The Use of 18F-FET-PET-MRI in Neuro-Oncology: The Best of Both Worlds-A Narrative Review.

Gliomas are the most frequent primary tumors of the brain. They can be divided into grade II-IV astrocytomas and grade II-III oligodendrogliomas, based on their histomolecular profile. The prognosis and treatment is highly dependent on grade and well-identified prognostic and/or predictive molecular markers. Multi-parametric MRI, including diffusion weighted imaging, perfusion, and MR spectroscopy, showed increasing value in the non-invasive characterization of specific molecular subsets of gliomas. Radiolabeled amino-acid analogues, such as 18F-FET, have also been proven valuable in glioma imaging. These tracers not only contribute in the diagnostic process by detecting areas of dedifferentiation in diffuse gliomas, but this technique is also valuable in the follow-up of gliomas, as it can differentiate pseudo-progression from real tumor progression. Since multi-parametric MRI and 18F-FET PET are complementary imaging techniques, there may be a synergistic role for PET-MRI imaging in the neuro-oncological imaging of primary brain tumors. This could be of value for both primary staging, as well as during treatment and follow-up.

The orange-III study: the use of preoperative laxatives prior to liver surgery in an enhanced recovery programme, a randomized controlled trial.

BACKGROUND: This study evaluates the effect of preoperative macrogol on gastrointestinal recovery and functional recovery after liver surgery combined with an enhanced recovery programme in a randomized controlled setting. METHODS: Patients were randomized to either 1 sachet of macrogol a day, one week prior to surgery versus no preoperative laxatives. Postoperative management for all patients was within an enhanced recovery programme. The primary outcome was recovery of gastrointestinal function, defined as Time to First Defecation. Secondary outcomes included Time to Functional Recovery. RESULTS: Between August 2012 and September 2016, 82 patients planned for liver resection were included in the study, 39 in the intervention group and 43 in the control group. Median Time to First Defecation was 4.0 days in the intervention group (IQR 2.8-5.0) and 4.0 days in the control group (IQR 2.9-5.0), P = 0.487. Median Time to Functional Recovery was day 6 (IQR 4.0-8.0) in the intervention group and day 5 (IQR 4.0-7.5) in the control group, P = 0.752. No significant differences were seen in complication rate, reinterventions or mortality. CONCLUSION: This randomized controlled trial showed no advantages of 1 sachet of macrogol preoperatively combined with an enhanced recovery programme, for patients undergoing liver surgery.

Bile Salt and FGF19 Signaling in the Early Phase of Human Liver Regeneration.

The involvement of bile salt-fibroblast growth factor 19 (FGF19) signaling in human liver regeneration (LR) is not well studied. Therefore, we studied aspects of bile salt-FGF19 signaling shortly after liver resection in patients. We compared plasma bile salt and FGF19 levels in arterial, portal and hepatic venous blood, calculated venous-arterial differences (ΔVA), and determined hepatic transcript levels on two intra-operative time points: before (< 1 hour) and immediately after (> 2-3 hours) liver resection (i.e., following surgery). Postoperative bile salt and FGF19 levels were assessed on days 1, 2, and 3. LR was studied by computed tomography (CT)-liver volumetry. Following surgery, the liver, arterial, and portal bile salt levels were elevated (P < 0.05). Furthermore, an increased amount of bile salts was released in portal blood and extracted by the remnant liver (P < 0.05). Postoperatively, bile salt levels were elevated from day 1 onward (P < 0.001). For FGF19, intra-operative or postoperative changes of ΔVA or plasma levels were not observed. The bile salt-homeostatic regulator farnesoid X receptor (FXR) was markedly up-regulated following surgery (P < 0.001). Cell-cycle re-entry priming factors (interleukin 6 [IL-6], signal transducer and activator of transcription 3 [STAT3], and cJUN) were up-regulated following surgery and were positively correlated with FXR expression (P < 0.05). Postoperative hyperbilirubinemia was preceded by postsurgery low FXR and high Na+/Taurocholate cotransporting polypeptide (NTCP) expression in the remnant liver coupled with higher liver bile salt content (P < 0.05). Finally, bile salt levels on postoperative day 1 were an independent predictor of LR (P < 0.05). Conclusion: Systemic, portal, and liver bile salt levels are rapidly elevated after liver resection. Postoperative bile salts were positively associated with liver volume gain. In the studied time frame, FGF19 levels remained unaltered, suggesting that FGF19 plays a minor role in human LR. These findings indicate a more relevant role of bile salts in human LR.

