adjuvant chemotherapy routinely for GBC. There were no major differences between the Nordic centers in diagnostics and follow-up. Conclusions: The surgical and oncological treatment strategies of GBC vary considerably between the Nordic centers and countries.publishedVersio

Circulating Osteopontin and Prediction of Hepatocellular Carcinoma Development in a Large European Population.

We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between prediagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function, and α-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95% CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10% increment, ORmultivariable = 1.30; 95% CI, 1.14-1.48). The association was stronger among cases diagnosed within 2 years of follow-up. Adding liver function tests to OPN improved the discriminatory performance for subjects who developed HCC (AUC = 0.86). For cases diagnosed within 2 years, the combination of OPN and AFP was best able to predict HCC risk (AUC = 0.88). The best predictive model for HCC in this low-risk population is OPN in combination with liver function tests. Within 2 years of diagnosis, the combination of OPN and AFP best predicted HCC development, suggesting that measuring OPN and AFP could identify high-risk groups independently of a liver disease diagnosis. Cancer Prev Res; 9(9); 758-65. ©2016 AACR.This work was supported by NIH R01 CA120719 to LB and by the French National Cancer Institute (Institut National du Cancer; INCA) grant number 2009-139 to MJ. The coordination of EPIC is financially supported by the European Commission (DG-SANCO); and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer; Institut Gustave Roussy; Mutuelle Générale de l’Education Nationale; and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (DKFZ); and Federal Ministry of Education and Research (Germany); Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC); National Research Council; and AIRE-ONLUS Ragusa, AVIS Ragusa, Sicilian Government (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS); Netherlands Cancer Registry (NKR); LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); and Statistics Netherlands (the Netherlands); European Research Council (ERC) (grant number ERC-2009-AdG 232997) and Nordforsk; and Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS); Regional Governments of Andalucía, Asturias, Basque Country, Murcia (No. 6236) and Navarra; and ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society; Swedish Scientific Council; and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK; Medical Research Council; Stroke Association; British Heart Foundation; Department of Health; Food Standards Agency; and Wellcome Trust (UK). Reagents for the hepatitis infection determinations were kindly provided by Abbott Diagnostics Division, Lyon, France.This is the author accepted manuscript. The final version is available from the American Association for Cancer Research via http://dx.doi.org/10.1158/1940-6207.CAPR-15-043

Circulating insulin-like growth factor I in relation to melanoma risk in the European Prospective Investigation into Cancer and Nutrition

Insulin-like growth factor-I (IGF-I) regulates cell proliferation and apoptosis, and is thought to play a role in tumour development. Previous prospective studies have shown that higher circulating concentrations of IGF-I are associated with a higher risk of cancers at specific sites, including breast and prostate. No prospective study has examined the association between circulating IGF-I concentrations and melanoma risk. A nested case-control study of 1,221 melanoma cases and 1,221 controls was performed in the European Prospective Investigation into Cancer and Nutrition cohort, a prospective cohort of 520,000 participants recruited from 10 European countries. Conditional logistic regression was used to estimate odds ratios (ORs) for incident melanoma in relation to circulating IGF-I concentrations, measured by immunoassay. Analyses were conditioned on the matching factors and further adjusted for age at blood collection, education, height, BMI, smoking status, alcohol intake, marital status, physical activity and in women only, use of menopausal hormone therapy. There was no significant association between circulating IGF-I concentration and melanoma risk (OR for highest vs lowest fifth = 0.93 [95% confidence interval [CI]: 0.71 to 1.22]). There was no significant heterogeneity in the association between IGF-I concentrations and melanoma risk when subdivided by gender, age at blood collection, BMI, height, age at diagnosis, time between blood collection and diagnosis, or by anatomical site or histological subtype of the tumour (Pheterogeneity≥0.078). We found no evidence for an association between circulating concentrations of IGF-I measured in adulthood and the risk of melanoma

Association between physical activity and risk of hepatobiliary cancers : A multinational cohort study

Background & Aims: To date, evidence on the association between physical activity and risk of hepatobiliary cancers has been inconclusive. Weexamined this association in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC). Methods: We identified 275 hepatocellular carcinoma (HCC) cases, 93 intrahepatic bile duct cancers (IHBCs), and 164 non-gallbladder extrahepatic bile duct cancers (NGBCs) among 467,336 EPIC participants (median follow-up 14.9 years). We estimated cause-specific hazard ratios (HRs) for total physical activity and vigorous physical activity and performed mediation analysis and secondary analyses to assess robustness to confounding (e.g. due to hepatitis virus infection). Results: In the EPIC cohort, the multivariable-adjusted HR of HCC was 0.55 (95% CI 0.38-0.80) comparing active and inactive individuals. Regarding vigorous physical activity, for those reporting >2 hours/week compared to those with no vigorous activity, the HR for HCC was 0.50 (95% CI 0.33-0.76). Estimates were similar in sensitivity analyses for confounding. Total and vigorous physical activity were unrelated to IHBC and NGBC. In mediation analysis, waist circumference explained about 40% and body mass index 30% of the overall association of total physical activity and HCC. Conclusions: These findings suggest an inverse association between physical activity and risk of HCC, which is potentially mediated by obesity. Lay summary: In a pan-European study of 467,336 men and women, we found that physical activity is associated with a reduced risk of developing liver cancers over the next decade. This risk was independent of other liver cancer risk factors, and did not vary by age, gender, smoking status, body weight, and alcohol consumption. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Peer reviewe

