Risk Of Liver Failure Research Articles

Diverse Effects of the NTCP p.Ser267Phe Variant on Disease Progression During Chronic HBV Infection and on HBV preS1 Variability.

The sodium taurocholate co-transporting polypeptide (NTCP) acts as a cellular receptor for the hepatitis B virus (HBV) infection on host hepatocytes. We aim to investigate how the NTCP p.Ser267Phe variant affects HBV-related disease progression and analyze viral genomic variability under a host genetic background carrying the p.Ser267Phe variant. A total of 3187 chronic hepatitis B (CHB) patients were enrolled and genotyped for the p.Ser267Phe variant. The variant's association with disease progression was evaluated by logistic regression analysis. We also enrolled 83 treatment-naive CHB patients to analyze the variability of the HBV preS1 region. The frequency of the NTCP p.Ser267Phe variant was significantly lower in patients diagnosed with acute-on-chronic liver failure [OR (95% CI) = 0.33 (0.18–0.58), P = 1.34 × 10−4], cirrhosis [OR (95% CI) = 0.47 (0.31–0.72), P = 4.04 × 10−4], and hepatocellular carcinoma [OR (95% CI) = 0.54 (0.34–0.86), P = 9.83 × 10−3] as compared with CHB controls under the additive model after adjustment. Furthermore, the percentage of amino acid mutations in HBV preS1 region was significantly higher in the NTCP p.Ser267Phe heterozygote group than in the NTCP wild type homozygote group (P < 0.05). We herein demonstrate that the NTCP p.Ser267Phe variant is a protective factor reducing CHB patient risk for liver failure, cirrhosis, and hepatocellular carcinoma. A host genetic background carrying NTCP p.Ser267Phe exerts selective pressure on the virus, leading to more variability.

Laparoscopic right hepatectomy after portal vein ligation: second step of two stage hepatectomy for colorectal liver metastases

Background: Hepatic resection is the treatment of choice for patients with colorectal liver metastases but 75- 85% of patients are unresectable at diagnosis. Many patients with multiple bilobar metastases are not eligible for surgery because of the small future remnant liver (FRL). Patients with impaired hepatic function, scheduled for extended hepatectomy are at greater risk of liver failure. Methods: Two stage hepatectomy (TSH) is a strategy designed to increase the number of patients who may benefit from liver surgery while reducing the risk of postoperative liver failure. Right hepatectomy is now frequently performed laparoscopically, but it may be challenging in the setting of two stage hepatectomy, after left liver clearance and portal vein ligation. Results: The video shows the case of a patient in whom TSH is completed with a laparoscopic right hepatectomy after laparoscopic left liver clearance and PVL. FLR had increased to 49% after portal vein alcohol injection and PLV performed during the first stage. Right hepatic vein is dissected at the caval confluence. Dissection of the right side of the liver pedicle is rather difficult because of the previous PVL. Right hepatic artery and right portal vein are clipped and divided. Parenchimal section is performed with ultrasound dissector. Right bile duct is stapled intraparenchimally. Right hepatectomy is concluded with section of the right hepatic vein. Conclusion: Two stage hepatectomy can performed entirely in laparoscopy in selected patients.

Postoperative liver failure risk score identifying patients with resectable perihilar cholangiocarcinoma who may benefit from portal vein embolization

Postoperative liver failure risk score identifying patients with resectable perihilar cholangiocarcinoma who may benefit from portal vein embolization

Postoperative liver failure risk score identifying patients with resectable perihilar cholangiocarcinoma who may benefit from portal vein embolization

