Receptor conversion and survival in breast cancer liver metastases.

BACKGROUND: Breast cancer liver metastases (BCLM) is a common cause of breast cancer-related death. The prognostic and predictive value of receptor expression and St Gallen classification is challenged by receptor status discordance in distant metastases. The aim of this study was to determine the rate of receptor conversion from breast cancer to BCLM and the impact on survival. METHOD: Patients registered with BCLM in two Swedish national cancer registers were recruited retrospectively. Data on receptor expression in primary breast cancer and BCLM were collected, as well as information about predictive factors for survival. The rate of receptor and subtype conversion was analyzed. A Cox regression model was used to investigate predictive factors for survival. RESULTS: A cohort of 132 patients with BCLM was identified. Estrogen receptor (ER), progesterone receptor (PgR) and HER2 converted in 17, 33 and 10%, respectively. PgR was lost in BCLM while 8/10 HER2 conversions went from negative to positive. The BC subtype was re-classified in 21% of the BCLM. Median survival after BCLM was 13 months and HER2 amplification was associated with improved survival (HR 0.28 CI 0.085-0.90). The highest predictive value (Harrell´s C-index) was obtained when including both BC and BCLM status. CONCLUSIONS: Receptor and subtype conversions are common in BCLM, and a liver biopsy is warranted to tailor BCLM treatment. HER2 amplification is associated with improved survival in a BCLM cohort.

Survival and prognostic factors after transplantation, resection and ablation in a national cohort of early hepatocellular carcinoma.

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.

Quality-of-life after bile duct injury repaired by hepaticojejunostomy: a national cohort study.

OBJECTIVES: Reports on quality-of-life (QoL) after bile duct injury (BDI) show conflicting results. The aim of this cohort study was to evaluate QoL stratified according to type of treatment. METHODS: QoL assessment using the SF-36 (36-item short form health survey) questionnaire. Patients with post-cholecystectomy BDI needing hepaticojejunostomy (HJ) were compared to all other treatments (BDI repair) and to patients without BDI at cholecystectomy (controls). RESULTS: Patients needing a HJ after BDI reported reduced long-term QoL irrespective of time for diagnosis and repair in both the physical (PCS; p < .001) and mental (MCS; p < .001) domain compared to both controls and patients with less severe BDI. QoL was comparable for BDI repair (n = 86) and controls (n = 192) in both PCS (p = .171) and MCS (p = .654). As a group, patients with BDI (n = 155) reported worse QoL than controls, in both the PCS (p < .001) and MCS (p = .012). Patients with a BDI detected intraoperatively (n = 124) reported better QoL than patients with a postoperative diagnosis. Patients with an immediate intraoperative repair (n = 99), including HJ, reported a better long-term QoL compared to patients subjected to a later procedure (n = 54). CONCLUSIONS: Patients with postoperative diagnosis and patients with BDIs needing biliary reconstruction with HJ both reported reduced long-term QoL.

eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies.

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.

Circulating insulin-like growth factor I in relation to melanoma risk in the European prospective investigation into cancer and nutrition.

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

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

BACKGROUND & AIMS: To date, evidence on the association between physical activity and risk of hepatobiliary cancers has been inconclusive. 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.

Coffee, tea and melanoma risk: findings from the European Prospective Investigation into Cancer and Nutrition.

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.

Exposure to bacterial products lipopolysaccharide and flagellin and hepatocellular carcinoma: a nested case-control study.

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: Antibody response to LPS and flagellin was associated with a statistically significant increase in the risk of hepatocellular carcinoma (highest vs. lowest quartile: RR = 11.76, 95% confidence interval = 1.70-81.40; P trend = 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.

Importance of resection margin after resection of colorectal liver metastases in the era of modern chemotherapy: population-based cohort study.

BACKGROUND: Resection margin has been associated with overall survival following liver resection for colorectal liver metastasis. The aim of this study was to examine how resection margins of 0.0 mm, 0.1-0.9 mm and ≥1 mm influence overall survival in patients resected for colorectal liver metastasis in a time of modern perioperative chemotherapy and surgery. METHODS: Using data from the national registries Swedish Colorectal Cancer Registry and Swedish National Quality Registry for Liver, Bile Duct and Gallbladder Cancer, patients that had liver resections for colorectal liver metastasis between 2009 and 2013 were included. In patients with a narrow or unknown surgical margin the original pathological reports were re-reviewed. Factors influencing overall survival were analysed using a Cox proportional hazard model. RESULTS: A total of 754 patients had a known margin status, of which 133 (17.6%) patients had a resection margin <1 mm. The overall survival in patients with a margin of 0 mm or 0.1-0.9 mm was 42 (95% c.i. 31 to 53) and 48 (95% c.i. 35 to 62) months respectively, compared with 75 (95% c.i. 65 to 85) for patients with ≥1 mm margin, P < 0.001. Margins of 0 mm or 0.1-0.9 mm were associated with poor overall survival in the multivariable analysis, HR 1.413 (95% c.i. 1.030 to 1.939), P = 0.032, and 1.399 (95% c.i. 1.025 to 1.910), P = 0.034, respectively. CONCLUSIONS: Despite modern chemotherapy the resection margin is still an important factor for the survival of patients resected for colorectal liver metastasis, and a margin of ≥1 mm is needed to achieve the best possible outcome.

Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial.

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. FUNDING: Norwegian Cancer Society, South Eastern Norwegian Health Authority, The Sjöberg Foundation, and Helsinki University Hospital Research Grants.