The reproducibility of skeletal muscle signal intensity on routine magnetic resonance imaging in Crohn's disease.

BACKGROUND AND AIM: Myosteatosis is a prognostic factor in cancer and liver cirrhosis. It can be determined noninvasively using computed tomography or, as shown recently, by magnetic resonance (MR) imaging. The primary aim was to analyze the reproducibility of skeletal muscle signal intensity on routine MR-enterographies, as indicator of myosteatosis, in Crohn's disease (CD) and to explore the association between skeletal muscle signal intensity at diagnosis with time to intestinal resection. METHODS: CD patients undergoing MR-enterography within 6 months from diagnosis and having a maximum of 5 years follow-up were included. Skeletal muscle signal intensity was analyzed on T1-weighted fat-saturated post-contrast images. Intra-observer and inter-observer reproducibilities were assessed by intra-class correlation coefficient and Cohen's kappa. Intra-observer and inter-observer variabilities were determined by Pearson correlation coefficient and displayed by Bland-Altman plots. Time to intestinal resection was studied by Kaplan-Meier analysis. RESULTS: Median time between diagnosis and MR-enterography was 5 weeks (inter-quartile range 1-9) in 35 CD patients. Skeletal muscle signal intensity showed good intra-class correlation and substantial agreement (for intra-observer, intraclass correlation coefficient = 0.948, κ = 0.677; and inter-observer reproducibility, intraclass correlation coefficient = 0.858, κ = 0.622). Resection free survival was shorter in the low skeletal muscle signal intensity group (P = 0.037). CONCLUSION: Skeletal muscle signal intensity on routine MR-enterographies is reproducible and was associated with unfavorable disease outcome, indicating potential clinical relevance.

Impact of chemotherapy-associated liver injury on tumour regression grade and survival in patients with colorectal liver metastases.

BACKGROUND: An inverse relation between chemotherapy-associated liver injury (CALI) and tumour response to chemotherapy has been reported. The aim was to validate these findings, and further investigate the impact of CALI on survival in patients who underwent partial hepatectomy for colorectal liver metastases (CRLM). METHODS: Patients who received neoadjuvant chemotherapy and underwent partial hepatectomy for CRLM between 2008 and 2014 were included. Liver and tumour specimens were histologically examined for CALI (steatosis, steatohepatitis, sinusoidal dilatation [SD], nodular regeneration) and tumour regression grade (TRG). TRG 1-2 was defined as complete tumour response. RESULTS: 166 consecutive patients were included with a median survival of 30 and 44 months for recurrence-free and overall survival, respectively. Grade 2-3 SD was found in 44 (27%) and TRG 1-2 was observed in 33 (20%) patients. Of studied CALI, only grade 2-3 SD was associated with increased TRG 3-5 (odds ratio 3.99, 95% CI 1.17-13.65, p = 0.027). CALI was not significantly related to survival. TRG 1-2 was associated with prolonged recurrence-free (hazard ratio 0.47, 95% CI 0.25-0.89, p = 0.020) and overall survival (hazard ratio 0.35, 95% CI 0.18-0.68, p = 0.002). CONCLUSION: CALI was not directly related to survival. CALI was, however, associated with diminished complete tumour response, and diminished complete tumour response, in turn, was associated with decreased survival.

Abandoning Prophylactic Abdominal Drainage after Hepatic Surgery: 10 Years of No-Drain Policy in an Enhanced Recovery after Surgery Environment.

