Background Liver surgery for perihilar cholangiocarcinoma (PHC) is associated with postoperative mortality ranging from 5% to 18%. The aim of this study was to develop a preoperative risk score for ...postoperative mortality after liver resection for PHC, and to assess the effect of biliary drainage of the future liver remnant (FLR). Study Design A consecutive series of 287 patients submitted to major liver resection for presumed PHC between 1997 and 2014 at 2 Western centers was analyzed; 228 patients (79%) underwent preoperative drainage for jaundice. Future liver remnant volumes were calculated with CT volumetry and completeness of FLR drainage was assessed on imaging. Logistic regression was used to develop a mortality risk score. Results Postoperative mortality at 90 days was 14% and was independently predicted by age (odds ratio OR per 10 years = 2.1), preoperative cholangitis (OR = 4.1), FLR volume <30% (OR = 2.9), portal vein reconstruction (OR = 2.3), and incomplete FLR drainage in patients with FLR volume <50% (OR = 2.8). The risk score showed good discrimination (area under the curve = 0.75 after bootstrap validation) and ranking patients in tertiles identified 3 (ie low, intermediate, and high) risk subgroups with predicted mortalities of 2%, 11%, and 37%. No postoperative mortality was observed in 33 undrained patients with FLR volumes >50%, including 10 jaundiced patients (median bilirubin level 11 mg/dL). Conclusions The mortality risk score for patients with resectable PHC can be used for patient counseling and identification of modifiable risk factors, which include FLR volume, FLR drainage status, and preoperative cholangitis. We found no evidence to support preoperative biliary drainage in patients with an FLR volume >50%.
Background: Bile duct injury (BDI) is a devastating complication following cholecystectomy. After initial management of BDI, patients stay at risk for late complications including anastomotic ...strictures, recurrent cholangitis, and secondary biliary cirrhosis. Methods: We provide a comprehensive overview of current literature on the long-term outcome of BDI. Considering the availability of only limited data regarding treatment of anastomotic strictures in literature, we also retrospectively analyzed patients with anastomotic strictures following a hepaticojejunostomy (HJ) from a prospectively maintained database of 836 BDI patients. Results: Although clinical outcomes of endoscopic, radiologic, and surgical treatment of BDI are good with success rates of around 90%, quality of life (QoL) may be impaired even after “clinically successful” treatment. Following surgical treatment, the incidence of anastomotic strictures varies from 5 to 69%, with most studies reporting incidences around 10–20%. The median time to stricture formation varies between 11 and 30 months. Long-term BDI-related mortality varies between 1.8 and 4.6%. Of 91 patients treated in our center for anastomotic strictures after HJ, 81 (89%) were treated by percutaneous balloon dilatation, with a long-term success rate of 77%. Twenty-four patients primarily or secondarily underwent surgical revision, with recurrent strictures occurring in 21%. Conclusions: The long-term impact of BDI is considerable, both in terms of clinical outcomes and QoL. Treatment should be performed in tertiary expert centers to optimize outcomes. Patients require a long-term follow-up to detect anastomotic strictures. Strictures should initially be managed by percutaneous dilatation, with surgical revision as a next step in treatment.
Endothelial cells are covered by a delicate meshwork of glycoproteins known as the glycocalyx. Under normophysiological conditions the glycocalyx plays an active role in maintaining vascular ...homeostasis by deterring primary and secondary hemostasis and leukocyte adhesion and by regulating vascular permeability and tone. During (micro)vascular oxidative and nitrosative stress, which prevails in numerous metabolic (diabetes), vascular (atherosclerosis, hypertension), and surgical (ischemia/reperfusion injury, trauma) disease states, the glycocalyx is oxidatively and nitrosatively modified and degraded, which culminates in an exacerbation of the underlying pathology. Consequently, glycocalyx degradation due to oxidative/nitrosative stress has far-reaching clinical implications. In this review the molecular mechanisms of reactive oxygen and nitrogen species-induced destruction of the endothelial glycocalyx are addressed in the context of hepatic ischemia/reperfusion injury as a model disease state. Specifically, the review focuses on (i) the mechanisms of glycocalyx degradation during hepatic ischemia/reperfusion, (ii) the molecular and cellular players involved in the degradation process, and (iii) its implications for hepatic pathophysiology. These topics are projected against a background of liver anatomy, glycocalyx function and structure, and the biology/biochemistry and the sources/targets of reactive oxygen and nitrogen species. The majority of the glycocalyx-related mechanisms elucidated for hepatic ischemia/reperfusion are extrapolatable to the other aforementioned disease states.
