Krijn P. van Lienden

Endovascular Thrombectomy and Thrombolysis for Severe Cerebral Sinus Thrombosis : A Prospective Study

Background and Purpose— Most patients with cerebral sinus thrombosis (CST) recover after treatment with heparin, but a subgroup has a poor prognosis. Those patients may benefit from endovascular thrombolysis. Methods— Prospective case series. Patients with sinus thrombosis were selected for thrombolysis if they had an altered mental status, coma, straight sinus thrombosis, or large space-occupying lesions. Urokinase was infused into the sinuses (bolus 120 to 600×103 U; then 100×103 U/h) via a jugular catheter, in 15 cases combined with mechanical thrombus disruption or removal. Results— We treated 20 patients (16 women), mean age 32 years. Twelve patients were comatose and 14 had hemorrhagic infarcts before thrombolysis. Twelve patients recovered (Rankin score 0 to 2), 2 survived with handicaps, and 6 died. Factors associated with a fatal outcome were leukemia (3/6 versus 0/14, P=0.02) and large hemorrhagic infarcts (4/6 versus 2/14, P=0.04). Seizures were less frequent in the fatal cases (P=0.05). Patients who died had a larger mean lesion surface than survivors (30.5 versus 13.6 cm2; P=0.03), larger midline shift (5.2 versus 1.7 mm; P=0.02), and a more rapid course (2.7 versus 8.2 days; P=0.01). Five patients who died had large hemispheric infarcts and edema before thrombolysis, causing herniation. Five patients had increased cerebral hemorrhage (3 minor, 2 major) after thrombolysis. Conclusions— Thrombolysis can be effective for severe sinus thrombosis, but patients may deteriorate because of increased cerebral hemorrhage. Patients with large infarcts and impending herniation did not benefit.

Risk Assessment of Posthepatectomy Liver Failure Using Hepatobiliary Scintigraphy and CT Volumetry

A major part of morbidity and mortality after liver resections is caused by inadequate remnant liver function leading to liver failure. It is therefore important to develop accurate diagnostic tools that can predict the risk of liver resection–related morbidity and mortality. In this study, preoperative hepatobiliary scintigraphy of the future remnant liver and CT volumetric measurement of the future remnant liver were performed on patients who were to undergo liver resection. The accuracy of risk assessment for postoperative morbidity, liver failure, and mortality was evaluated. Methods: Forty-six patients who were scheduled for liver resection because of hepatobiliary tumors, including 17 patients with parenchymal disease (37%) and 13 patients with hilar cholangiocarcinoma (28%), were assessed preoperatively. Hepatobiliary scintigraphy was performed by drawing regions of interest around the future remnant to calculate 99mTc-mebrofenin uptake in it. CT volumetry was used to measure the volume of the total liver, the tumors, and the future remnant. Receiver-operating-characteristic analysis was performed to assess cutoff values for risk assessment of morbidity, liver failure, and mortality. Furthermore, univariate and multivariate analyses were performed to determine factors related to morbidity and mortality. Results: Morbidity and mortality rates were 61% and 11%, respectively. Liver failure occurred in 6 patients (13%). Significantly decreased uptake in the future remnant was found in patients in whom liver failure and liver failure–related mortality developed (P = 0.003 and 0.02, respectively). The volume of the future remnant was not significantly associated with any of the outcome parameters. In receiver-operating-characteristic analysis, uptake cutoff values for liver failure and liver failure–related mortality were 2.5%/min/body surface area and 2.2%/min/body surface area, respectively. In multivariate analysis, uptake was the only significant factor associated with liver failure. Conclusion: Preoperative measurement of 99mTc-mebrofenin uptake in the future remnant liver on hepatobiliary scintigraphy proved more valuable than measurement of the volume of the future remnant on CT in assessing the risk of liver failure and liver failure–related mortality after partial liver resection.

Tumor progression after preoperative portal vein embolization.