BACKGROUND: Routine prophylactic abdominal drainage after hepatic surgery is still being debated, as it may be unnecessary, possibly harmful, and uncomfortable for patients. This study evaluated the safety of a no-drain policy after liver resection within an Enhanced Recovery after Surgery (ERAS) programme. METHODS: All hepatectomies performed without prophylactic drainage during 2005-2014 were included. Primary end points were resection-surface-related (RSR) morbidity, defined as the presence of postoperative biloma, hemorrhage or abscess, and reinterventions. Secondary end points were length of stay, total postoperative morbidity, the composite end point of liver surgery-specific complications, readmissions, and 90-day mortality. Uni- and multivariate analyses were performed to identify independent risk factors for RSR morbidity. A systematic search was performed to compare the results of this study to literature. RESULTS: A total of 538 resections were included in the study. The RSR complication and reintervention rate was 15 and 12%, respectively. Major liver resection (≥3 segments) was an independent risk factor for the development of RSR morbidity (OR 3.01, 95% CI 1.61-5.62; p = 0.001) and need for RSR reintervention (OR 3.02, 95% CI 1.59-5.73; p = 0.001). CONCLUSION: RSR morbidity, mortality, and reintervention rates after liver surgery without prophylactic drainage in patients, treated within an ERAS programme, were comparable to previously published data. A no-drain policy after partial hepatectomy seems safe and feasible.

Fast and accurate liver volumetry prior to hepatectomy.

BACKGROUND: Volumetric assessment of the liver is essential in the prevention of postresectional liver failure after partial hepatectomy. Currently used methods are accurate but time-consuming. This study aimed to test a new automated method for preoperative volumetric liver assessment. METHODS: Patients who underwent a contrast enhanced portovenous phase CT-scan prior to hepatectomy in 2012 were included. Total liver volume (TLV) and future remnant liver volume (FRLV) were measured using TeraRecon Aquarius iNtuition(®) (autosegmentation) and OsiriX(®) (manual segmentation) software by two observers for each software package. Remnant liver volume percentage (RLV%) was calculated. Time needed to determine TLV and FRLV was measured. Inter-observer variability was assessed using Bland-Altman plots. RESULTS: Twenty-seven patients were included. There were no significant differences in measured volumes between OsiriX(®) and iNtuition(®). Moreover, there were significant correlations between the OsiriX(®) observers, the iNtuition(®) observers and between OsiriX(®) and iNtuition(®) post-processing systems (all R(2) > 0.97). The median time needed for complete liver volumetric analysis was 18.4 ± 4.9 min with OsiriX(®) and 5.8 ± 1.7 min using iNtuition(®) (p < 0.001). CONCLUSION: Both OsiriX(®) and iNtuition(®) liver volumetry are accurate and easily applicable. However, volumetric assessment of the liver with iNtuition(®) auto-segmentation is three times faster compared to manual OsiriX(®) volumetry.

Validation of the peak bilirubin criterion for outcome after partial hepatectomy.

INTRODUCTION: Postoperative liver failure (PLF) is a dreaded complication after partial hepatectomy. The peak bilirubin criterion (>7.0 mg/dL or ≥120 µmol/L) is used to define PLF. This study aimed to validate the peak bilirubin criterion as postoperative risk indicator for 90-day liver-related mortality. METHODS: Characteristics of 956 consecutive patients who underwent partial hepatectomy at the Maastricht University Medical Centre or Royal Free London between 2005 and 2012 were analyzed by uni- and multivariable analyses with odds ratios (OR) and 95% confidence intervals (95%CI). RESULTS: Thirty-five patients (3.7%) met the postoperative peak bilirubin criterion at median day 19 with a median bilirubin level of 183 [121-588] µmol/L. Sensitivity and specificity for liver-related mortality after major hepatectomy were 41.2% and 94.6%, respectively. The positive predictive value was 22.6%. Predictors of liver-related mortality were the peak bilirubin criterion (p < 0.001, OR = 15.9 [95%CI 5.2-48.7]), moderate-severe steatosis and fibrosis (p = 0.013, OR = 8.5 [95%CI 1.6-46.6]), ASA 3-4 (p = 0.047, OR = 3.0 [95%CI 1.0-8.8]) and age (p = 0.044, OR = 1.1 [95%CI 1.0-1.1]). CONCLUSION: The peak bilirubin criterion has a low sensitivity and positive predictive value for 90-day liver-related mortality after major hepatectomy.

Sarcopenia, obesity and sarcopenic obesity: effects on liver function and volume in patients scheduled for major liver resection.

