Clinical added value of MRI to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): study protocol for an international multicentre prospective diagnostic accuracy study.

BACKGROUND: Abdominal computed tomography (CT) is the standard imaging method for patients with suspected colorectal liver metastases (CRLM) in the diagnostic workup for surgery or thermal ablation. Diffusion-weighted and gadoxetic-acid-enhanced magnetic resonance imaging (MRI) of the liver is increasingly used to improve the detection rate and characterization of liver lesions. MRI is superior in detection and characterization of CRLM as compared to CT. However, it is unknown how MRI actually impacts patient management. The primary aim of the CAMINO study is to evaluate whether MRI has sufficient clinical added value to be routinely added to CT in the staging of CRLM. The secondary objective is to identify subgroups who benefit the most from additional MRI. METHODS: In this international multicentre prospective incremental diagnostic accuracy study, 298 patients with primary or recurrent CRLM scheduled for curative liver resection or thermal ablation based on CT staging will be enrolled from 17 centres across the Netherlands, Belgium, Norway, and Italy. All study participants will undergo CT and diffusion-weighted and gadoxetic-acid enhanced MRI prior to local therapy. The local multidisciplinary team will provide two local therapy plans: first, based on CT-staging and second, based on both CT and MRI. The primary outcome measure is the proportion of clinically significant CRLM (CS-CRLM) detected by MRI not visible on CT. CS-CRLM are defined as liver lesions leading to a change in local therapeutical management. If MRI detects new CRLM in segments which would have been resected in the original operative plan, these are not considered CS-CRLM. It is hypothesized that MRI will lead to the detection of CS-CRLM in ≥10% of patients which is considered the minimal clinically important difference. Furthermore, a prediction model will be developed using multivariable logistic regression modelling to evaluate the predictive value of patient, tumor and procedural variables on finding CS-CRLM on MRI. DISCUSSION: The CAMINO study will clarify the clinical added value of MRI to CT in patients with CRLM scheduled for local therapy. This study will provide the evidence required for the implementation of additional MRI in the routine work-up of patients with primary and recurrent CRLM for local therapy. TRIAL REGISTRATION: The CAMINO study was registered in the Netherlands National Trial Register under number NL8039 on September 20th 2019.

Comparing practice and outcome of laparoscopic liver resection between high-volume expert centres and nationwide low-to-medium volume centres.

BACKGROUND: Based on excellent outcomes from high-volume centres, laparoscopic liver resection is increasingly being adopted into nationwide practice which typically includes low-medium volume centres. It is unknown how the use and outcome of laparoscopic liver resection compare between high-volume centres and low-medium volume centres. This study aimed to compare use and outcome of laparoscopic liver resection in three leading European high-volume centres and nationwide practice in the Netherlands. METHOD: An international, retrospective multicentre cohort study including data from three European high-volume centres (Oslo, Southampton and Milan) and all 20 centres in the Netherlands performing laparoscopic liver resection (low-medium volume practice) from January 2011 to December 2016. A high-volume centre is defined as a centre performing >50 laparoscopic liver resections per year. Patients were retrospectively stratified into low, moderate- and high-risk Southampton difficulty score groups. RESULTS: A total of 2425 patients were included (1540 high-volume; 885 low-medium volume). The median annual proportion of laparoscopic liver resection was 42.9 per cent in high-volume centres and 7.2 per cent in low-medium volume centres. Patients in the high-volume centres had a lower conversion rate (7.4 versus 13.1 per cent; P < 0.001) with less intraoperative incidents (9.3 versus 14.6 per cent; P = 0.002) as compared to low-medium volume centres. Whereas postoperative morbidity and mortality rates were similar in the two groups, a lower reintervention rate (5.1 versus 7.2 per cent; P = 0.034) and a shorter postoperative hospital stay (3 versus 5 days; P < 0.001) were observed in the high-volume centres as compared to the low-medium volume centres. In each Southampton difficulty score group, the conversion rate was lower and hospital stay shorter in high-volume centres. The rate of intraoperative incidents did not differ in the low-risk group, whilst in the moderate-risk and high-risk groups this rate was lower in high-volume centres (absolute difference 6.7 and 14.2 per cent; all P < 0.004). CONCLUSION: High-volume expert centres had a sixfold higher use of laparoscopic liver resection, less conversions, and shorter hospital stay, as compared to a nationwide low-medium volume practice. Stratification into Southampton difficulty score risk groups identified some differences but largely outcomes appeared better for high-volume centres in each risk group.

Volume-outcome relationship of liver surgery: a nationwide analysis.