Background: Major liver resection for perihilar cholangiocarcinoma is associated with an incidence of postoperative liver failure (PLF) of 22-33%. The aim of this study was to analyze the predictive value of future liver remnant (FLR) volume and to develop a risk score for PLF after resection for PHC. Methods: The 217 patients included from 1997 to 2014 at two Western centers were analyzed; FLR volumes were calculated with CT volumetry. Other variables included jaundice at presentation, immediate preoperative bilirubin, and preoperative cholangitis. FLR volume was categorized as < 30%, 30%-45% or >45%. A risk score for PLF (grade B/C according to the ISGLS criteria) was developed using multivariable logistic regression. Results: PLF incidence was 24% and PLF-related mortality 12%. Risk factors for PLF were FLR volume below <30% (OR 4.0 95%CI (3.2-6.4) and FLR volume of 45-30% (OR 2.0(1.6-3.12)). Also jaundice at presentation (OR 3.1(1.1-9.0), immediate preoperative bilirubin above 50μmol/L (OR 4.3(1.7-10.7)) and preoperative cholangitis (OR 3.4(1.6-7.4) were risk factors for PLF. These variables were included in a risk score that showed good discrimination (AUC 0.79(0.72-0.86) and good calibration. Conclusion: The selection of patients for PVE using only liver volume is insufficient considering the other predictors of PLF in PHC patients. The proposed risk score can be used for selection of patients for PVE, for adequate patient counseling and identification of other modifiable risk factors besides liver volume.

Hepatitis B Testing Rates in Patients with Chronic Lymphocytic Leukemia before and during Administration of Anti-CD20 Therapy

IntroductionFront-line treatment for patients with active chronic lymphocytic leukemia (CLL) often includes an anti-CD20 monoclonal antibody. However, treatment with anti-CD20 therapy has the potential to reactivate latent hepatitis B virus (HBV). Thus, in 2015 an American Society of Clinical Oncology (ASCO) panel advised screening all patients for HBV infection before starting anti-CD20 therapies. Both Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (HBcAb) testing are required for proper screening. In addition, the ASCO panel recommended testing for both IgM and IgG isotypes of HBcAb, as patients with remote HBV infection may have undetectable levels of HBcAb IgM. We evaluated guideline adherence for HBV testing in a large, real-world cohort of patients with CLL.MethodsThis retrospective analysis leveraged data derived from electronic health records (EHRs) in the Flatiron Health database. The database included 7,795 patients with CLL who received at least one order for an antineoplastic treatment between January 1, 2011 and May 31, 2018. We included only patients who received an anti-CD20 therapy (rituximab, ofatumumab, obinutuzumab) and excluded patients whose start of CLL treatment (as captured through chart abstraction) was >30 days before the start of structured EHR data (N=4,288). Using structured EHR data (based on Logical Observation Identifiers Names and Codes [LOINC]), we evaluated the frequency of HBsAg and HBcAb testing, including a separate analysis of HBcAb IgM and IgG testing.ResultsOf 4,288 patients in the cohort treated with anti-CD20, 2,034 (47%) had evidence of HBV testing at any point during their care, and 1,765 (41%) had evidence of HBV testing at any point prior to and up to 90 days following anti-CD20 therapy initiation. Over time, the proportion of HBV infection testing up to 90 days following anti-CD20 treatment initiation increased steadily, from <15% in early 2011, reaching as high as 70% in 2017 (Figure). Following the ASCO guideline publication in 2015, the proportion of patients tested for both HBsAg and HBcAb increased by 33%, while the proportion of HBsAg-only tested patients dropped by 35% (Table). However, even if unspecified HBcAb tests are assumed to represent testing for both IgG and IgM isotypes, in the most recent timeframe nearly half (46%) of the patients who were tested did not receive the requisite screening tests (i.e., for both isotypes). Additionally, nearly 20% received only one test (HBsAg or HBcAb) and another 25% received both tests but the HBcAb test was for the IgM isotype alone (Table).DiscussionIn this real-world cohort of patients with CLL treated with anti-CD20 therapies, overall HBV testing increased throughout the study period, in accordance with ASCO guidelines. Although the most recent data points may not yet capture testing up to 90 days following treatment initiation, and HBV testing information for some patients may not be captured in the EHR, our findings suggest that a sizable proportion of patients are not receiving appropriate screening for HBV. In addition, a significant proportion (25%) of patients were tested for both HBsAg and HBcAb, but the HBcAb test was for the IgM isotype alone, which could result in a false negative test and missed cases of latent HBV. These findings suggest a need for additional quality improvement efforts. Further research is needed to determine demographic and clinical characteristics of tested versus untested patients, and whether testing is associated with reduced risk of liver failure in patients undergoing anti-CD20 therapy. [Display omitted] DisclosuresHooley:Flatiron Health: Employment. Chen:MedCyclops LLC: Equity Ownership; Nootrobox: Consultancy; Flatiron Health: Employment. Maignan:Flatiron Health: Employment. Carson:Roche: Consultancy; Washington University in St. Louis: Employment; Flatiron Health: Employment.

