Knut Jørgen Labori

Tumour exosome integrins determine organotropic metastasis.

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

Multiple inflammatory-, tissue remodelling- and fibrosis genes are differentially transcribed in the livers of Abcb4 (−/ − ) mice harbouring chronic cholangitis

Objective. Abcb4 (−/−) mice secrete phosphatidylcholine-free, cytotoxic bile and develop chronic cholangitis. The aim of this study was to identify differentially transcribed genes whose products contribute to the liver tissue pathology during this disease. Material and methods. Hepatic gene transcription was measured in 3-, 6-, 9- and 20-week-old Abcb4 (−/−) mice (FVB.129P2-abcb4tm1Bor/J) using cDNA microarrays, with FVB/NJ Abcb4 (+/+) mice serving as controls. Focus was on inflammatory-, remodelling- and fibrosis genes. Marked differential transcription of inflammatory-, tissue remodelling- and fibrosis genes found by cDNA microarrays was verified by real-time polymerase chain reaction (PCR). Liver pathology was quantified by histopathology scoring. Results. Transcription of clade A3 Serpin genes showed early, marked down-regulation. The chemokine genes Ccl2, Ccl20 and Cxcl10 were markedly up-regulated. Tissue remodelling- and fibrosis genes exhibiting markedly up-regulated transcription included: Ctgf, Elf3, Lgals3, Mmp12, Mmp15, Spp1, Loxl2, Pdgfa, Pdgfrb, Sparc, Tgfb1, Tgfb2, Tgfbi, Tgfbr2 and Col1a1, Col1a2, Col2a1, Col3a1, Col4a1 genes. Microarray-based recordings of differential gene transcription of the majority of these genes harmonized with the liver histopathology score. Thus, cDNA microarray-based analysis showed increasing differential transcription of several inflammatory-, tissue remodelling- and fibrosis genes during the first 9 weeks of disease and a tendency towards differential transcription to stabilize at an elevated level from 9 to 20 weeks of disease. Conclusions. Multiple genes regulating inflammation, tissue remodelling and fibrosis not previously linked to Abcb4 (−/−) cholangitis are identified as being differentially transcribed in Abcb4 (−/−) livers, where they contribute to the pathogenesis of liver tissue pathology.

ABCB4 sequence variations in young adults with cholesterol gallstone disease

Background and Aims: Mutations in the gene encoding the ABCB4 [adenosine triphosphate (ATP)‐binding cassette, sub‐family B (MDR/TAP), member 4] transporter lower phosphatidylcholine output into bile and contribute to cholesterol gallstone formation by decreasing the solubility of cholesterol in bile. Mutations in ABCB4 have been identified in patients with low phospholipid‐associated cholelithiasis. The aim of the present study was to determine the types and frequencies of ABCB4 mutations in cholecystectomized patients aged <40 years.

Impact of early disease progression and surgical complications on adjuvant chemotherapy completion rates and survival in patients undergoing the surgery first approach for resectable pancreatic ductal adenocarcinoma – A population-based cohort study

Background. Multimodality treatment (MMT) improves survival for patients with pancreatic ductal adenocarcinoma (PDAC). The surgery-first (SF) strategy is the most universally accepted approach. Material and methods. Population-based retrospective cohort study of all cases of resectable PDAC from 2006 to 2012. Patients were planned for adjuvant chemotherapy (AC) with the Nordic 5-fluorouracil/leucovorin regimen. Reasons for and rates of failure to complete AC, postoperative major complications (PMC), and overall survival (OS) were analysed. Results. Of 203 patients, 85 (41.9%) completed AC, 41 (20.2%) failed to complete AC, and 77 (37.9%) never initiated AC. Primary reasons for not initiating or completing AC were early disease progression (34.7%), postoperative complications/poor performance status (32.2%), and age > 75 years (24.6%). Median OS in the whole cohort was 17.0 months, and 20.0 months in patients who initiated AC. Median OS in patients who completed AC was higher than in patients who did not (25.0 months vs. 12.0 months, p < 0.001). PMC (n = 41) were associated with decreased initiation rate (p < 0.001) and completion rate (p = 0.007) of AC, and decreased median OS (11.0 months vs. 19.0 months, p = 0.028). Among patients with R1 resection, PMC again were associated with worse median OS (8.0 months vs. 16.0 months, p = 0.028). Multivariate analysis demonstrated that completion of MMT and tumour grade (G1/G2) were related to mortality rate (p < 0.001). Mortality risk for patients who completed AC was reduced also when adjusting for competing risk (SHR 0.426, p < 0.001). Conclusions. MMT completion is strongly associated with reduced mortality risk in patients with resectable PDAC undergoing the SF approach. Early disease progression and PMC/poor performance status preclude MMT completion in more than one third of the patients. These reasons for failure to complete MMT underscore the need for strategies to improve patient selection and reduce surgical morbidity in patients with resectable PDAC.

