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  • 1. Baumeister, Sebastian E.
    et al.
    Schlesinger, Sabrina
    Aleksandrova, Krasimira
    Jochem, Carmen
    Jenab, Mazda
    Gunter, Marc J.
    Overvad, Kim
    Tjonneland, Anne
    Boutron-Ruault, Marie-Christine
    Carbonnel, Franck
    Fournier, Agnes
    Kuehn, Tilman
    Kaaks, Rudolf
    Pischon, Tobias
    Boeing, Heiner
    Trichopoulou, Antonia
    Bamia, Christina
    La Vecchia, Carlo
    Masala, Giovanna
    Panico, Salvatore
    Fasanelli, Francesca
    Tumino, Rosario
    Grioni, Sara
    de Mesquita, Bas Bueno
    Vermeulen, Roel
    May, Anne M.
    Borch, Kristin B.
    Oyeyemi, Sunday O.
    Ardanaz, Eva
    Rodriguez-Barranco, Miguel
    Chirlaque Lopez, Maria Dolores
    Felez-Nobrega, Mireia
    Sonestedt, Emily
    Ohlsson, Bodil
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Werner, Mårten
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Perez-Cornago, Aurora
    Ferrari, Pietro
    Stepien, Magdalena
    Freisling, Heinz
    Tsilidis, Konstantinos K.
    Ward, Heather
    Riboli, Elio
    Weiderpass, Elisabete
    Leitzmann, Michael F.
    Association between physical activity and risk of hepatobiliary cancers: A multinational cohort study2019In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 70, no 5, p. 885-892Article in journal (Refereed)
    Abstract [en]

    Background & Aims: To date, evidence on the association between physical activity and risk of hepatobiliary cancers has been inconclusive. We examined 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.

  • 2.
    Billing, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Holmgren, Ylva
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nosek, Daniel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance2021In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 40, p. 3707-3718Article in journal (Refereed)
    Abstract [en]

    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.

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  • 3. Boussemart, Lise
    et al.
    Malka-Mahieu, Hélène
    Girault, Isabelle
    Allard, Delphine
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Inserm UMR981, F-94805 Villejuif, France.
    Tomasic, Gorana
    Thomas, Marina
    Basmadjian, Christine
    Ribeiro, Nigel
    Thuaud, Frédéric
    Mateus, Christina
    Routier, Emilie
    Kamsu-Kom, Nyam
    Agoussi, Sandrine
    Eggermont, Alexander M
    Désaubry, Laurent
    Robert, Caroline
    Vagner, Stéphan
    eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 513, no 7516, p. 105-109Article in journal (Refereed)
    Abstract [en]

    In BRAF(V600)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway, on activation of the alternative, PI(3)K-AKT-mTOR, pathway (which is ERK independent) or on modulation of the caspase-dependent apoptotic cascade. All three pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNA, thereby modulating the translation of specific mRNAs. Here we show that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF, anti-MEK and anti-BRAF plus anti-MEK drug combinations in BRAF(V600)-mutant melanoma, colon and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with one of three mechanisms: reactivation of MAPK signalling, persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 or increased pro-apoptotic BCL-2-modifying factor (BMF)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions shows that eIF4F complex formation is decreased in tumours that respond to anti-BRAF therapy and increased in resistant metastases compared to tumours before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergizes with inhibiting BRAF(V600) to kill the cancer cells. eIF4F not only appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target. Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.

  • 4. Bradbury, Kathryn E.
    et al.
    Appleby, Paul N.
    Tipper, Sarah J.
    Travis, Ruth C.
    Allen, Naomi E
    Kvaskoff, Marina
    Overvad, Kim
    Tjønneland, Anne
    Halkjaer, Jytte
    Cervenka, Iris
    Mahamat-Saleh, Yahya
    Bonnet, Fabrice
    Kaaks, Rudolf
    Fortner, Renée T.
    Boeing, Heiner
    Trichopoulou, Antonia
    La Vecchia, Carlo
    Stratigos, Alexander J.
    Palli, Domenico
    Grioni, Sara
    Matullo, Giuseppe
    Panico, Salvatore
    Tumino, Rosario
    Peeters, Petra H.
    Bueno-de-Mesquita, H Bas
    Ghiasvand, Reza
    Veierød, Marit B.
    Weiderpass, Elisabete
    Bonet, Catalina
    Molina, Elena
    Huerta, José M.
    Larrañaga, Nerea
    Barricarte, Aurelio
    Merino, Susana
    Isaksson, Karolin
    Stocks, Tanja
    Ljuslinder, Ingrid
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Wareham, Nick
    Khaw, Kay-Tee
    Gunter, Marc J.
    Rinaldi, Sabina
    Tsilidis, Konstantinos K.
    Aune, Dagfinn
    Riboli, Elio
    Key, Timothy J.
    Circulating insulin-like growth factor I in relation to melanoma risk in the European prospective investigation into cancer and nutrition2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 5, p. 957-966Article in journal (Refereed)
    Abstract [en]

    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.

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  • 5. Caini, Saverio
    et al.
    Masala, Giovanna
    Saieva, Calogero
    Kvaskoff, Marina
    Sacerdote, Carlotta
    Savoye, Isabelle
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Bech, Bodil Hammer
    Overvad, Kim
    Tjonneland, Anne
    Petersen, Kristina E. N.
    Mancini, Francesca Romana
    Boutron-Ruault, Marie-Christine
    Cervenka, Iris
    Kaaks, Rudolf
    Kuehn, Tilman
    Boeing, Heiner
    Floegel, Anna
    Trichopoulou, Antonia
    Valanou, Elisavet
    Kritikou, Maria
    Tagliabue, Giovanna
    Panico, Salvatore
    Tumino, Rosario
    Bueno-de-Mesquita, H. B(as)
    Peeters, Petra H.
    Veierod, Marit B.
    Ghiasvand, Reza
    Lukic, Marko
    Ramon Quiros, Jose
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Salamanca Fernandez, Elena
    Larranaga, Nerea
    Zamora-Ros, Raul
    Nilsson, Lena Maria
    Umeå University, Arctic Research Centre at Umeå University. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Jirstrom, Karin
    Sonestedt, Emily
    Key, Timothy J.
    Wareham, Nick
    Khaw, Kay-Tee
    Gunter, Marc
    Huybrechts, Inge
    Murphy, Neil
    Tsilidis, Konstantinos K.
    Weiderpass, Elisabete
    Palli, Domenico
    Coffee, tea and melanoma risk: findings from the European Prospective Investigation into Cancer and Nutrition2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 10, p. 2246-2255Article in journal (Refereed)
    Abstract [en]