BACKGROUND: Evidence for an association between hospital volume and outcomes for liver surgery is abundant. The current Dutch guideline requires a minimum volume of 20 annual procedures per centre. The aim of this study was to investigate the association between hospital volume and postoperative outcomes using data from the nationwide Dutch Hepato Biliary Audit. METHODS: This was a nationwide study in the Netherlands. All liver resections reported in the Dutch Hepato Biliary Audit between 2014 and 2017 were included. Annual centre volume was calculated and classified in categories of 20 procedures per year. Main outcomes were major morbidity (Clavien-Dindo grade IIIA or higher) and 30-day or in-hospital mortality. RESULTS: A total of 5590 liver resections were done across 34 centres with a median annual centre volume of 35 (i.q.r. 20-69) procedures. Overall major morbidity and mortality rates were 11·2 and 2·0 per cent respectively. The mortality rate was 1·9 per cent after resection for colorectal liver metastases (CRLMs), 1·2 per cent for non-CRLMs, 0·4 per cent for benign tumours, 4·9 per cent for hepatocellular carcinoma and 10·3 per cent for biliary tumours. Higher-volume centres performed more major liver resections, and more resections for hepatocellular carcinoma and biliary cancer. There was no association between hospital volume and either major morbidity or mortality in multivariable analysis, after adjustment for known risk factors for adverse events. CONCLUSION: Hospital volume and postoperative outcomes were not associated.

ANTECEDENTES: La asociación entre el volumen hospitalario y los resultados de la cirugía hepática no está clara. Según la recomendación actual de las guías holandesas se requiere un volumen mínimo de 20 procedimientos anuales por centro. El objetivo de este estudio fue analizar la asociación entre el volumen hospitalario con los resultados postoperatorios en la auditoría hepatobiliar obligatoria holandesa a nivel nacional. MÉTODOS: Se realizó un estudio a nivel nacional en los Países Bajos. Se incluyeron todas las resecciones hepáticas registradas en la auditoría hepatobiliar holandesa entre 2014 y 2017. El volumen anual del centro se calculó y se clasificó en categorías de 20 procedimientos por año. Los objetivos principales fueron la morbilidad de mayor grado (Clavien-Dindo grado IIIA o superior) y la mortalidad hospitalaria o la mortalidad a los 30 días. RESULTADOS: Se realizaron un total de 5.590 resecciones en 34 centros con una mediana (rango intercuartílico) de volumen anual de 35 procedimientos (20-69). La tasa global de morbilidad mayor fue del 11% y la mortalidad del 2%. La mortalidad fue de 1,9% después de la resección por metástasis hepáticas colorrectales (colorectal liver metastases, CRLM), 1,2% para no CRLM, 0,4% para tumores benignos, 4,9% para carcinoma hepatocelular, y 10,3% para tumores biliares. Los centros de mayor volumen realizaron más resecciones hepáticas mayores y más resecciones por carcinoma hepatocelular y cáncer biliar. En el análisis multivariable después de ajustar por factores de riesgo conocidos de eventos adversos, no se observó ninguna asociación entre el volumen hospitalario y la morbilidad o mortalidad mayor. CONCLUSIÓN: No hubo asociación entre el volumen hospitalario y los resultados postoperatorios de la cirugía hepática en los Países Bajos.

Laparoscopic combined resection of liver metastases and colorectal cancer: a multicenter, case-matched study using propensity scores.

BACKGROUND: Combined laparoscopic resection of liver metastases and colorectal cancer (LLCR) may hold benefits for selected patients but could increase complication rates. Previous studies have compared LLCR with liver resection alone. Propensity score-matched studies comparing LLCR with laparoscopic colorectal cancer resection (LCR) alone have not been performed. METHODS: A multicenter, case-matched study was performed comparing LLCR (2009-2016, 4 centers) with LCR alone (2009-2016, 2 centers). Patients were matched based on propensity scores in a 1:1 ratio. Propensity scores were calculated with the following preoperative variables: age, sex, ASA grade, neoadjuvant radiotherapy, type of colorectal resection and T and N stage of the primary tumor. Outcomes were compared using paired tests. RESULTS: Out of 1020 LCR and 64 LLCR procedures, 122 (2 × 61) patients could be matched. All 61 laparoscopic liver resections were minor hepatectomies, mostly because of a solitary liver metastasis (n = 44, 69%) of small size (≤ 3 cm) (n = 50, 78%). LLCR was associated with a modest increase in operative time [206 (166-308) vs. 197 (148-231) min, p = 0.057] and blood loss [200 (100-700) vs. 75 (5-200) ml, p = 0.011]. The rate of Clavien-Dindo grade 3 or higher complications [9 (15%) vs. 13 (21%), p = 0.418], anastomotic leakage [5 (8%) vs. 4 (7%), p = 1.0], conversion rate [3 (5%) vs. 5 (8%), p = 0.687] and 30-day mortality [0 vs. 1 (2%), p = 1.0] did not differ between LLCR and LCR. CONCLUSION: In selected patients requiring minor hepatectomy, LLCR can be safely performed without increasing the risk of postoperative morbidity compared to LCR alone.