ASNA1 and cisplatin resistance : studies in C. elegans and in human tumor cells

Platinum based chemotherapy is widely used to treat cancer. Cisplatin (diamminedichloroplatinum) combination treatments provide cure for metastatic testicular cancer and prolong survival for patients suffering from ovarian, head and neck, bladder and non small cell lung cancer. Tumors that initially respond to treatment may eventually acquire resistance, resulting in treatment failure. Cisplatin resistant cells are crossresistant to arsenite and antimonite and these metalloids are exported from bacteria by the ars-operon. In this thesis, we describe the human ArsA homolog, ASNA1, as a protein involved in a novel resistance mechanism to cisplatin, arsenite and antimonite. ASNA1 was downregulated by antisense and siRNA techniques in human melanoma and ovarian carcinoma cell lines. These cells displayed increased sensitivity to arsenite and the platinum based drugs cisplatin, carboplatin and oxaliplatin. In both melanoma and ovarian carcinoma, cisplatin resistant cells overexpressed ASNA1. Blockage of ASNA1 resulted in increased apoptosis and retarded growth, complicating further characterization of ASNA1 in human cell lines. ASNA1 also promotes insulin signaling and mediates membrane insertion of tail-anchored proteins. To explore different aspects of ASNA1 function with respect to cisplatin resistance, we used the model organism C. elegans. In the nematode C. elegans, asna-1 (rnai) treated larvae were hypersensitive to cisplatin, arsenite and antimonite. Adult asna-1 mutant worms were cisplatin sensitive and this hypersensitivity was seen even when apoptosis was blocked. Expression of human ASNA1 rescued the cisplatin hypersensitivity in asna-1 mutants, showing conservation of function. Transgene expression of mutated forms of asna-1 separated the cisplatin hypersensitivity phenotype from the insulin signaling phenotype of asna-1 mutants. Three ASNA-1 residues, His164, Cys285 and Cys288 were identified as essential for ASNA-1 promoted cisplatin resistance but not for insulin signaling. Finally, studies of the C. elegans germline revealed increased numbers of apoptotic cells in asna-1 mutants. In conclusion, C. elegans is a suitable model organism to identify and characterize cisplatin response mechanisms. A targeted therapy against ASNA1 could sensitize cisplatin resistant cells and improve outcome for cancer patients

Regional variations in the treatment of gallstone disease may affect patient outcome : A large, population-based register study in sweden

Background: The lack of studies showing benefit from surgery in patients with symptoms of gallstone disease has led to a divergence in local practices and standards of care. This study aimed to explore regional differences in management and complications in Sweden. Furthermore, to study whether population density had an impact on management. Methods: Data were collected from the Swedish National Register for Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (GallRiks). Cholecystectomies undertaken for gallstone disease between January 2006 and December 2017 were included. Age, sex, American Society of Anesthesiologists (ASA) classification, intra- and post-operative complications, and the proportion of patients with acute cholecystitis who underwent surgery within 2 days of hospital admission were analyzed. The 21 different geographical regions in Sweden were compared, and each variable was analyzed according to population density. Results: A total of 139,444 cholecystectomies cases were included in this study. There were large differences between regions regarding indications for surgery and intra- and post-operative complications. In the analyses, there were greater divergences than would be expected by chance for most of the variables analyzed. Age of the cholecystectomized patients correlated with population density of the regions (R2 = 0.310; p = 0.0088). Conclusion: There are major differences between the different regions in Sweden in terms of the treatment of gallstone disease and outcome, but these did not correlate to population density, suggesting that local routines are more likely to have an impact on treatment strategies rather than demographic factors. These differences need further investigation to reveal the underlying causes

LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance

Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-negative regulator of receptor tyrosine kinase (RTK) signaling and a tumor suppressor in several cancers, but its involvement in melanoma is largely unexplored. Here, we aim to determine the role of LRIG1 in melanoma tumorigenesis, RTK signaling, and BRAF inhibitor resistance. We find that LRIG1 is downregulated during early tumorigenesis and that LRIG1 affects activation of the epidermal growth factor receptor (EGFR) in melanoma cells. LRIG1-dependent regulation of EGFR signaling is evolutionary conserved to the roundworm C. elegans, where negative regulation of the EGFR-Ras-Raf pathway by sma-10/LRIG completely depends on presence of the receptor let-23/EGFR. In a cohort of metastatic melanoma patients, we observe an association between LRIG1 and survival in the triple wild-type subtype and in tumors with high EGFR expression. During in vitro development of BRAF inhibitor resistance, LRIG1 expression decreases; and mimics LRIG1 knockout cells for increased EGFR expression. Treating resistant cells with recombinant LRIG1 suppresses AKT activation and proliferation. Together, our results show that sma-10/LRIG is a conserved regulator of RTK signaling, add to our understanding of LRIG1 in melanoma and identifies recombinant LRIG1 as a potential therapeutic against BRAF inhibitor-resistant melanoma