Impact of contrast-enhanced intraoperative ultrasound on operation strategy in case of colorectal liver metastasis

Background Surgical treatment is the only option for long-term survival in patients with colorectal liver metastasis (CRLM). Contrast-enhanced CT and MRI are usually used for preoperative liver imaging. The initial surgical strategy for liver resection is based upon these findings. Further optimization of the surgical strategy by contrast-enhanced intraoperative ultrasound (CE-IOUS) might further improve the surgical outcome. Purpose To evaluate the current impact of CE-IOUS with SonoVue® on the initial surgical strategy for CRLM. Material and Methods Eighty-six consecutive patients undergoing open liver resection for CRLM were evaluated retrospectively over a 2.5-year period. The patients underwent 97 operations. Preoperative staging was performed with contrast-enhanced CT in all patients and MRI was available in 66 of 86 patients. CE-IOUS was performed in all patients according to a standardized examination technique. Curved array and linear transducers were used. CRLM were identified in venous phase as hypovascular lesions. CE-IOUS findings were compared with preoperative staging. Results Combined CT/MRI identified preoperatively 328 CRLM (mean 3.4, range 0-14). Seventy-two additional lesions (18%) were identified in 38 patients during the operation. Intraoperatively 41 additional CRLM in 20 patients were identified by inspection, palpation, and CE-IOUS (10%), and another 31 CRLM in 17 patients were identified by CE-IOUS alone (8%). All additional CRLM detected by CE-IOUS were confirmed by histology if resection was performed. CE-IOUS changed planned operation strategy in 29.9% of operations. A larger resection was necessary in 13.4% of the cases, reduced liver resection was found sufficient in 11.3%, and 5.2% were found inoperable. For patients diagnosed preoperatively with solitary lesions CE-IOUS changed operation strategy in 19% and radical tumor resection would have failed in 4.8% without CE-IOUS. Conclusion CE-IOUS is essential to ensure optimal and complete tumor resection both in patient with solitary CRLM and multiple metastases.

Endoscopic sealing of pancreatic fistulas: four case reports and review of the literature.

Abstract We report four patients with pancreatic fistulas that failed to respond to conservative treatment. The fistulas were closed by endoscopic injection of N-butyl-2-cyanoacrylate (Histoacryl) diluted with an oily contrast agent (Lipiodol). A literature review revealed 32 similar cases in which endoscopic treatment with fibrin sealants (n = 11) or cyanoacrylate (n = 21) was used to close the fistulas. Based on our own experience and the literature review, we conclude that endoscopic sealing of pancreatic fistulas can be performed safely and effectively by experienced endoscopists in a tertiary centre. The procedure seems useful in the management of complicated pancreatic fistulas which do not respond to conservative treatment and may obviate the need for surgery.

Surgical Treatment of Sporadic Pancreatic Neuroendocrine Tumors: A State of the Art Review

Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms. They are clinically diverse and divided into functioning and nonfunctioning disease, depending on their ability to produce symptoms due to hormone production. Surgical resection is the only curative treatment and remains the cornerstone therapy for this patient group, even in patients with advanced disease. Over the last decade there has been a noticeable trend towards more aggressive surgery as well as more minimally invasive surgery in patients with PNETs. This has resulted in improved long-term survival in patients with locally advanced and metastatic disease treated aggressively, as well as shorter hospital stays and comparable long-term outcomes in patients with limited disease treated minimally invasively. There are still controversies related to issues of surgical treatment of PNETs, such as to what extent enucleation, lymph node sampling, and vascular reconstruction are beneficial for the oncologic outcome. Histopathologic tumor classification is of high clinical importance for treatment planning and prognostic evaluation of patients with PNETs. A constant challenge, which relates to the treatment of PNETs, is the lack of an internationally accepted histopathological classification system. This paper reviews current issues on the surgical treatment of sporadic PNETs with specific focus on surgical approaches and tumor classification.