Objective:To evaluate tumor growth in a series of patients undergoing liver resection after portal vein embolization (PVE). Background:The regenerative response after PVE leading to compensatory hypertrophy of the nonembolized liver segments potentially enhances tumor growth. Methods:Portal vein embolization was performed in 28 patients diagnosed with colorectal metastases between 2004 and 2011. Tumor volume was measured by computed tomography (CT) volumetry before and after PVE. Tumor growth rate (TGR) was measured by CT volumetry and compared with that of a non-PVE control group with colorectal metastases of whom 30 had 2 CT scans preoperatively. Also, newly diagnosed tumors in the future remnant liver (FRL) after PVE and after resection were analyzed. Results:The median TGR of PVE patients was 0.53 mL/d (interquartile range [IQR], 0.02–1.88) versus 0.09 mL/d (IQR, −0.04 to 0.40; P = 0.03) in non-PVE patients. The TGR was 0.15 (IQR, −0.52 to 0.66) mL/d before PVE and 0.85 (IQR, −0.10 to 1.62) mL/d after PVE in the same patients (P = 0.03). Seven patients (25%) showed new tumor lesions in the FRL after PVE, of whom 3 patients (11%) were not resectable. Patients (8 of 19; 42%) after PVE also showed a higher rate of recurrent metastases in the remnant liver at follow-up than non-PVE patients (1 of 28; 4%). Survival was significantly better for non-PVE patients, with a 3-year survival rate of 77% versus 26% in patients undergoing PVE. Conclusions:Portal vein embolization is associated with increased TGR and new tumor in the FRL and recurrent tumor after resection. Short intervals and interval chemotherapy between PVE and resection are, therefore, advised.

Controversies in the Use of Portal Vein Embolization

Background/Aims: Portal vein embolization (PVE) has reached worldwide acceptance to increase future remnant liver (FRL) volume before undertaking major liver resection. The aim of this overview is to point out and discuss current controversies in the application of PVE. Methods: Review of literature pertaining to techniques of PVE, complications, tumor proliferation, timing of resection, and hypertrophy response after PVE. Results: Procedure-related complications after PVE include hematoma, hemobilia, overflow of embolization material, and thrombosis of portal vein branch(es) of the non-embolized lobe. Persistence of the embolized, atrophic lobe is usually not harmful. Embolization of the portal branches to segment 4 in addition to embolization of the right portal trunk is controversial and is advised only in selected cases. It remains undecided whether embolization of the portal venous system is more effective in inducing hypertrophy of the FRL than ligation of the portal vein. Accelerated tumor growth after PVE is a major concern and requires consideration of post-PVE chemotherapy. A waiting time of 3 weeks between PVE and liver resection is advised. Post-hepatectomy regeneration is not hampered after preoperative PVE. Conclusion: PVE is a useful preoperative intervention to increase volume and function of the FRL. Further progress awaits clarification of the mechanisms of the hypertrophy response induced by PVE in conjunction with new embolization materials and protective chemotherapy.

Liver Regeneration After Portal Vein Embolization Using Absorbable and Permanent Embolization Materials in a Rabbit Model

Objective: To compare the safety and hypertrophy response after portal vein embolization (PVE) using 2 absorbable and 3 permanent embolization materials. Background: Portal vein embolization is used to increase future remnant liver volume preoperatively. Application of temporary, absorbable embolization materials could be advantageous in some situations, provided sufficient hypertrophy is achieved from the nonembolized lobe. Methods: Six groups of rabbits (n = 5) underwent PVE of 80% of the total liver volume using saline (sham), gelatin sponge, fibrin glue, polyvinyl alcohol particles with coils, n-butyl cyanoacrylate, or polidocanol. The rabbits were killed after 7 days. Portography, computed tomographic volumetry, Doppler ultrasonography, laboratory liver function and damage parameters (nonembolized) liver-to-body weight ratio, immunohistochemistry, and cytokine and growth factor tissue levels were assessed to examine the differences in the liver regeneration response. Results: Polidocanol was discontinued because of toxic reactions in 3 rabbits. Gelatin sponge was the only material that was absorbed after 7 days and resulted in less hypertrophy of the nonembolized lobe than the other 3 materials. There were no significant differences in hypertrophy response between the other 3 embolization groups. Volumetric data obtained from computed tomography were supported by liver-to-body weight ratio and the amount of proliferating hepatocytes. The volume gain of the nonembolized lobe was proportional to the volume loss of the embolized liver lobes. The number of Kupffer cells in the embolized liver lobe was significantly higher in the fibrin glue, polyvinyl alcohol particles with coils, and n-butyl cyanoacrylate groups than in the sham and gelatin sponge groups. However, the levels of interleukin-6, tumor necrosis factor-&agr;, hepatocyte growth factor, and transforming growth factor-&bgr;1 were significantly lower. Conclusions: Temporary occlusion using gelatin sponge for PVE resulted in significantly less hypertrophy response than the use of permanent embolization materials. Except for polidocanol, none of the embolization materials exhibited evident hepatotoxicity.