    What's new? Laboratory studies suggest that coffee and tea protect against melanoma, but epidemiological findings are inconsistent. Here the authors studied more than 400,000 participants within the European Prospective Investigation into Cancer and Nutrition (EPIC) and confirmed an inverse association between caffeinated coffee consumption and melanoma risk. No association was found with decaffeinated coffee or tea. Interestingly, drinking coffee only protected men, but not women, from developing the often fatal skin cancer, raising interesting questions about gender-specific hormones or coffee habits influencing this association. In vitro and animal studies suggest that bioactive constituents of coffee and tea may have anticarcinogenic effects against cutaneous melanoma; however, epidemiological evidence is limited to date. We examined the relationships between coffee (total, caffeinated or decaffeinated) and tea consumption and risk of melanoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a multicentre prospective study that enrolled over 500,000 participants aged 25-70 years from ten European countries in 1992-2000. Information on coffee and tea drinking was collected at baseline using validated country-specific dietary questionnaires. We used adjusted Cox proportional hazards regression models to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations between coffee and tea consumption and melanoma risk. Overall, 2,712 melanoma cases were identified during a median follow-up of 14.9 years among 476,160 study participants. Consumption of caffeinated coffee was inversely associated with melanoma risk among men (HR for highest quartile of consumption vs. non-consumers 0.31, 95% CI 0.14-0.69) but not among women (HR 0.96, 95% CI 0.62-1.47). There were no statistically significant associations between consumption of decaffeinated coffee or tea and the risk of melanoma among both men and women. The consumption of caffeinated coffee was inversely associated with melanoma risk among men in this large cohort study. Further investigations are warranted to confirm our findings and clarify the possible role of caffeine and other coffee compounds in reducing the risk of melanoma.

  • 6. Duarte-Salles, Talita
    et al.
    Misra, Sandeep
    Stepien, Magdalena
    Plymoth, Amelie
    Muller, David
    Overvad, Kim
    Olsen, Anja
    Tjonneland, Anne
    Baglietto, Laura
    Severi, Gianluca
    Boutron-Ruault, Marie-Christine
    Turzanski-Fortner, Renee
    Kaaks, Rudolf
    Boeing, Heiner
    Aleksandrova, Krasimira
    Trichopoulou, Antonia
    Lagiou, Pagona
    Bamia, Christina
    Pala, Valeria
    Palli, Domenico
    Mattiello, Amalia
    Tumino, Rosario
    Naccarati, Alessio
    Bueno-de-Mesquita, H. B(as).
    Peeters, Petra H.
    Weiderpass, Elisabete
    Quiros, J. Ramon
    Agudo, Antonio
    Sanchez-Cantalejo, Emilio
    Ardanaz, Eva
    Gavrila, Diana
    Dorronsoro, Miren
    Werner, Mårten
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ohlsson, Bodil
    Sjoberg, Klas
    Wareham, Nicholas J.
    Khaw, Kay-Tee
    Bradbury, Kathryn E.
    Gunter, Marc J.
    Cross, Amanda J.
    Riboli, Elio
    Jenab, Mazda
    Hainaut, Pierre
    Beretta, Laura
    Circulating Osteopontin and Prediction of Hepatocellular Carcinoma Development in a Large European Population2016In: Cancer Prevention Research, ISSN 1940-6207, E-ISSN 1940-6215, Vol. 9, no 9, p. 758-765Article in journal (Refereed)
    Abstract [en]

    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 a-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.

  • 7.
    Eilard, Malin S.
    et al.
    Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden; Department of Transplantation, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Naredi, Peter
    Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden; Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Helmersson, Madeleine
    Regional Cancer Center West, Western Sweden Health Care Region, Gothenburg, Sweden.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Isaksson, Bengt
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Lindell, Gert
    Department of Surgery, Skåne University Hospital, Lund, Sweden.
    Sandström, Per
    Department of Surgery, County Council of Östergötland, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Strömberg, Cecilia
    Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden.
    Rizell, Magnus
    Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden; Department of Transplantation, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Survival and prognostic factors after transplantation, resection and ablation in a national cohort of early hepatocellular carcinoma2021In: HPB, ISSN 1365-182X, E-ISSN 1477-2574, Vol. 23, no 3, p. 394-403Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In patients with early hepatocellular cancer (HCC) and preserved liver function, the choice between transplantation, resection and ablation and which factors to consider is not obvious and guidelines differ. In this national cohort study, we aimed to compare posttreatment survival in patients fulfilling predefined criteria, and to analyse preoperative risk factors that could influence decision.

    METHODS: We used data from HCC-patients registered with primary transplantation, resection or ablation 2008-2016 in the SweLiv-registry. In Child A-subgroups, 18-75 years, we compared survival after transplantation or resection, with different tumour criteria; either corresponding to our transplantation criteria (N = 257) or stricter with single tumours ≤50 mm (N = 159). A subgroup with single tumours ≤30 mm, compared all three treatments (N = 193).

    RESULTS: We included 1022 HCC-patients; transplantation n = 223, resection n = 438, ablation n = 361. In the transplant criteria subgroup, differences in five-year survival, adjusted for age and gender, were not significant, with 71.2% (CI 62.3-81.3) after transplantation (n = 109) and 63.5% (CI 54.9-73.5) after resection (n = 148). Good liver function (Child 5 vs. 6, Albumin ≥36), increased the risk after transplantation, but decreased the risk after resection and ablation.

    CONCLUSION: Even within Child A, detailed liver function assessment is important before treatment decision, and for stratifying survival comparisons.