Aetiology and prognostic implication of severe jaundice in surgical trauma patients

BACKGROUND Pronounced postoperative jaundice occurs not infrequently in trauma patients. The aim of this study was to elucidate the implication of early, pronounced jaundice (serum-bilirubin >100 micromol x l(-1)) for 30-day survival of such patients. METHODS From 1995 through 2001, 53 surgical trauma patients developing pronounced postoperative jaundice were identified. Nine were excluded from the study because of major hepatobiliary injury or pre-existing liver disease. The clinical course and laboratory chemistry profiles of the remaining 44 patients were analysed. RESULTS Thirty-one patients survived and 13 died within 30 days of trauma. Non-survivors had higher age, higher injury severity score (ISS) and lower probability of survival (PS) (P < 0.05) than survivors. ISS averaged 34 in survivors and 45 in non-survivors. Survivors and non-survivors received a mean of 46 (range 10-97) and 55 units of blood (range 11-128), respectively (P = 0.366). Systemic hypotension, local infections and sepsis were common in both groups. Bilirubin levels peaked around the 11th day in survivors (median 189 micromol x l(-1)). In non-survivors, serum bilirubin values rose progressively, reaching maximum levels at time of death (median 231 micromol x l(-1)). These patients died in a setting of sepsis and multiple organ failure. CONCLUSION Large endogenous production of bilirubin because of rapid breakdown of transfused and extravasated blood can cause pronounced jaundice in multitransfused trauma patients. In such patients, serum bilirubin rising >100 micromol x l(-1) does not by itself signal poor outcome. However, progressive pronounced jaundice outlasting the trauma incident by 10-12 days portends fatal outcome for the patient.

Regulatory T cells that co-express RORγt and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is highly infiltrated by CD4+T cells that express RORγt and IL-17 (TH17). Compelling evidence from the tumor microenvironment suggest that regulatory T cells (Treg) contribute to TH17 mediated inflammation. Concurrently, PDAC patients have elevated levels of pro-inflammatory cytokines that may lead to TH17 associated functional plasticity in Treg. In this study, we investigated the phenotype and functional properties of Treg in patients with PDAC. We report that PDAC patients have elevated frequency of FOXP3+Treg, which exclusively occurred within the FOXP3+RORγt+Treg compartment. The FOXP3+RORγt+Treg retained FOXP3+Treg markers and represented an activated subset. The expression of RORγt in Treg may indicate a phenotypic switch toward TH17 cells. However, the FOXP3+RORγt+Treg produced both TH17 and TH2 associated pro-inflammatory cytokines, which corresponded with elevated TH17 and TH2 immune responses in PDAC patients. Both the FOXP3+Treg and FOXP3+RORγt+Treg from PDAC patients strongly suppressed T cell immune responses, but they had impaired anti-inflammatory properties. We conclude that FOXP3+RORγt+Treg have a dual phenotype with combined pro-inflammatory and immunosuppressive activity, which may be involved in the pathogenesis of PDAC.

Diagnostic performance of CT, MRI and PET/CT in patients with suspected colorectal liver metastases: the superiority of MRI.

Background Meticulous imaging of colorectal liver metastases (CRLM) is mandatory to optimize outcome after liver resection. However, the detection of CRLM is still challenging. Purpose To evaluate prospectively if magnetic resonance imaging (MRI) with diffusion-weighted and Gd-EOB-DTPA-enhanced sequences had a better diagnostic performance for CRLM compared to computed tomography (CT) and fluorine-18 fluorodeoxyglucose positron emission tomography (PET/CT). Material and Methods Forty-six patients scheduled for resection of suspected CRLM were evaluated prospectively from September 2011 to January 2013. None of the patients had undergone previous treatment for their CRLM. Multiphase CT, liver MRI with diffusion-weighted and dynamic Gd-EOB-DTPA-enhanced sequences and low-dose PET/CT were performed. Two independent, blinded readers evaluated the examinations. The reference standard was histopathological confirmation (81/140 CRLM) or follow-up. Results A total of 140 CRLM and 196 benign lesions were identified. On a per-lesion basis, MRI had the significantly highest sensitivity overall and for CRLM < 10 mm (P < 0.001). Overall sensitivity/specificity and PPV/NPV were 68%/94% and 89%/81% for CT, 90%/87% and 82%/93% for MRI, and 61%/99% and 97%/78% for PET/CT. For CRLM < 10 mm it was 16%/96% and 54%/80% for CT, 74%/88% and 64%/93% for MRI, and 9%/98% and 57%/79% for PET/CT. Conclusion MRI had the significantly highest sensitivity compared with CT and PET/CT, particularly for CRLM < 10 mm. Therefore, detection of CRLM should be based on MRI.