Endoscopic or surgical step-up approach for infected necrotising pancreatitis: a multicentre randomised trial

BACKGROUND Infected necrotising pancreatitis is a potentially lethal disease and an indication for invasive intervention. The surgical step-up approach is the standard treatment. A promising alternative is the endoscopic step-up approach. We compared both approaches to see whether the endoscopic step-up approach was superior to the surgical step-up approach in terms of clinical and economic outcomes. METHODS In this multicentre, randomised, superiority trial, we recruited adult patients with infected necrotising pancreatitis and an indication for invasive intervention from 19 hospitals in the Netherlands. Patients were randomly assigned to either the endoscopic or the surgical step-up approach. The endoscopic approach consisted of endoscopic ultrasound-guided transluminal drainage followed, if necessary, by endoscopic necrosectomy. The surgical approach consisted of percutaneous catheter drainage followed, if necessary, by video-assisted retroperitoneal debridement. The primary endpoint was a composite of major complications or death during 6-month follow-up. Analyses were by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN09186711. FINDINGS Between Sept 20, 2011, and Jan 29, 2015, we screened 418 patients with pancreatic or extrapancreatic necrosis, of which 98 patients were enrolled and randomly assigned to the endoscopic step-up approach (n=51) or the surgical step-up approach (n=47). The primary endpoint occurred in 22 (43%) of 51 patients in the endoscopy group and in 21 (45%) of 47 patients in the surgery group (risk ratio [RR] 0·97, 95% CI 0·62-1·51; p=0·88). Mortality did not differ between groups (nine [18%] patients in the endoscopy group vs six [13%] patients in the surgery group; RR 1·38, 95% CI 0·53-3·59, p=0·50), nor did any of the major complications included in the primary endpoint. INTERPRETATION In patients with infected necrotising pancreatitis, the endoscopic step-up approach was not superior to the surgical step-up approach in reducing major complications or death. The rate of pancreatic fistulas and length of hospital stay were lower in the endoscopy group. The outcome of this trial will probably result in a shift to the endoscopic step-up approach as treatment preference. FUNDING The Dutch Digestive Disease Foundation, Fonds NutsOhra, and the Netherlands Organization for Health Research and Development.

Portal vein embolization induces more liver regeneration than portal vein ligation in a standardized rabbit model

BACKGROUND Portal vein ligation (PVL) and portal vein embolization (PVE) are used to induce hypertrophy of the future remnant liver before major liver resection. The aim of our study was to compare the hypertrophy response of the liver after PVL versus PVE in a rabbit model. METHODS Twenty rabbits were divided into an embolization group (n = 10) and a ligation group (n = 10). Both groups were divided in 2 subgroups of 5 rabbits that were humanely killed after days 7 and 14. The portal vein branches to the 3 cranial liver lobes (80% of the liver) were occluded. Regeneration of the caudal liver lobe was measured using volumetry based on computed tomography on days 3, 7, 10, and 14. Immunohistochemistry for Ki-67 and RAM11 was performed to quantify proliferating cells and macrophages. In addition, tissue tumor necrosis factor-α and interleukin-6 were assessed. RESULTS The caudal liver volume increased over time in both groups (P < .001), but this increase was greater after PVE than after PVL (P = .001) with a mean degree of hypertrophy of 15% ± 4% and 20% ± 2%, respectively. When comparing the groups on the separate time points, a difference was found on days 10 and 14 (P = .008 and P = .016, respectively). These data were confirmed by Ki-67 staining, which showed a greater number of proliferating hepatocytes on day 7 after embolization (P = .016). Cytokine analysis of liver tissue did not show significant differences between the ligation and embolization groups on days 7 and 14. CONCLUSION PVE is superior to PVL in terms of the extent of the hypertrophy response in this rabbit model.