Portomesenteric venous contact ≤180° and overall survival in resectable head and body pancreatic adenocarcinoma treated with upfront surgery

Introduction: Upfront surgery is the standard of care for resectable pancreatic cancer, defined as the absence of or ≤180° tumour contact with the portal/superior mesenteric vein. We hypothesized that portomesenteric venous contact is prognostically unfavourable and aimed to assess whether it is associated with poorer outcomes compared with no venous contact in resectable head and body pancreatic cancer. Methods: This single-centre retrospective study included patients undergoing upfront surgery for resectable head and body pancreatic cancer in 2010–2020 at Umeå University Hospital, Sweden. No venous contact was compared with portomesenteric venous contact of ≤180° based on preoperative imaging. Survival on an intention-to-treat basis was compared with Kaplan-Meier curves, a log-rank test and Cox proportional hazards models. Results: The final study cohort included 39 patients with portomesenteric venous contact and 144 patients without venous contact. Patients with portomesenteric tumour contact had a median overall survival of 15.3 months compared to 23.0 months (log rank P = 0.059). Portomesenteric venous contact was an independent negative prognostic factor for survival in the multivariable Cox model (HR 1.68; 95% CI 1.11–2.55, P = 0.014) and was associated with higher rates of microscopically non-radical resections (R1) (50% vs 26.1%, P = 0.012) and pathological lymph node metastasis (76.7% vs 56.8%, P = 0.012). There was no difference in adjuvant chemotherapy receipt or postoperative complications between the groups. Conclusions: Portomesenteric venous contact is associated with poorer overall survival and higher rates of R1 resections and lymph node metastasis in patients with resectable head and body pancreatic cancer treated with upfront surgery

Surgical treatment of breast cancer liver metastases : A nationwide registry-based case control study

Introduction: The benefit of liver resection or ablation for breast cancer liver metastases (BCLM) remains unclear. The aim of the study was to determine survival after isolated BCLM in nationwide cohorts and compare surgical versus systemic treatment regimens. Materials and methods: The Swedish register for cancer in the liver and the bile ducts (SweLiv) and the National register for breast cancer (NBCR) was studied to identify patients with 1-5 BCLM without extrahepatic spread diagnosed 2009-2016. Data from the registers were validated and completed by review of medical records. A Kaplan-Meier plot and log rank test were used to analyse survival. Prognostic and predictive factors were evaluated by Cox regression analysis. Results: A surgical cohort (n = 29) was identified and compared to a control cohort (n = 33) receiving systemic treatment only. There was no 90-day mortality after surgery. Median survival from BCLM diagnosis was 77 months (95% CI 41-113) in the surgical cohort and 28 months (95% CI 13-43) in the control cohort, (p = 0.004). There was a longer disease-free interval and more oestrogen receptor positive tumours in the surgical cohort. Surgery was a significant positive predictive factor in univariate analysis while a multivariable analysis resulted in HR 0.478 (CI 0.193-1.181, p = 0.110) for surgical treatment. Conclusion: Surgery for BCLM is safe and might provide a survival benefit in selected patients but prospective trials are warranted to avoid selection bias

Does 18F-FDG PET/CT change the surgical management of potentially resectable colorectal liver metastases?

PURPOSE: Resectability assessment of patients with colorectal liver metastases is based on computed tomography and liver magnetic resonance imaging. Addition of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography has been recommended, but the impact of the added information remains unclear. The primary aim of this study was to determine how preoperative positron emission tomography/computed tomography changed management in patients with potentially resectable colorectal liver metastases. The secondary aim was to investigate whether findings on positron emission tomography/computed tomography correlated to metastatic disease in cases with extended surgery and influenced oncological outcomes. METHODS: A retrospective observational study of the impact of adding positron emission tomography/computed tomography to conventional imaging in the surgical decision-making of colorectal liver metastases. All patients with colorectal liver metastases diagnosed by conventional imaging were included and assessed by a multidisciplinary team conference at Umeå University Hospital between June 2013 and December 2017. Eligibility criteria were all patients with potentially resectable colorectal liver metastases. Patients who underwent preoperative positron emission tomography/computed tomography in addition to conventional radiology were compared with those who underwent conventional imaging only. RESULTS: 151/220 patients underwent preoperative positron emission tomography/computed tomography. Findings on positron emission tomography/computed tomography changed the management in 10.6% of the patients. Eight patients were excluded from surgery after detection by positron emission tomography/computed tomography of extrahepatic disease. Eight patients underwent more extended surgery than initially planned due to positron emission tomography/computed tomography. Five of these positron emission tomography-positive resected sites were verified by pathology as metastatic disease. No difference in overall survival was seen following surgical resection in patients with and without a preoperative positron emission tomography/computed tomography. CONCLUSIONS: Preoperative positron emission tomography/computed tomography resulted in a changed surgical management in 10.6% of cases in a selected cohort