BACKGROUND: Sarcopenia, obesity and sarcopenic obesity have been linked to impaired outcome after liver surgery. Preoperative liver function of sarcopenic, obese and sarcopenic-obese patients might be reduced, possibly leading to more post-operative morbidity. The aim of this study was to explore whether liver function and volume were influenced by body composition in patients undergoing liver resection. METHODS: In 2011 and 2012, all consecutive patients undergoing the methacetin breath liver function test were included. Liver volumetry and muscle mass analysis were performed using preoperative CT scans and Osirix(®) software. Muscle mass and body-fat% were calculated. Predefined cut-off values for sarcopenia and the top two body-fat% quintiles were used to identify sarcopenia and obesity, respectively. Histologic assessment of the resected liver gave insight in background liver disease. RESULTS: A total number of 80 patients were included. Liver function and volume were comparable in sarcopenic(-obese) and non-sarcopenic(-obese) patients. Obese patients showed significantly reduced liver function [295 (95-508) vs. 358 (96-684) µg/kg/h, P = 0.018] and a trend towards larger liver size [1694 (1116-2685) vs. 1533 (869-2852) mL, P = 0.079] compared with non-obese patients. Weight (r = -0.40), body surface area (r = -0.32), estimated body-fat% (r = -0.43) and body mass index (r = -0.47) showed a weak but significant negative (all P < 0.05) correlation with liver function. Moreover, body-fat% was identified as an independent factor negatively affecting the liver function. CONCLUSION: Sarcopenia and sarcopenic obesity did not seem to influence liver size and function negatively. However, obese patients had larger, although less functional, livers, indicating dissociation of liver function and volume in these patients.

Are sarcopenia, obesity and sarcopenic obesity predictive of outcome in patients with colorectal liver metastases?

BACKGROUND: The impact of body composition on outcomes after surgery for colorectal liver metastases (CRLM) remains unclear. The aim of the present study was to determine the influence of sarcopenia, obesity and sarcopenic obesity on morbidity, disease-free (DFS) and overall survival (OS). METHOD: Between 2005 and 2012, all patients undergoing a partial liver resection for CRLM in the Maastricht University Medical Centre, and who underwent computed tomography (CT) imaging within 3 months before liver surgery, were included. Body composition was primarily based on pre-operative CT measurements. Sarcopenia was based on total muscle area at the level of the third lumbar vertebra and predefined body mass index (BMI)- and gender-specific cut-off values for sarcopenia were used. Body fat percentages were calculated and the top 40% for men and women were considered obese. RESULTS: Of the 171 included patients undergoing liver surgery for CRLM, 80 (46.8%) patients were sarcopenic, 69 (40.4%) obese and 49 (28.7%) sarcopenic obese. The presence of sarcopenia, obesity or sarcopenic obesity did not affect the complication rates. However, readmission rates were significantly increased in patients with (sarcopenic) obesity (P < 0.05). Surprisingly, obesity seemed to prolong OS (P = 0.021) and was identified as an independent predictor [hazard ratio (HR):0.58 and P = 0.046] for better OS. Sarcopenia and sarcopenic obesity did not affect DFS or OS. CONCLUSION: Sarcopenia, obesity and sarcopenic obesity did not worsen DFS, OS and complication rates after a partial liver resection for CRLM.

Near-infrared fluorescence laparoscopy of the cystic duct and artery in pigs: performance of a preclinical dye.

BACKGROUND: Near-infrared fluorescence laparoscopy after intravenous indocyanine green (ICG) administration has been proposed as a promising surgical imaging technique for real-time visualization of the extrahepatic bile ducts and arteries in clinical laparoscopic cholecystectomies. However, optimization of this new technique with respect to the imaging system combined with the fluorophore is desirable. The performance of a preclinical near-infrared dye, CW800-CA, was compared with that of ICG for near-infrared fluorescence laparoscopy of the cystic duct and artery in pigs. MATERIALS AND METHODS: Laparoscopic cholecystectomy was performed in six pigs (average weight, 35 kg) using a commercially available laparoscopic fluorescence imaging system. The fluorophores CW800-CA and ICG (both 800 nm fluorescent dyes) were administered by intravenous injection in four and two pigs, respectively. CW800-CA was administered in three different doses (consecutively 0.25, 1, and 3 mg); ICG was intravenously injected (2.5 mg) for comparison. Intraoperative recognition of the biliary structures was recorded at set time points. The target-to-background ratio was determined to quantify the fluorescence signal of the designated tissues. RESULTS: A clinically proven dose of 2.5 mg of ICG resulted in a successful fluorescence delineation of both the cystic duct and artery. In the CW800-CA-injected pigs a clear visualization of the cystic duct and artery was obtained after administration of 3 mg of CW800-CA. Time from injection until fluorescence identification of the cystic duct was reduced when CW800-CA was used compared with ICG (11.5 minutes versus 21.5 minutes, respectively). CW800-CA provided clearer illumination of the cystic artery, in terms of target-to-background ratio. CONCLUSIONS: As well as ICG, CW800-CA can be applied for fluorescence identification of the cystic artery and duct using a commercially available laparoscopic fluorescence imaging system. Fluorescence cholangiography of the cystic duct can be obtained earlier after intravenous injection of CW800-CA, compared with ICG. These findings increase the possibilities of use and of optimization of this imaging technique.