[New developments in the treatment of pancreatic cancer]. / Nieuwe ontwikkelingen in de behandeling van het pancreascarcinoom.

- The incidence of pancreatic cancer is increasing due to the ageing population among other things, while 5-year survival has improved in the past two decades from 3 to 7%.- In case of biliary obstruction due to pancreatic cancer, biliary drainage before surgery or ablative therapy using a covered metal stent instead of plastic reduces the rate of complications.- In patients with metastasized pancreatic cancer a combination of folinic acid, fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) results in improved survival. Approximately 20% of patients with locally, unresectable pancreatic cancer can undergo surgical resection following treatment with FOLFIRINOX.- The effectiveness of radiofrequency ablation, irreversible electroporation and stereotactic radiotherapy for locally, unresectable pancreatic cancer is currently investigated in multicenter trials.- The effectiveness of neo-adjuvant chemoradiation and minimal invasive surgery in patients with resectable pancreatic cancer is currently investigated in randomized multicenter trials.

Hepatic regeneration and functional recovery following partial liver resection in an experimental model of hepatic steatosis treated with omega-3 fatty acids.

BACKGROUND: Omega-3 fatty acids (FAs) have been shown to reduce experimental hepatic steatosis and protect the liver from ischaemia-reperfusion injury. The aim of this study was to examine the effects of omega-3 FAs on regeneration of steatotic liver. METHODS: Steatosis was induced in rats by a 3-week methionine/choline-deficient diet, which was continued for an additional 2 weeks in conjunction with oral administration of omega-3 FAs or saline solution. Steatosis was graded histologically and quantified by proton magnetic resonance spectroscopy ((1) H-MRS) before and after the diet/treatment. Liver function was determined by (99m) Tc-labelled mebrofenin hepatobiliary scintigraphy (HBS). In separate experiments, the hepatic regenerative capacity and functional recovery of omega-3 FA-treated, saline-treated or non-steatotic (control) rats were investigated 1, 2, 3 and 5 days after partial (70 per cent) liver resection by measurement of liver weight change and hepatocyte proliferation (Ki-67) and HBS. RESULTS: Severe steatosis (over 66 per cent) in the saline group was reduced by omega-3 FAs to mild steatosis (less than 33 per cent), and hepatic fat content as assessed by (1) H-MRS decreased 2·2-fold. (99m) Tc-mebrofenin uptake in the saline group was more than 50 per cent lower than in the control group, confirming the functional effects of steatosis. (99m) Tc-mebrofenin uptake and regenerated liver mass were significantly greater in the omega-3 group compared with the saline group on days 1 and 3. The posthepatectomy proliferation peak response was delayed until day 2 in saline-treated rats, compared with day 1 in the omega-3 and control groups. CONCLUSION: Omega-3 FAs effectively reduced severe hepatic steatosis, which was associated with improved liver regeneration and functional recovery following partial hepatectomy.

Hepatic steatosis assessment with CT or MRI in patients with colorectal liver metastases after neoadjuvant chemotherapy.

PURPOSE: Preoperative radiological assessment of hepatic steatosis is recommended in patients undergoing a liver resection, but few studies investigated the diagnostic accuracy after neoadjuvant chemotherapy. The aim of this study was to compare diagnostic accuracy of preoperative CT or MRI measurements of steatosis in patients with colorectal liver metastases after induction chemotherapy. METHODS: MRI measurements (relative signal intensity decrease; RSID), N = 36, and CT scan measurements (Hounsfield units; HU), N = 32, were compared with histological steatosis assessment. Diagnostic accuracy was determined for detecting any (>5%) or marked macrovesicular steatosis (>33%). RESULTS: MRI showed the highest correlation with histology (r = 0.82, P < 0.001), compared to CT measurements (r = -0.65, P < 0.001). Based on linear regression analysis, radiological cut-off values for 5% and 33% macrovesicular steatosis, corresponded to 0.7% and 19.2% RSID in the MRI-group, and 60.4 and 54.2 HU in the CT-group, respectively. Sensitivity and specificity for the detection of any and marked macrovesicular steatosis using MRI was 87% and 69%, and 78% and 100%, respectively, and for CT, 83% and 64%, and 70% and 87%, respectively. CONCLUSION: In patients treated with neoadjuvant chemotherapy MRI measurements of steatosis showed the highest correlation coefficient and the best diagnostic accuracy, as compared to CT measurements.