  • 8. Engstrand, J.
    et al.
    Abreu de Carvalho, L.F.
    Aghayan, D.
    Balakrishnan, A.
    Belli, A.
    Björnsson, B.
    Dasari, B.V.M.
    Detry, O.
    Di Martino, M.
    Edwin, B.
    Erdmann, J.
    Fristedt, R.
    Fusai, G.
    Gimenez-Maurel, T.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hidalgo Salinas, C.
    Isaksson, B.
    Ivanecz, A.
    Izzo, F.
    Knoefel, W.T.
    Kron, P.
    Lehwald-Tywuschik, N.
    Lesurtel, M.
    Lodge, J.P.A.
    Machairas, N.
    Marino, M.V.
    Martin, V.
    Paterson, A.
    Rystedt, J.
    Sandström, P.
    Serrablo, A.
    Siriwardena, A.K.
    Taflin, H.
    van Gulik, T.M.
    Yaqub, S.
    Özden, I.
    Ramia, J.M.
    Sturesson, C.
    Liver resection and ablation for squamous cell carcinoma liver metastases2021In: BJS Open, E-ISSN 2474-9842, Vol. 5, no 4, article id zrab060Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Limited evidence exists to guide the management of patients with liver metastases from squamous cell carcinoma (SCC). The aim of this retrospective multicentre cohort study was to describe patterns of disease recurrence after liver resection/ablation for SCC liver metastases and factors associated with recurrence-free survival (RFS) and overall survival (OS).

    METHOD: Members of the European-African Hepato-Pancreato-Biliary Association were invited to include all consecutive patients undergoing liver resection/ablation for SCC liver metastases between 2002 and 2019. Patient, tumour and perioperative characteristics were analysed with regard to RFS and OS.

    RESULTS: Among the 102 patients included from 24 European centres, 56 patients had anal cancer, and 46 patients had SCC from other origin. RFS in patients with anal cancer and non-anal cancer was 16 and 9 months, respectively (P = 0.134). A positive resection margin significantly influenced RFS for both anal cancer and non-anal cancer liver metastases (hazard ratio 6.82, 95 per cent c.i. 2.40 to 19.35, for the entire cohort). Median survival duration and 5-year OS rate among patients with anal cancer and non-anal cancer were 50 months and 45 per cent and 21 months and 25 per cent, respectively. For the entire cohort, only non-radical resection was associated with worse overall survival (hazard ratio 3.21, 95 per cent c.i. 1.24 to 8.30).

    CONCLUSION: Liver resection/ablation of liver metastases from SCC can result in long-term survival. Survival was superior in treated patients with liver metastases from anal versus non-anal cancer. A negative resection margin is paramount for acceptable outcome.

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  • 9.
    Engstrand, Jennie
    et al.
    Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Taflin, Helena
    Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Göteborg, Sweden.
    Rystedt, Jenny Lundmark
    Department of Surgery, Skåne University Hospital, Lund University, Lund, Sweden.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Urdzik, Jozef
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Sandström, Per
    Department of Surgery in Linköping, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Björnsson, Bergthor
    Department of Surgery in Linköping, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Hasselgren, Kristina
    Department of Surgery in Linköping, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    The resection rate of synchronously detected liver and lung metastasis from colorectal cancer is low: a national registry-based study2023In: Cancers, ISSN 2072-6694, Vol. 15, no 5, article id 1434Article in journal (Refereed)
    Abstract [en]

    Population-based data on the incidence and surgical treatment of patients with colorectal cancer (CRC) and synchronous liver and lung metastases are lacking as are real-life data on the frequency of metastasectomy for both sites and outcomes in this setting. This is a nationwide population-based study of all patients having liver and lung metastases diagnosed within 6 months of CRC between 2008 and 2016 in Sweden identified through the merging of data from the National Quality Registries on CRC, liver and thoracic surgery and the National Patient Registry. Among 60,734 patients diagnosed with CRC, 1923 (3.2%) had synchronous liver and lung metastases, of which 44 patients had complete metastasectomy. Surgery of liver and lung metastases yielded a 5-year OS of 74% (95% CI 57–85%) compared to 29% (95% CI 19–40%) if liver metastases were resected but not the lung metastases and 2.6% (95% CI 1.5–4%) if non-resected, p < 0.001. Complete resection rates ranged from 0.7% to 3.8% between the six healthcare regions of Sweden, p = 0.007. Synchronous liver and lung CRC metastases are rare, and a minority undergo the resection of both metastatic sites but with excellent survival. The reasons for differences in regional treatment approaches and the potential of increased resection rates should be studied further.

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  • 10. Fedirko, Veronika
    et al.
    Tran, Hao Quang
    Gewirtz, Andrew T
    Stepien, Magdalena
    Trichopoulou, Antonia
    Aleksandrova, Krasimira
    Olsen, Anja
    Tjønneland, Anne
    Overvad, Kim
    Carbonnel, Franck
    Boutron-Ruault, Marie-Christine
    Severi, Gianluca
    Kühn, Tilman
    Kaaks, Rudolf
    Boeing, Heiner
    Bamia, Christina
    Lagiou, Pagona
    Grioni, Sara
    Panico, Salvatore
    Palli, Domenico
    Tumino, Rosario
    Naccarati, Alessio
    Peeters, Petra H
    Bueno-de-Mesquita, H B
    Weiderpass, Elisabete
    Castaño, José María Huerta
    Barricarte, Aurelio
    Sánchez, María-José
    Dorronsoro, Miren
    Quirós, J Ramón
    Agudo, Antonio
    Sjöberg, Klas
    Ohlsson, Bodil
    Hemmingsson, Oskar
    Department of Surgical and Perioperative Sciences, Kirurgcentrum, Norrlands Universitetssjukhus, Umeå, Sweden.
    Werner, Mårten
    Department of Medicine Sections for Hepatology and Gastroenterology, Umeå University Hospital, SE-90185 Umeå, Sweden.
    Bradbury, Kathryn E
    Khaw, Kay-Tee
    Wareham, Nick
    Tsilidis, Konstantinos K
    Aune, Dagfinn
    Scalbert, Augustin
    Romieu, Isabelle
    Riboli, Elio
    Jenab, Mazda
    Exposure to bacterial products lipopolysaccharide and flagellin and hepatocellular carcinoma: a nested case-control study2017In: BMC Medicine, E-ISSN 1741-7015, Vol. 72, no 15Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer. However, human studies, particularly from prospective settings, are lacking.