Application of a new dye for near-infrared fluorescence laparoscopy of the ureters: demonstration in a pig model.

BACKGROUND: Ureteral injury during laparoscopic colorectal surgery is a rare but serious complication with a reported incidence rate of 0.66%. The early detection and prevention of ureteral injury is clinically relevant and important. The successful use of preclinical near-infrared fluorophore CW800-CA for real-time intraoperative identification of the anatomical course of the ureters with the use of a laparoscopic fluorescence imaging system is reported. METHODS: The usefulness of this new imaging technique was explored in two 35-kg pigs. Intravenous CW800-CA was administered 10 minutes before fluorescence imaging was conducted with the use of a commercially available laparoscopic fluorescence imaging system. RESULTS: A dose of 1 mg/mL CW800-CA (bolus injection of 3 mL) provided clear delineation of the course of both ureters by using the fluorescence mode of the laparoscope. There were no adverse reactions to the injected dye. CONCLUSION: Near-infrared fluorescence laparoscopy of the ureters, following intravenous CW800-CA administration, is easily applicable and provides real-time identification of the course of the ureters.

Outcomes of extended versus limited indications for patients undergoing a liver resection for colorectal cancer liver metastases.

BACKGROUND: Currently, resection criteria for colorectal cancer liver metastases (CRCLM) are only limited by remnant liver function. Morbidity and survival after a partial hepatectomy with limited or extended indication criteria were compared. METHODS/DESIGN: Between 1991 and 2010, patients undergoing a liver resection for CRCLM with limited (n = 169) or extended indication criteria (n = 129) were retrospectively identified in a prospectively collected single-centre database. Limited indication criteria were defined as less than three unilateral, not centrally located liver metastases in the absence of extra hepatic metastases. The extended criteria were only limited by predicted remnant liver volume and patients fitness. Data on co-morbidity, resection margin, short- and long-term morbidity, disease-free (DFS) and overall survival were compared. RESULTS: Patients with limited indications had less major complications (19.5% vs. 33.1%, P < 0.01), longer overall survival of 68.8 months [confidence interval (CI) 46.5-91.1] vs. 41.4 months (CI 33.4-49.0, P ≤ 0.001) and longer median DFS of 22.0 months [confidence interval (CI) 15.8-28.2] vs 10.2 months (CI 8.4-11.9, P < 0.001) compared with the extended indication group. Cure rates, defined as 10-year DFS, were 35.5% and 15.8%, respectively. Fewer patients in the extended indication group underwent an R0 resection (92.9% vs. 77.5%, P < 0.001). Only 17% of all R1 resected patients had recurrences at the transection plane. CONCLUSION: A partial hepatectomy for CRCLM with extended indications seems justified but is associated with higher complication rates, earlier recurrence and lower overall survival compared with limited indications. However, the median 5-year survival was substantial and a cure was achieved in 15.8% of patients.

Sarcopenia negatively affects preoperative total functional liver volume in patients undergoing liver resection.