Noninvasive quantification of hepatic steatosis in rats using 3.0 T 1H-magnetic resonance spectroscopy.

PURPOSE: To assess the accuracy of noninvasive 3.0 T (1)H-magnetic resonance spectroscopy ((1)H-MRS) in an experimental steatosis model for the discrimination of clinically relevant macrovesicular steatosis degrees and to evaluate three different (1)H-MR spectrum-based fat quantification methods. MATERIALS AND METHODS: Steatosis was induced in rats by a methionine/choline-deficient diet for 0-5 weeks. (1)H-MRS measurements of hepatic fat content were compared with histopathological and biochemical steatosis degree. In (1)H-MR spectra, areas under the curve (AUC) of fat (1.3 ppm), water (4.7 ppm), total fat (0.5-5.3 ppm), and total spectrum peaks (0.5-5.3 ppm) were determined and hepatic fat content calculated as follows: [AUC(total fat peaks)/AUC(total peaks)], [AUC(fat)/AUC(fat) + (AUC(water)/0.7)], and [AUC(fat)/AUC(water)]. RESULTS: A significant correlation was found between (1)H-MRS and macrovesicular steatosis (r = 0.932, P < 0.0001) and between (1)H-MRS and total fatty acids (r = 0.935, P < 0.0001). (1)H-MRS accurately distinguished mild from moderate and moderate from severe steatosis. Calculations using [AUC(fat)/AUC(water)] ratio in severe steatotic livers resulted in higher hepatic fat percentages as compared to the other methods due to a decrease in hepatic water content. CONCLUSION: (1)H-MRS quantification of hepatic fat content showed high correlations with histological and biochemical steatosis determination in an experimental steatosis rat model and accurately discriminated between clinically relevant steatosis degrees. These results encourage further application of (1)H-MRS in patients for accurate steatosis assessment.

Biliary drainage attenuates postischemic reperfusion injury in the cholestatic rat liver.

BACKGROUND: The combination of hepatic ischemia and cholestasis, both identified as risk factors for oxidative stress, potentially enhances postischemic reperfusion (I/R) injury. Preoperative biliary drainage relieves oxidative stress and therefore seems a worthwhile intervention in cholestatic patients undergoing major liver resection. AIM: To assess the effect of biliary decompression on I/R injury in a reversible bile duct ligation (BDL) model in the rat. METHODS: Male Wistar rats were randomized into 3 groups. The first group underwent 30 minutes of partial liver ischemia after 7 days BDL; the second group underwent internal drainage (ID) after 7 days BDL and after 5 days, were subjected to partial liver ischemia. The last group (control animals) underwent 2 sham laparotomies and subsequent ischemia. Inflammatory response (interleukin [IL]-6, IL-10, GRO/KC, and interferon-gamma), hepatic damage and oxidative stress were assessed during 24 hours of reperfusion. RESULTS: Cholestatic rats, as compared with the ID and control groups, showed significantly increased I/R injury as determined by transaminase release, histologic injury score and neutrophil infiltration. Plasma IL-6, IL-10, and GRO/KC (a CXC chemokine) were significantly increased in the BDL group (P < .05 vs control and ID). Moreover, the hepatic antioxidant capacity was strongly decreased in the BDL group (P < .01 vs control and ID). No significant differences for most parameters were seen in the ID group as compared to the control group. CONCLUSION: The cholestatic rat is more susceptible to postischemic liver injury and these injurious effects were significantly attenuated by biliary decompression.

Extra-hepatic factor VIII expression in porcine fulminant hepatic failure.

In humans, fulminant hepatic failure (FHF) is frequently associated with increased factor VIII (FVIII) levels, despite widespread liver cell death. The mechanisms leading to increased FVIII levels and cellular sites of this enhanced FVIII production are poorly understood. We studied the effect of total hepatectomy in pigs, a large-animal model of FHF, on the expression of plasma and tissue FVIII during 24-hour follow-up. Tissue FVIII expression was determined before and 24 h after hepatectomy, both at the mRNA level and immunohistochemically. The expression of plasma and tissue von Willebrand factor (VWF), the natural stabilizing carrier protein of FVIII, was also measured. Total hepatectomy elicited a gradual and sustained twofold elevation of circulating FVIII, whereas FVIII mRNA levels in various organs did not increase after hepatectomy. The half-life of FVIII increased from 7.7 to 10.3 h and VWF levels were also elevated in anhepatic pigs. The increase in the half-life of FVIII and increased levels of VWF were not sufficient to explain the rise in plasma FVIII levels. At the protein level, prominent changes in the cellular distribution of FVIII were seen in spleen and kidney. These observations suggest that in this model of FHF the lack of hepatic FVIII synthesis is adequately compensated by other organs, notably spleen and kidneys.