    METHODS: We used a case-control study design nested within a large prospective cohort to assess the association between circulating levels of anti-lipopolysaccharide (LPS) and anti-flagellin immunoglobulin A (IgA) and G (IgG) (reflecting long-term exposures to LPS and flagellin, respectively) and risk of hepatocellular carcinoma. A total of 139 men and women diagnosed with hepatocellular carcinoma between 1992 and 2010 were matched to 139 control subjects. Multivariable rate ratios (RRs), including adjustment for potential confounders, hepatitis B/C positivity, and degree of liver dysfunction, were calculated with conditional logistic regression.

    RESULTS:  = 0.021). This finding did not vary substantially by time from enrollment to diagnosis, and did not change after adjustment for chronic infection with hepatitis B and C viruses.

    CONCLUSIONS: These novel findings, based on exposures up to several years prior to diagnosis, support a role for gut-derived bacterial products in hepatocellular carcinoma development. Further study into the role of gut barrier failure and exposure to bacterial products in liver diseases is warranted.

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  • 11.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    ASNA1 and cisplatin resistance: studies in C. elegans and in human tumor cells2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    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.

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  • 12.
    Hemmingsson, Oskar
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Binnermark, Felix
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Odensten, Christoffer
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University Educational Unit at Sunderby Hospital, Sunderby, Sweden.
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Franklin, Karl A.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Haapamäki, Markku M
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Author response to: Excision and suture in the midline versus Karydakis flap surgery for pilonidal sinus: randomized clinical trial2022In: BJS Open, E-ISSN 2474-9842, Vol. 6, no 4, article id zrac106Article in journal (Other academic)
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  • 13.
    Hemmingsson, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Binnermark, Felix
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Odensten, Christoffer
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University Educational Unit at Sunderby Hospital, Sunderby, Sweden.
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Franklin, Karl A.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Haapamäki, Markku M.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Excision and suture in the midline versus Karydakis flap surgery for pilonidal sinus: randomized clinical trial2022In: BJS Open, E-ISSN 2474-9842, Vol. 6, no 2, article id zrac007Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There are several surgical options for the management of pilonidal disease, including midline and off midline closure, but prospective studies are rare. The study hypothesis was that Karydakis flap surgery would result in shorter wound healing and fewer recurrences than excision of pilonidal sinus and suture in the midline.

    METHODS: A randomized clinical trial was conducted in two hospitals in Sweden between 2006 and 2015 to compare excision and suture in the midline with Karydakis flap surgery. Adult patients with a chronic pilonidal sinus disease were randomized 1:1 at the outpatient clinic without blinding. Power calculation based on recurrence of 2 per cent for Karydakis flap and 10 per cent for excision and primary closure in the midline required 400 patients with 90 per cent statistical power at 5 per cent significance assuming 10 per cent loss during follow-up. Participants were followed up until complete wound healing; late follow-up after 6-13 years was performed by telephone by two blinded assessors. The two co-primary outcomes were time to complete wound healing and recurrence rate.

    RESULTS: The study was terminated early at a planned interim analysis due slow recruitment and a significant difference in primary outcome. In total, 125 patients were randomized, of whom 116 were available for the present analysis. Median wound healing time was 49 days (95 per cent confidence interval (c.i.) 32 to 66) for excision with suture in the midline and 14 days (95 per cent c.i. 12 to 20) for Karydakis flap surgery (P < 0.001). There were five recurrences in each group, after a median follow-up of 11 years (P = 0.753).

    CONCLUSION: Karydakis flap surgery for pilonidal sinus disease led to a shorter wound healing time than excision and suture in the midline but no difference in recurrence rates.Registration number: NCT00412659 (http://www.clinicaltrials.gov).

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  • 14.
    Hemmingsson, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Still, Maria
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    ASNA-1 activity modulates sensitivity to cisplatin2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 24, p. 10321-10328Article in journal (Refereed)
    Abstract [en]

    Cancer can be cured by platinum based chemotherapy but resistance is a major cause of treatment failure. Here we present the nematode Caenorhabditis elegans as a model to study interactions between the platinum drug cisplatin and signaling pathways in vivo. Null mutations in a single gene, asna-1, makes worms hypersensitive to cisplatin. The metalloregulated ATPase ASNA-1 promotes insulin secretion and membrane insertion of tail-anchored proteins. Using structural data from ASNA-1 homologs, we identify specific ASNA-1 mutants that are sensitive to cisplatin while still able to promote insulin signaling. Mutational analysis reveals that hypersensitivity of ASNA-1 mutants to cisplatin remains in absence of CEP-1/p53 or apoptosis. Human ASNA1 can substitute for the worm gene, indicating a conserved function. Cisplatin sensitivity is not affected by decreased insulin signaling in wild type nematodes or restored insulin signaling in asna-1 mutants. These findings provide a functional insight into ASNA-1, demonstrate that C. elegans can be used to characterize cisplatin resistance mechanisms and propose that rationally designed drugs against ASNA-1 can sensitize cancer cells to cisplatin.

  • 15.
    Hemmingsson, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Nöjd, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Increased sensitivity to platinating agents and arsenite in human ovarian cancer by downregulation of ASNA12009In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 22, no 4, p. 869-875Article in journal (Refereed)
    Abstract [en]

    Platinating agents constitute the first line treatment for ovarian cancer but treatment failure is common because of intrinsic and acquired resistance. Cancer cells develop the RASP-phenotype (cross resistance against arsenite, antimonite and platinum) associated with decreased accumulation of cisplatin and arsenite. ASNA1 is a possible subunit of a transport system for cisplatin and arsenite due to homology to arsA, an ATPase in the E. coli ars-complex responsible for efflux of arsenite and antimonite. Eukaryotic ASNA1 is a targeting factor for membrane insertion of tail-anchored proteins involved in the secretory pathway and cellular stress responses. The purpose with this study was to evaluate if ASNA1 expression influenced cisplatin, carboplatin, oxaliplatin or arsenite sensitivity in ovarian cancer. Human ovarian cancer cell line 2008 was transfected with a sense or an antisense ASNA1 construct. ASNA1 downregulated and overexpressing clones were identified by Western blots. Cell growth and chemosensitivity was determined by the MTT assay. Down-regulated ASNA1 expression was associated with retarded growth and increased sensitivity to cisplatin, carboplatin, oxaliplatin and arsenite whereas the cisplatin resistant 2008/A overexpresses ASNA1. These observations support the hypothesis that ASNA1 is a target to overcome platinum resistance in ovarian cancer.