OBJECTIVES: Sarcopenia may negatively affect short-term outcomes after liver resection. The present study aimed to explore whether total functional liver volume (TFLV) is related to sarcopenia in patients undergoing partial liver resection. METHODS: Analysis of total liver volume and tumour volume and measurements of muscle surface were performed in patients undergoing liver resection using OsiriX(®) and preoperative computed tomography. The ratio of TFLV to bodyweight was calculated as: [TFLV (ml)/bodyweight (g)]*100%. The L3 muscle index (cm(2) /m(2) ) was then calculated by normalizing muscle areas (at the third lumbar vertebral level) for height. RESULTS: Of 40 patients, 27 (67.5%) were classified as sarcopenic. There was a significant correlation between the L3 skeletal muscle index and TFLV (r= 0.64, P < 0.001). Median TFLV was significantly lower in the sarcopenia group than in the non-sarcopenia group [1396 ml (range: 1129-2625 ml) and 1840 ml (range: 867-2404 ml), respectively; P < 0.05]. Median TFLV : bodyweight ratio was significantly lower in the sarcopenia group than in the non-sarcopenia group [2.0% (range: 1.4-2.5%) and 2.3% (range: 1.5-2.5%), respectively; P < 0.05]. CONCLUSIONS: Sarcopenic patients had a disproportionally small preoperative TFLV compared with non-sarcopenic patients undergoing liver resection. The preoperative hepatic physiologic reserve may therefore be smaller in sarcopenic patients.

A survey in the hepatopancreatobiliary community on ways to enhance patient recovery.

OBJECTIVES: Both laparoscopic techniques and multimodal enhanced recovery programmes have been shown to improve recovery and reduce length of hospital stay. Interestingly, evidence-based care programmes are not widely implemented, whereas new, minimally invasive surgical procedures are often adopted with very little evidence to support their effectiveness. The present survey aimed to shed light on experiences of the adoption of both methods of optimizing recovery. METHODS: An international, web-based, 18-question, electronic survey was composed in 2010. The survey was sent out to 673 hepatopancreatobiliary (HPB) centres worldwide in June 2010 to investigate international experiences with laparoscopic liver surgery, fast-track recovery programmes and surgery-related equipoise in open and laparoscopic techniques and to assess opinions on strategies for adopting laparoscopic liver surgery in HPB surgical practice. RESULTS: A total of 507 centres responded (response rate: 75.3%), 161 of which finished the survey completely. All units reported performing open liver resections, 24.2% performed open living donor resections, 39.1% carried out orthotopic liver transplantations, 87.6% had experience with laparoscopic resections and 2.5% performed laparoscopic living donor resections. A median of 50 (range: 2-560) open and 9.5 (range: 1-80) laparoscopic liver resections per surgical unit were performed in 2009. Patients stayed in hospital for a median of 7 days (range: 2-15 days) after uncomplicated open liver resection and a median of 4 days (range: 1-10 days) after uncomplicated laparoscopic liver resection. Only 28.0% of centres reported having experience with fast-track programmes in liver surgery. The majority considered the instigation of a randomized controlled trial or a prospective register comparing the outcomes of open and laparoscopic techniques to be necessary. CONCLUSIONS: Worldwide dissemination of laparoscopic liver resection is substantial, although laparoscopic volumes are low in the majority of HPB centres. The adoption of enhanced recovery programmes in liver surgery is limited and should be given greater attention.

Laparoscopic liver resection in the Netherlands: how far are we?

BACKGROUND: The objective of this study was to provide a systematic review on the introduction of laparoscopic liver surgery in the Netherlands, to investigate the initial experience with laparoscopic liver resections and to report on the current status of laparoscopic liver surgery in the Netherlands. METHODS: A systematic literature search of laparoscopic liver resections in the Netherlands was conducted using PubMed/MEDLINE. Analysis of initial experience with laparoscopic liver surgery was performed by case-control comparison of patients undergoing laparoscopic left lateral sectionectomy matched with patients undergoing the open procedure in the Netherlands between the years 2000 and 2008. Furthermore, a nationwide survey was conducted in 2011 on the current status of laparoscopic liver surgery. RESULTS: The systematic review revealed only 6 Dutch reports on actual laparoscopic liver surgery. Matched case-control comparison showed significant differences in the length of hospital stay, blood loss and operation time. Complications did not differ significantly between the two groups (26 vs. 21%). The 2011 survey showed that 21 centers in the Netherlands performed formal liver resections and that 49 (5% of total) laparoscopic liver resections were performed in 2010. CONCLUSION: The systematic review revealed that very few laparoscopic liver resections were performed in the Netherlands in the previous millennium. The matched case-control comparison of laparoscopic and open left lateral resection showed a reduction in hospital length of stay with comparable morbidity. The laparoscopic technique has been slowly adopted in the Netherlands, but its popularity seems to increase in recent years.