Display omitted
► Hepatic ischemia/reperfusion (I/R) injury is characterized by the production of reactive oxygen and nitrogen species. ► The glycocalyx is a protective sugar layer that normally coats the endothelium. ► Reactive oxygen and nitrogen species degrade the glycocalyx, thereby exacerbating hepatic I/R injury. ► Glycocalyx degradation increases oxidative stress and facilitates leukocyte adhesion. ► Oxidative glycocalyx degradation yields immunogenic circulating fragments.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) induces a rapid and extensive increase in liver volume. The functional quality of this hypertrophic response has ...been called into question because ALPPS is associated with a substantial incidence of liver failure and high perioperative mortality. This multicenter study aimed to evaluate functional liver regeneration in contrast to volumetric liver regeneration in ALPPS, using technetium-99m hepatobiliary scintigraphy and computed tomography volumetry, respectively.
Patients who underwent ALPPS and hepatobiliary scintigraphy in 6 centers were included. Hepatobiliary scintigraphy data were analyzed centrally at the Academic Medical Center in Amsterdam according to established protocols. Increase in liver function as measured by hepatobiliary scintigraphy after stage 1 of ALPPS was compared with the increase in liver volume. In addition, we analyzed the impact of liver function and volume on postoperative outcomes including liver failure, morbidity, and mortality.
In 60 patients, future liver remnant volume increased by a median 78% (interquartile range 48–110) during a median 8 (interquartile range 6–14) days after stage 1, while function as measured by hepatobiliary scintigraphy increased by a median 29% (interquartile range 1–55) throughout 7 days (interquartile range 6–10) in the 27 patients with paired measurements. After stage 2 of ALPPS, liver failure occurred in 5/60 (8%) patients, severe complications in 24/60 (40%), and mortality occurred in 4/60 (7%).
In ALPPS, volumetry overestimates liver function as measured by hepatobiliary scintigraphy and may be responsible for the high rate of liver failure. Quantitative liver function tests are highly recommended to avoid post hepatectomy liver failure.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
No standard treatment is available for advanced biliary tract cancer (BTC) after first-line therapy with gemcitabine plus cisplatin (GEMCIS). The objective of this study was to evaluate safety and ...anti-tumour activity of fluorouracil, leucovorin, irinotecan plus oxaliplatin (FOLFIRINOX) as salvage treatment in patients with previously treated advanced BTC.
In this two-stage phase 2 study, patients with advanced BTC who had disease progression or unacceptable toxicity after ≥3 cycles of GEMCIS were eligible. Primary endpoints were safety and efficacy (defined as objective response rate, ORR). In stage one, ten patients were treated with FOLFIRINOX every 2 weeks. In stage two, an additional 20 patients were enrolled at a starting dose as defined in stage one, provided that in stage ≥1 objective response or ≥2 stable diseases were observed and ≤3 patients had serious adverse events (SAEs) within the first 6 weeks of treatment. Secondary endpoints were progression-free survival (PFS) and overall survival (OS).
Forty patients were screened for eligibility and 30 patients were enrolled. In stage one, one patient had a partial response and five patients had stable disease. One patient had a SAE during the first 6 weeks of treatment, and five patients required a dose reduction due to adverse events. The most common grade 3-4 adverse events in stage one were neutropaenia, mucositis and diarrhoea. Stage two was initiated with FOLFIRINOX in an adapted dose. In stage two, grade 3-4 neutropaenia, diarrhoea, nausea and vomiting were the most common adverse events. The ORR, median PFS and OS in all patients were 10%, 6.2 and 10.7 months, respectively.
In patients with advanced BTC who progressed after or were intolerant to GEMCIS, FOLFIRINOX can be administered safely and could be considered as an option for salvage treatment in these patients.