  • 16.
    Hemmingsson, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Zhang, Youyi
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Still, Maria
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    ASNA1, an ATPase targeting tail-anchored proteins, regulates melanoma cell growth and sensitivity to cisplatin and arsenite2009In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 63, no 3, p. 491-499Article in journal (Refereed)
    Abstract [en]

    Purpose ASNA1 is homologous to E. coli ArsA, a well characterized ATPase involved in efflux of arsenite and antimonite. Cells resistant to arsenite and antimonite are cross-resistant to the chemotherapeutic drug cisplatin. ASNA1 is also an essential ATPase for the insertion of tail-anchored proteins into ER membranes and a novel regulator of insulin secretion. The aim of this study was to determine if altered ASNA1 levels influenced growth and sensitivity to arsenite and cisplatin in human melanoma cells.

    Methods Cultured melanoma T289 cells were transfected with plasmids containing sense or antisense ASNA1. Cells were exposed to cisplatin, arsenite and zinc. Cell growth and chemosensitivity were evaluated by the MTT assay and apoptosis by a TUNEL assay.

    Results ASNA1 expression was necessary for growth. T289 clones with decreased ASNA1 expression exhibited 51 ± 5% longer doubling times than wildtype T289 (P = 0.0091). After exposure to cisplatin, ASNA1 downregulated cells displayed a significant increase in apoptosis. The cisplatin IC50 in ASNA1 underexpressing cells was 41.7 ± 1.8% compared to wildtype (P = 0.00097) and the arsenite IC50 was 59.9 ± 3.2% of wildtype IC50 (P = 0.0067).

    Conclusions Reduced ASNA1 expression is associated with significant inhibition of cell growth, increased apoptosis and increased sensitivity to cisplatin and arsenite.

  • 17. Henriksson, M.
    et al.
    Bjornsson, B.
    Sternby Eilard, M.
    Lindell, G.
    Stromberg, C.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Isaksson, B.
    Rizell, M.
    Sandstrom, P.
    Treatment patterns and survival in patients with hepatocellular carcinoma in the Swedish national registry SweLiv2020In: BJS Open, E-ISSN 2474-9842, Vol. 4, no 1, p. 109-117Article in journal (Refereed)
    Abstract [en]

    Background: Consistent data on clinical features, treatment modalities and long‐term survival in patients with hepatocellular carcinoma (HCC) using nationwide quality registers are lacking. This study aimed to describe treatment patterns and survival outcomes in patients diagnosed with HCC using a national maintained database.

    Methods: Characteristics and treatment patterns in patients diagnosed with HCC and registered in the national register of liver and bile duct tumours (SweLiv) between 2009 and 2016 were reviewed. Overall survival (OS) was estimated using Kaplan–Meier analysis and the log rank test to compare subgroups for clinical features, treatment modalities and outcomes according to the year of treatment.

    Results: A total of 3376 patients with HCC were registered over 8 years, 246 (7·3 per cent) of whom underwent transplantation. Some 501 (14·8 per cent) and 390 patients (11·6 per cent) had resection and ablation as primary treatment. Transarterial chemoembolization and systemic sorafenib treatment were intended in 476 (14·1 per cent) and 426 patients (12·6 per cent) respectively; the remaining 1337 (39·6 per cent) were registered but referred for best supportive care (BSC). The 5‐year survival rate was approximately 75 per cent in the transplantation group. Median OS was 4·6 (i.q.r. 2·0 to not reached) years after resection and 3·1 (2·3–6·7) years following ablation. In patients referred for palliative treatment, median survival was 1·4 (0·8–2·9), 0·5 (0·3–1·2) and 0·3 (0·1–1·0) years for the TACE, sorafenib and BSC groups respectively (P < 0·001). Median survival was 0·9 years for the total HCC cohort in 2009–2012, before publication of the Swedish national treatment programme, increasing to 1·4 years in 2013–2016 (P < 0·001).

    Conclusion: The survival outcomes reported were in line with previous results from smaller cohorts. The introduction of national guidelines may have contributed to improved survival among patients with HCC in Sweden.

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  • 18. Hughes, David J.
    et al.
    Duarte-Salles, Talita
    Hybsier, Sandra
    Trichopoulou, Antonia
    Stepien, Magdalena
    Aleksandrova, Krasimira
    Overvad, Kim
    Tjonneland, Anne
    Olsen, Anja
    Affret, Aurelie
    Fagherazzi, Guy
    Boutron-Ruault, Marie-Christine
    Katzke, Verena
    Kaaks, Rudolf
    Boeing, Heiner
    Bamia, Christina
    Lagiou, Pagona
    Peppa, Eleni
    Palli, Domenico
    Krogh, Vittorio
    Panico, Salvatore
    Tumino, Rosario
    Sacerdote, Carlotta
    Bueno-de-Mesquita, Hendrik Bastiaan
    Peeters, Petra H.
    Engeset, Dagrun
    Weiderpass, Elisabete
    Lasheras, Cristina
    Agudo, Antonio
    Sanchez, Maria-Jose
    Navarro, Carmen
    Ardanaz, Eva
    Dorronsoro, Miren
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Wareham, Nicholas J.
    Khaw, Kay-Tee
    Bradbury, Kathryn E.
    Cross, Amanda J.
    Gunter, Marc
    Riboli, Elio
    Romieu, Isabelle
    Schomburg, Lutz
    Jenab, Mazda
    Prediagnostic selenium status and hepatobiliary cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort2016In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 104, no 2, p. 406-414Article in journal (Refereed)
    Abstract [en]

    Background: Selenium status is suboptimal in many Europeans and may be a risk factor for the development of various cancers, including those of the liver and biliary tract.

    Objective: We wished to examine whether selenium status in advance of cancer onset is associated with hepatobiliary cancers in the EPIC (European Prospective Investigation into Cancer and Nutrition) study.