Treatment strategies in colorectal cancer patients with initially unresectable liver-only metastases, a study protocol of the randomised phase 3 CAIRO5 study of the Dutch Colorectal Cancer Group (DCCG)

BackgroundColorectal cancer patients with unresectable liver-only metastases may be cured after downsizing of metastases by neoadjuvant systemic therapy. However, the optimal neoadjuvant induction regimen has not been defined, and the lack of consensus on criteria for (un)resectability complicates the interpretation of published results.Methods/designCAIRO5 is a multicentre, randomised, phase 3 clinical study. Colorectal cancer patients with initially unresectable liver-only metastases are eligible, and will not be selected for potential resectability. The (un)resectability status is prospectively assessed by a central panel consisting of at least one radiologist and three liver surgeons, according to predefined criteria. Tumours of included patients will be tested for RAS mutation status. Patients with RAS wild type tumours will be treated with doublet chemotherapy (FOLFOX or FOLFIRI) and randomised between the addition of either bevacizumab or panitumumab, and patients with RAS mutant tumours will be randomised between doublet chemotherapy (FOLFOX or FOLFIRI) plus bevacizumab or triple chemotherapy (FOLFOXIRI) plus bevacizumab. Radiological evaluation to assess conversion to resectability will be performed by the central panel, at an interval of two months.The primary study endpoint is median progression-free survival. Secondary endpoints are the R0/1 resection rate, median overall survival, response rate, toxicity, pathological response of resected lesions, postoperative morbidity, and correlation of baseline and follow-up evaluation with respect to outcomes by the central panel.DiscussionCAIRO5 is a prospective multicentre trial that investigates the optimal systemic induction therapy for patients with initially unresectable, liver-only colorectal cancer metastases.Trial registrationCAIRO 5 is registered at European Clinical Trials Database (EudraCT) (2013-005435-24).CAIRO 5 is registered at ClinicalTrials.gov: NCT02162563, June 10, 2014.

Brief Report: Altered Innate Lymphoid Cell Subsets in Human Lymph Node Biopsy Specimens Obtained During the At‐Risk and Earliest Phases of Rheumatoid Arthritis

Innate lymphoid cells (ILCs) are emerging mediators of immunity, and accumulation of inflammatory ILC populations can occur in inflammatory‐mediated conditions. Since early lymph node (LN) activation has been shown in rheumatoid arthritis (RA), we aimed to investigate the frequency and distribution of ILCs in LN biopsy specimens obtained during the earliest phases of RA.

The influence of a metal stent on the distribution of thermal energy during irreversible electroporation

Purpose Irreversible electroporation (IRE) uses short duration, high-voltage electrical pulses to induce cell death via nanoscale defects resulting from altered transmembrane potential. The technique is gaining interest for ablations in unresectable pancreatic and hepatobiliary cancer. Metal stents are often used for palliative biliary drainage in these patients, but are currently seen as an absolute contraindication for IRE due to the perceived risk of direct heating of the metal and its surroundings. This study investigates the thermal and tissue viability changes due to a metal stent during IRE. Methods IRE was performed in a homogeneous tissue model (polyacrylamide gel), without and with a metal stent placed perpendicular and parallel to the electrodes, delivering 90 and 270 pulses (15–35 A, 90 μsec, 1.5 cm active tip exposure, 1.5 cm interelectrode distance, 1000–1500 V/cm, 90 pulses/min), and in-vivo in a porcine liver (4 ablations). Temperature changes were measured with an infrared thermal camera and with fiber-optic probes. Tissue viability after in-vivo IRE was investigated macroscopically using 5-triphenyltetrazolium chloride (TTC) vitality staining. Results In the gel, direct stent-heating was not observed. Contrarily, the presence of a stent between the electrodes caused a higher increase in median temperature near the electrodes (23.2 vs 13.3°C [90 pulses]; p = 0.021, and 33.1 vs 24.8°C [270 pulses]; p = 0.242). In-vivo, no temperature difference was observed for ablations with and without a stent. Tissue examination showed white coagulation 1mm around the electrodes only. A rim of vital tissue remained around the stent, whereas ablation without stent resulted in complete tissue avitality. Conclusion IRE in the vicinity of a metal stent does not cause notable direct heating of the metal, but results in higher temperatures around the electrodes and remnant viable tissue. Future studies should determine for which clinical indications IRE in the presence of metal stents is safe and effective.