ClinicalTrials.gov Identifier NCT02456714.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Photodynamic therapy (PDT) has emerged as a promising alternative to conventional cancer therapies such as surgery, chemotherapy, and radiotherapy. PDT comprises the administration of a ...photosensitizer, its accumulation in tumor tissue, and subsequent irradiation of the photosensitizer-loaded tumor, leading to the localized photoproduction of reactive oxygen species (ROS). The resulting oxidative damage ultimately culminates in tumor cell death, vascular shutdown, induction of an antitumor immune response, and the consequent destruction of the tumor. However, the ROS produced by PDT also triggers a stress response that, as part of a cell survival mechanism, helps cancer cells to cope with the PDT-induced oxidative stress and cell damage. These survival pathways are mediated by the transcription factors activator protein 1 (AP-1), nuclear factor E2-related factor 2 (NRF2), hypoxia-inducible factor 1 (HIF-1), nuclear factor κB (NF-κB), and those that mediate the proteotoxic stress response. The survival pathways are believed to render some types of cancer recalcitrant to PDT and alter the tumor microenvironment in favor of tumor survival. In this review, the molecular mechanisms are elucidated that occur post-PDT to mediate cancer cell survival, on the basis of which pharmacological interventions are proposed. Specifically, pharmaceutical inhibitors of the molecular regulators of each survival pathway are addressed. The ultimate aim is to facilitate the development of adjuvant intervention strategies to improve PDT efficacy in recalcitrant solid tumors.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The inability to preserve vascular organs beyond several hours contributes to the scarcity of organs for transplantation
. Standard hypothermic preservation at +4 °C (refs.
) limits liver ...preservation to less than 12 h. Our group previously showed that supercooled ice-free storage at -6 °C can extend viable preservation of rat livers
However, scaling supercooling preservation to human organs is intrinsically limited because of volume-dependent stochastic ice formation. Here, we describe an improved supercooling protocol that averts freezing of human livers by minimizing favorable sites of ice nucleation and homogeneous preconditioning with protective agents during machine perfusion. We show that human livers can be stored at -4 °C with supercooling followed by subnormothermic machine perfusion, effectively extending the ex vivo life of the organ by 27 h. We show that viability of livers before and after supercooling is unchanged, and that after supercooling livers can withstand the stress of simulated transplantation by ex vivo normothermic reperfusion with blood.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background Preoperative portal vein embolization is widely used to increase the future remnant liver. Identification of nonresponders to portal vein embolization is essential because these patients ...may benefit from associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), which induces a more powerful hypertrophy response.99m Tc-mebrofenin hepatobiliary scintigraphy is a quantitative method for assessment of future remnant liver function with a calculated cutoff value for the prediction of postoperative liver failure. The aim of this study was to analyze future remnant liver function before portal vein embolization to predict sufficient functional hypertrophy response after portal vein embolization. Methods Sixty-three patients who underwent preoperative portal vein embolization and computed tomography imaging were included. Hepatobiliary scintigraphy was performed to determine pre–portal vein embolization and post–portal vein embolization future remnant liver function. Receiver operator characteristic analysis of pre–portal vein embolization future remnant liver function was performed to identify patients who would meet the post–portal vein embolization cutoff value for sufficient function (ie, 2.7%/min/m2 ). Results Mean pre–portal vein embolization future remnant liver function was 1.80% ± 0.45%/min/m2 and increased to 2.89% ± 0.97%/min/m2 post–portal vein embolization. Receiver operator characteristic analysis in 33 patients who did not receive chemotherapy revealed that a pre–portal vein embolization future remnant liver function of ≥1.72%/min/m2 was able to identify patients who would meet the safe future remnant liver function cutoff value 3 weeks after portal vein embolization (area under the curve = 0.820). The predictive value was less pronounced in 30 patients treated with neoadjuvant chemotherapy (area under the curve = 0.618). A total of 45 of 63 patients underwent liver resection, of whom 5 of 45 developed postoperative liver failure; 4 of 5 patients had a post–portal vein embolization future remnant liver function below the cutoff value for safe resection. Conclusion When selecting patients for portal vein embolization, future remnant liver function assessed with hepatobiliary scintigraphy can be used as a predictor of insufficient functional hypertrophy after portal vein embolization, especially in nonchemotherapy patients. These patients are potential candidates for ALPPS.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
To evaluate tumor growth in a series of patients undergoing liver resection after portal vein embolization (PVE).
The regenerative response after PVE leading to compensatory hypertrophy of the ...nonembolized liver segments potentially enhances tumor growth.
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.
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.
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.
PDF