    Design: We assessed prediagnostic selenium status by measuring serum concentrations of selenium and selenoprotein P (SePP; the major circulating selenium transfer protein) and examined the association with hepatocellular carcinoma (HCC; n = 121), gallbladder and biliary tract cancers (GBTCs; n = 100), and intrahepatic bile duct cancer (IHBC; n = 40) risk in a nested case-control design within the EPIC study. Selenium was measured by total reflection X-ray fluorescence, and SePP was determined by a colorimetric sandwich ELISA. Multivariable ORs and 95% CIs were calculated by using conditional logistic regression.

    Results: HCC and GBTC cases, but not IHBC cases, showed significantly lower circulating selenium and SePP concentrations than their matched controls. Higher circulating selenium was associated with a significantly lower HCC risk (OR per 20-mg/L increase: 0.41; 95% CI: 0.23, 0.72) but not with the risk of GBTC or IHBC. Similarly, higher SePP concentrations were associated with lowered HCC risk only in both the categorical and continuous analyses (HCC: P-trend <= 0.0001; OR per 1.5-mg/L increase: 0.37; 95% CI: 0.21, 0.63).

    Conclusion: These findings from a large prospective cohort provide evidence that suboptimal selenium status in Europeans may be associated with an appreciably increased risk of HCC development.

  • 19.
    Jonsson, Josefin
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Strengbom, Rebecca
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University Hospital Kirurgcentrum By 10A SE-901 85 Umeå Sweden, Sweden.
    Does 18F-FDG PET/CT change the surgical management of potentially resectable colorectal liver metastases?2022In: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 111, no 1Article in journal (Refereed)
    Abstract [en]

    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.

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  • 20.
    Kao, Gautam
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Chitturi, Jyothsna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    ­ASNA-1 influence on apoptosis in C. elegansManuscript (preprint) (Other academic)
  • 21.
    Labori, Knut Jørgen
    et al.
    Department of Hepato Pancreato Biliary Surgery, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Bratlie, Svein Olav
    Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Andersson, Bodil
    Department of Clinical Sciences Lund, Surgery, Lund University and Skåne University Hospital, Lund, Sweden.
    Angelsen, Jon-Helge
    Department of Gastrointestinal Surgery, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
    Biörserud, Christina
    Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Surgery, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Björnsson, Bergthor
    Department of Surgery in Linköping, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Bringeland, Erling Audun
    Department of Gastrointestinal Surgery, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
    Elander, Nils
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, United Kingdom.
    Garresori, Herish
    Department of Hematology and Oncology, Stavanger University Hospital, Stavanger, Norway.
    Grønbech, Jon Erik
    Department of Gastrointestinal Surgery, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
    Haux, Johan
    Department of Oncology, Skaraborg Hospital Skövde, Skövde, Sweden; School of Health Sciences, University of Skövde, Skövde, Sweden.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Liljefors, Maria Gustafsson
    Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Myklebust, Tor Åge
    Department of Registration, Cancer Registry of Norway, Oslo, Norway; Department of Research and Innovation, Møre and Romsdal Hospital Trust, Ålesund, Norway.
    Nymo, Linn Såve
    Department of Gastrointestinal Surgery, University Hospital of North Norway, Tromsø, Norway; Institute of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway.
    Peltola, Katriina
    Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland.
    Pfeiffer, Per
    Department of Medical Oncology, Odense University Hospital, Odense, Denmark.
    Sallinen, Ville
    Gastroenterological Surgery/ Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
    Sandström, Per
    Department of Surgery in Linköping, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Sparrelid, Ernesto
    Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Stenvold, Helge
    Department of Oncology, University Hospital of North Norway, Tromsø, Norway.
    Søreide, Kjetil
    Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway.
    Tingstedt, Bobby
    Department of Clinical Sciences Lund, Surgery, Lund University and Skåne University Hospital, Lund, Sweden.
    Verbeke, Caroline
    Department of Pathology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Klint, Leif
    Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Dueland, Svein
    Department of Oncology, Oslo University Hospital, Oslo, Norway.
    Lassen, Kristoffer
    Department of Hepato Pancreato Biliary Surgery, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway.
    Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial2024In: The Lancet Gastroenterology & Hepatology, ISSN 2468-1253, Vol. 9, no 3, p. 205-217Article in journal (Refereed)
    Abstract [en]

    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/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 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/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 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/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 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=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2–34·9) versus 38·5 months (27·6–not reached; hazard ratio [HR] 1·52 [95% CI 1·00–2·33], log-rank p=0·050). 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=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2–34·9) versus 34·4 months (19·4–not reached; HR 1·46 [95% CI 0·99–2·17], log-rank p=0·058). 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=0·24). 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=0·56). 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.

  • 22.
    Lindqvist, Lisa
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Andersson, Andreas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Österberg, Johanna
    Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden; Department of Surgery, Mora Hospital, Mora, Sweden.
    Sandblom, Gabriel
    Department of Clinical Science and Education Södersjukhuset, Karolinska Institute, Stockholm, Sweden; Department of Surgery, Södersjukhuset, Stockholm, Sweden.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Nordin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Enochsson, Lars
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden; Department of Surgery, Sunderby Hospital, Luleå, Sweden.
    The Impact of Hospital Level of Care on the Management of Acute Cholecystitis: a Population-Based Study2022In: Journal of Gastrointestinal Surgery, ISSN 1091-255X, E-ISSN 1873-4626, Vol. 26, p. 2551-2558Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The organization of healthcare could have an impact on the outcome of patients treated for acute cholecystitis (AC). The aim of this study was to analyze the way in which patients with AC are managed relative to the level of care by the treating hospital.

    METHODS: Data were collected from the Swedish Register for Gallstone Surgery and ERCP (GallRiks). Cholecystectomies between 2010 and 2019 were included. The inclusion criterion was acute cholecystectomy in patients with AC operated at either tertiary referral centers (TRCs) or regional hospitals.

    RESULTS: A total of 24,194 cholecystectomies with AC met the inclusion criterion. The time between admission and acute surgery was significantly elongated at TRCs compared with regional hospitals (2.2 ± 1.7 days vs. 1.6 ± 1.4 days, mean ± SD; p < 0.0001). Patients with a history of AC were more frequent at TRC (10.1% vs. 8.9%, p < 0.0056) and had a higher adverse event rate compared with those at regional hospitals (OR 1.61; CI 1.40-1.84, p < 0.0001). Surprisingly, an increased number of hospital beds correlated slightly with an increased number of days between admission and surgery (R2 = 0.132; p = 0.0075).