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

INTRODUCTION: Upfront surgery is the standard of care for resectable pancreatic cancer, defined as the absence of or ≤180° tumour contact with the portal/superior mesenteric vein. We hypothesized that portomesenteric venous tumour contact is prognostically unfavourable and aimed to assess whether it is associated with poorer survival 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. Overall 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 tumour contact and 144 patients without venous tumour contact. Patients with venous tumour contact had a median overall survival of 15.3 months compared to 23.0 months (log rank P = 0.059). Portomesenteric venous tumour 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 tumour 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.

Improved Survival in At-Risk Patients Undergoing Surveillance for Hepatocellular Carcinoma - A Nationwide Swedish Register-Based Study.

Purpose: Surveillance for hepatocellular carcinoma (HCC) is recommended in at-risk patients, but its effectiveness in Western populations has been questioned. The purpose was to evaluate the effect of surveillance in patients with HCC in a Northern European setting. Patients and Methods: Data on patients diagnosed with HCC between 2009 and 2019 were collected from the nationwide Swedish National Registry for Tumors of the Liver and Bile Ducts (SweLiv). Patients who had undergone HCC surveillance were compared to those who had not (but had an obvious indication for surveillance, ie, liver cirrhosis or hepatic porphyria and an age of ≥50 years) regarding etiology, tumor burden, presence of extrahepatic spread, treatment and lead-time adjusted overall survival. Results: A total of 4979 patients with index HCC were identified and information regarding surveillance was available in 4116 patients. Among these, 1078 had got their HCC diagnosis during surveillance, whereas 1647 had been diagnosed without surveillance despite a presumed indication. The most common underlying etiologies for HCC were hepatitis C (28.2%) and alcoholic liver disease (26.9%), and 94.8% had cirrhosis. The surveillance cohort more frequently met the University of California San Francisco-criteria (79% vs 53%, p <0.001), more often received a potentially curative treatment (62% vs 28%, p <0.001) and had less extrahepatic spread (7.6% vs 22.4% p <0.001). After adjustment for lead-time bias (sojourn time of 270 days), the surveillance group had a significantly longer estimated median survival time than the non-surveillance group (34 months vs 11 months, p <0.001). A multivariable cox regression analysis showed an adjusted hazard ratio of 0.59 (95% CI 0.51-0.67) in favor of surveillance. Conclusion: Surveillance for HCC in at-risk patients is associated with diagnosis at an earlier tumor stage, treatment with curative intent and with improved lead-time adjusted overall survival. These findings encourage HCC surveillance of at-risk patients also in a Western population.

The Resection Rate of Synchronously Detected Liver and Lung Metastasis from Colorectal Cancer Is Low-A National Registry-Based Study.

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.

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

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

Excision and suture in the midline versus Karydakis flap surgery for pilonidal sinus: randomized clinical trial.

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).

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

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

The Impact of Hospital Level of Care on the Management of Acute Cholecystitis: a Population-Based Study.

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.

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

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

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

BACKGROUND: The lack of studies showing benefit from surgery in patients with symptoms of gallstone disease has led to a divergence in local practices and standards of care. This study aimed to explore regional differences in management and complications in Sweden. Furthermore, to study whether population density had an impact on management. METHODS: Data were collected from the Swedish National Register for Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (GallRiks). Cholecystectomies undertaken for gallstone disease between January 2006 and December 2017 were included. Age, sex, American Society of Anesthesiologists (ASA) classification, intra- and post-operative complications, and the proportion of patients with acute cholecystitis who underwent surgery within 2 days of hospital admission were analyzed. The 21 different geographical regions in Sweden were compared, and each variable was analyzed according to population density. RESULTS: A total of 139,444 cholecystectomies cases were included in this study. There were large differences between regions regarding indications for surgery and intra- and post-operative complications. In the analyses, there were greater divergences than would be expected by chance for most of the variables analyzed. Age of the cholecystectomized patients correlated with population density of the regions (R2 = 0.310; p = 0.0088). CONCLUSIONS: 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.

Pharmacokinetics of preoperative intraperitoneal 5-FU in patients with pancreatic ductal adenocarcinoma.

PURPOSE: The aim was to investigate the pharmacokinetics of preoperatively administered intraperitoneal (IP) 5-FU in patients with resectable pancreatic ductal adenocarcinoma (PDAC) by analyzing levels of 5-FU and target metabolites in peritoneal fluid, plasma, liver, lymph nodes, pancreatic tumour, and pancreatic tissue. These results were correlated to expression of genes encoding enzymes of the 5-FU pathway and cell membrane transporters of 5-FU and FdUMP. METHODS: Twenty-two patients with PDAC were treated with IP 5-FU before surgery. The postoperative treatment followed a routine clinical protocol. 5-FU and its metabolites were analyzed by LC-MS/MS. The expression of genes encoding enzymes and transporters in the 5-FU pathway was analyzed by qPCR. RESULTS: After IP treatment, 5-FU could be detected in plasma, lymph nodes, liver, pancreatic tumour, and pancreatic tissue. The highest 5-FU concentration was found in the liver, also expressing high levels of the 5-FU transporter OAT2. 5-FU was converted to active FdUMP in all tissues and the highest concentration was measured in lymph nodes, liver and pancreatic tumour (18.5, 6.1 and 6.7 pmol/g, respectively). There was a correlation between the FdUMP and dUr levels in lymph nodes (r = 0.70, p = 0.0076). In tumours, there was an association between OAT2 expression and FdUMP concentration. CONCLUSION: The study shows uptake of IP 5-FU and drug metabolism to active FdUMP in pancreatic tumour, liver, and lymph nodes. Extended studies are warranted to evaluate the IP route for 5-FU administration in PDAC patients.