| 1. |
- Molnár, Adrienne, et al.
(författare)
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Portomesenteric venous contact ≤180° and overall survival in resectable head and body pancreatic adenocarcinoma treated with upfront surgery
- 2023
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Ingår i: European Journal of Surgical Oncology. - : Elsevier. - 0748-7983 .- 1532-2157. ; 49:11
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 2. |
- Baumeister, Sebastian E., et al.
(författare)
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Association between physical activity and risk of hepatobiliary cancers : A multinational cohort study
- 2019
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 70:5, s. 885-892
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Billing, Ola, 1981-, et al.
(författare)
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LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance
- 2021
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Ingår i: Oncogene. - : Springer Nature. - 0950-9232 .- 1476-5594. ; 40, s. 3707-3718
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 4. |
- Boussemart, Lise, et al.
(författare)
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eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 513:7516, s. 105-109
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Bradbury, Kathryn E., et al.
(författare)
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Circulating insulin-like growth factor I in relation to melanoma risk in the European prospective investigation into cancer and nutrition
- 2019
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 144:5, s. 957-966
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 6. |
- Caini, Saverio, et al.
(författare)
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Coffee, tea and melanoma risk : findings from the European Prospective Investigation into Cancer and Nutrition
- 2017
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 140:10, s. 2246-2255
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Duarte-Salles, Talita, et al.
(författare)
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Circulating Osteopontin and Prediction of Hepatocellular Carcinoma Development in a Large European Population
- 2016
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Ingår i: Cancer Prevention Research. - 1940-6207 .- 1940-6215. ; 9:9, s. 758-765
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
- Engstrand, J., et al.
(författare)
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Liver resection and ablation for squamous cell carcinoma liver metastases
- 2021
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Ingår i: BJS Open. - Oxford, United Kingdom : Oxford University Press. - 2474-9842. ; 5:4
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Tidskriftsartikel (refereegranskat)abstract
- 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, J., et al.
(författare)
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The Resection Rate of Synchronously Detected Liver and Lung Metastasis from Colorectal Cancer Is Low-A National Registry-Based Study
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Real-life data on the occurrence and treatment of synchronously detected liver and lung metastases from colorectal cancer are lacking. Through the merging of several Swedish nationwide patient quality registries, we aimed to answer these questions. We found that synchronous liver and lung colorectal metastases are rare and that a minority undergo resection of both metastatic sites, but if they do, they have an excellent survival. It is likely that a larger proportion of patients could be offered treatment that leads to a prolonged overall survival. We also found differences in regional treatment approaches across Sweden, but the reasons for this are unknown, which warrants further studies. 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.
(författare)
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Exposure to bacterial products lipopolysaccharide and flagellin and hepatocellular carcinoma : a nested case-control study
- 2017
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Ingår i: BMC Medicine. - : BioMed Central. - 1741-7015. ; 72:15
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Tidskriftsartikel (refereegranskat)abstract
- 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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