    CONCLUSION: Compared with regional hospitals, patients with AC had to wait longer at TRCs before surgery. A history of AC significantly increased the risk of adverse events. These findings indicate that logistic and organizational aspects of hospital care may affect the management of patients with AC. However, whether these findings can be generalized to healthcare organizations outside Sweden requires further investigation.

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  • 23.
    Lindqvist, Lisa
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sandblom, G.
    Nordin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Enochsson, Lars
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Regional variations in the treatment of gallstone disease may affect patient outcome: A large, population-based register study in sweden2021In: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 110, no 3, p. 335-343Article in journal (Refereed)
    Abstract [en]

    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.

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  • 24.
    Molnár, Adrienne
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Halimi, Asif
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Svensson, Johan
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Bayadsi, Haytham
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Innala, Marcus
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Hansén, Maria
    Oncology Clinic, Sundsvall Regional Hospital, Sundsvall, Sweden.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Franklin, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Aurora, CO, USA.
    Portomesenteric venous contact ≤180° and overall survival in resectable head and body pancreatic adenocarcinoma treated with upfront surgery2023In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 49, no 11, article id 107097Article in journal (Refereed)
    Abstract [en]

    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.

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  • 25.
    Natarajan, Balasubramanian
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Gaur, Rahul
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Depletion of the ER chaperone ENPL-1 sensitizes C. elegans to the anticancer drug cisplatin2013In: Worm, ISSN 2162-4046, Vol. 2, no 1, article id e24059Article in journal (Refereed)
    Abstract [en]

    Cisplatin is an essential chemotherapeutic drug in the treatment of many cancers. Its use, however, is limited by the development of resistance in many tumors. The ability to re-sensitize resistant tumors could significantly strengthen cisplatin therapy in patients. Caenorhabditis elegans is a suitable model for studying the cytoplasmic role of cisplatin in tumor cells. We have previously shown that the ATPase ASNA-1 has similar roles as a factor governing cisplatin sensitivity in mammalian tumor cells and C. elegans. Here we study the endoplasmic reticulum (ER) resident chaperone ENPL-1/GRP94 and find that its depletion makes worms sensitive to cisplatin. Elevated ER stress levels in enpl-1 mutants is the likely cause of this sensitivity because a correlation can be made between cisplatin sensitivity and the high ER stress levels. We also find that asna-1 mutants have elevated unfolded protein response (UPR) activity and that the intrinsically cisplatin resistant wild-type worms become sensitive when ER stress is high. We conclude that enpl-1 is a cisplatin sensitizing factor and suggest that manipulation of its levels or of UPR activity will enhance the effects of cisplatin based cancer therapy.

  • 26.
    Natarajan, Balasubramanian
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Unfolded protein response and enpl-1 depletion sensitize C. elegans to the anti-cancer drug cisplatinManuscript (preprint) (Other academic)
  • 27. Raj, Dorota
    et al.
    Billing, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Podraza-Farhanieh, Agnieszka
    Kraish, Bashar
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Naredi, Peter
    Alternative redox forms of ASNA-1 separate insulin signaling from tail-anchored protein targeting and cisplatin resistance in C. elegans2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 8678Article in journal (Refereed)
    Abstract [en]

    Cisplatin is a frontline cancer therapeutic, but intrinsic or acquired resistance is common. We previously showed that cisplatin sensitivity can be achieved by inactivation of ASNA-1/TRC40 in mammalian cancer cells and in Caenorhabditis elegans. ASNA-1 has two more conserved functions: in promoting tail-anchored protein (TAP) targeting to the endoplasmic reticulum membrane and in promoting insulin secretion. However, the relation between its different functions has remained unknown. Here, we show that ASNA-1 exists in two redox states that promote TAP-targeting and insulin secretion separately. The reduced state is the one required for cisplatin resistance: an ASNA-1 point mutant, in which the protein preferentially was found in the oxidized state, was sensitive to cisplatin and defective for TAP targeting but had no insulin secretion defect. The same was true for mutants in wrb-1, which we identify as the C. elegans homolog of WRB, the ASNA1/TRC40 receptor. Finally, we uncover a previously unknown action of cisplatin induced reactive oxygen species: cisplatin induced ROS drives ASNA-1 into the oxidized form, and selectively prevents an ASNA-1-dependent TAP substrate from reaching the endoplasmic reticulum. Our work suggests that ASNA-1 acts as a redox-sensitive target for cisplatin cytotoxicity and that cisplatin resistance is likely mediated by ASNA-1-dependent TAP substrates. Treatments that promote an oxidizing tumor environment should be explored as possible means to combat cisplatin resistance.

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  • 28.
    Rutegård, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hassmén, N
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Haapamäki, Markku M
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Matthiessen, P
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Anterior Resection for Rectal Cancer and Visceral Blood Flow: An Explorative Study2016In: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 105, no 2, p. 78-83Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Impaired blood perfusion may be implicated in anastomotic leakage after anterior resection for rectal cancer. We investigated whether high ligation of the inferior mesenteric artery or total mesorectal excision compromises visceral blood flow in the colonic limb and the rectal stump, respectively.

    MATERIAL AND METHODS: A prospective cohort study was conducted in a university hospital setting. We used Laser Doppler flowmetry to evaluate the impact of level of tie on colonic limb perfusion and the extent of the mesorectal excision on the rectal blood flow. In the rectum, different quadrants were also assessed. The Mann-Whitney U test was used to compare mean blood flow ratios between groups.

    RESULTS: Some 23 patients were recruited in a convenience sample during a period in 2012-2013. The mean blood flow ratio was not decreased after high tie compared to low tie surgery (1.71 vs 1.19; p = 0.28). Total mesorectal excision reduced the mean blood flow ratio in the rectum, as compared with partial mesorectal excision (0.76 vs 1.28; p = 0.14). This was especially pronounced in the posterior aspect of the rectum (0.66 vs 1.68; p = 0.02).

    CONCLUSION: High tie ligation did not seem to decrease colonic limb perfusion, while total mesorectal excision may decrease rectal blood flow. The posterior quadrant of the rectum might be particularly vulnerable to the dissection involved in total mesorectal excision.

  • 29.
    Rutegård, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Matthiessen, P.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    High tie in anterior resection for rectal cancer confers no increased risk of anastomotic leakage2012In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 99, no 1, p. 127-132Article in journal (Refereed)
    Abstract [en]

    Background: It is controversial whether division of the inferior mesenteric artery close to the aorta influences the risk of anastomotic leakage, especially in the elderly and unfit. This population-based study was carried out to evaluate the independent association between a high arterial ligation and anastomotic leakage in anterior resection for rectal cancer. Methods: All patients who had anterior resection for rectal cancer from 2007 to 2009 inclusive were identified in the Swedish Colorectal Cancer Registry. The association between high tie and anastomotic leakage was evaluated in a logistic regression model, with adjustment for confounders. Stratification was performed for co-morbidity as judged by the American Society of Anesthesiologists (ASA) classification. Results: Symptomatic anastomotic leakage occurred in 81 (9.9 per cent) of 818 patients with a high tie and 108 (9.8 per cent) of 1101 without. Overall, the use of a high tie was not associated with a higher risk of anastomotic leakage (odds ratio (OR) 1.00, 95 per cent confidence interval 0.72 to 1.39). There was no increased risk in patients classifed as ASA grade I or II (OR 0.97, 0.69 to 1.35), or in those graded ASA III or IV (OR 1.26, 0.58 to 2.75). Conclusion: In the present population-based setting, use of a high tie was not associated with an increased rate of symptomatic anastomotic leakage.

  • 30. Rystedt, Jenny M. L.
    et al.
    Kleeff, Joerg
    Salvia, Roberto
    Besselink, Mark G.
    Prasad, Raj
    Lesurtel, Mickael
    Sturesson, Christian
    Abu Hilal, M.
    Aljaiuossi, A.
    Antonucci, A.
    Ardito, F.
    Ausania, F.
    Bernon, M.
    Berrevoet, F.
    Bjornsson, B.
    Bonsing, B. A.
    Boonstra, E. A.
    Bracke, B.
    Brusadin, R.
    Burda, L.
    Caraballo, M.
    Casellas-Robert, M.
    Coker, A.
    Davide, J.
    De Gelder, A.
    De Rose, A. M.
    Djokic, M.
    Dudek, K.
    Ekmekcigil, E.
    Filauro, M.
    Fulop, A.
    Gallagher, T. K.
    Gastaca, M.
    Gefen, R.
    Giuliante, F.
    Habibeh, H.
    Halle-Smith, J.
    Haraldsdottir, K. H.
    Hartman, V
    Hauer, A.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hoskovec, D.
    Isaksson, B.
    Jonas, E.
    A, Khalaileh
    Klug, R.
    Krige, J.
    Lignier, D.
    Lindemann, J.
    Lopez-Lopez, V
    Lucidi, V
    Mabrut, J-Y
    Mansson, C.
    Mieog, S.
    Mirza, D. F.
    Oldhafer, K. J.
    Omoshoro-Jones, J. A. O.
    Ortega-Torrecilla, N.
    Otto, W.
    Panaro, F.
    Pando, E.
    Paterna-Lopez, S.
    Pekmezci, S.
    Pesce, A.
    Porte, R. J.
    Poves, I
    Prieto Calvo, M.
    Primavesi, F.
    Puleo, S.
    Recordare, A.
    Rizell, M.
    Roberts, K.
    Robles-Campos, R.
    Sanchiz-Cardenas, E.
    Sandstrom, P.
    Saribeyoglu, K.
    Schauer, M.
    Schreuder, M.
    Siriwardena, A. K.
    Smith, M. D.
    Silva, Sousa D.
    Sparrelid, E.
    Staettner, S.
    Stavrou, G. A.
    Straka, M.
    Stromberg, C.
    Sutcliffe, R. P.
    Szijarto, A.
    Taflin, H.
    Trotovsek, B.
    van Gulik, T.
    Wallach, N.
    Zieniewicz, K.
    Post cholecystectomy bile duct injury: early, intermediate or late repair with hepaticojejunostomy - an E-AHPBA multi-center study2019In: HPB, ISSN 1365-182X, E-ISSN 1477-2574, Vol. 21, no 12, p. 1641-1647Article in journal (Refereed)
    Abstract [en]

    Background: Treatment of bile duct injuries (BDI) during cholecystectomy depends on the severity of injury and the timing of diagnosis. Standard of care for severe BDIs is hepaticojejunostomy. The aim of this retrospective multi-center study was to assess the optimal timing for repair of BDI with hepaticojejunostomy.

    Methods: Members of the European-African HepatoPancreatoBiliary Association were invited to report all consecutive patients with hepaticojejunostomy after BDI from January 2000 to June 2016. Patients were stratified according to the timing of biliary reconstruction with hepaticojejunostomy: early (day 0-7), intermediate (1-6 weeks) and late (6 weeks-6 months). Primary endpoint was re-intervention >90 days after the hepaticojejunostomy and secondary endpoints were severe 90-day complications and liver-related mortality.

    Results: In total 913 patients from 48 centers were included in the analysis. In 401 patients (44%) the bile duct injury was diagnosed intraoperatively, and 126 patients (14%) suffered from concomitant vascular injury. In multivariable analysis the timing of hepaticojejunostomy had no impact on postoperative complications, the need for re-intervention after 90 days nor liver-related mortality. The rate of re-intervention more than 90 days after the hepaticojejunostomy was significantly increased in male patients but decreased in older patients. Severe co-morbidity increased the risk for liver-related mortality (HR 3.439; CI 1.37-8.65; p = 0.009).

    Conclusion: After BDI occurring during cholecystectomy, the timing of biliary reconstruction with hepaticojejunostomy did not have any impact on severe postoperative complications, the need for re-intervention or liver-related mortality. Individualised treatment after iatrogenic bile duct injury is still advisable.

  • 31. Sturesson, Christian
    et al.
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Mansson, Christopher
    Sandstrom, Per
    Stromberg, Cecilia
    Taflin, Helena
    Rystedt, Jenny
    Quality-of-life after bile duct injury repaired by hepaticojejunostomy: a national cohort study2020In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 55, no 9, p. 1087-1092Article in journal (Refereed)