Impact of right upper quadrant cytoreductive techniques with extensive liver mobilization on postoperative hepatic function and risk of liver failure in patients with advanced ovarian cancer

ObjectiveEvaluate postoperative hepatic-function in patients with advanced ovarian cancer (OC) who underwent extensive right upper-quadrant (RUQ) cytoreduction in primary, relapsed or interval settings. MethodsWe retrospectively reviewed all patients with OC who underwent liver resection, mobilization and/or diaphragmatic-stripping between 01/2013 and 12/2016. Postoperative liver enzyme function (LFTs), assessed by alanine transaminase (ALT), alkaline phosphatase (ALP) and bilirubin (Bil), was correlated with postoperative complications. Results132 patients were identified. 81 patients (61%) underwent upfront, 25(19%) interval and 26(20%) secondary cytoreduction. The surgical procedures were right diaphragmatic peritoneal stripping (81/132;61%), full-thickness resection (42/132;32%), liver-capsule resection (85/132;64%), porta-hepatis tumor resection (11/132;8%) and partial hepatectomy (5/132;4%). 74%(98/132) of patients increased their LFTs postoperatively with a peak at 24-hours. Highest ALT median was 1.7-fold of upper normal limit (UNL), with the highest ALT value rising up to 28-fold UNL on the 1st postoperative day (PoD)(range 6–1792 IU/L). Median value of highest ALP was within normal, with the highest ALP value rising up to 4-fold UNL on PoD 5(range 22–512 IU/L). Median value of highest Bilirubin level was also within normal, with highest Bilirubin level rising up to 6-fold UNL on PoD 5(range: 2–120 μmol/L). Mean LFT-normalization time was 7 days (range: 3–14 days). No significant morbidity was directly linked to LFT deterioration, apart from one case (0.8%) of fatal fulminant hepatic-failure. ConclusionRUQ-cytoreduction is almost always associated with a transient LFT-increase, with no significant clinical implications and spontaneous normalization within the first postoperative week. Due to the existing risk of fulminant liver failure, albeit rare and difficult to predict, postoperatively elevated LFTs should be monitored, until normalization. Large prospective studies are required to assess the predictive value of LFTs and other risk factors for postoperative hepatic failure in patients with OC undergoing extensive RUQ-cytoreduction.

Covered Transjugular Intrahepatic Portosystemic Shunt in the Treatment of Portal Hypertension: Looking for the Right Patient and the Right Time

Transjugular intrahepatic portosystemic shunt (TIPS) offers an effective treatment for patients with complications of portal hypertension, specifically prevention of variceal rebleeding and recurrent or refractory ascites. TIPS reduces portal pressure and increases effective blood volume and cardiac output, but long-term adverse effects may include increased risk of liver failure, hepatic encephalopathy, and cardiac dysfunction. As such, TIPS is not indicated for primary prophylaxis of variceal bleeding. Critical to the success of TIPS is a dedicated, multidisciplinary team, along with careful patient selection and appropriate timing of the procedure; for example, in high-risk patients TIPS may offer clinical benefits when performed early in the disease course. Important patient factors to consider before performing TIPS include cardiac and renal function, severity of liver dysfunction, history of hepatic encephalopathy, and inflammatory status. Recent studies indicate that technical considerations, specifically diameter control and downsizing covered stents, may reduce adverse events and increase clinical benefits of TIPS. This review focusses on the optimisation of the use of a covered TIPS endoprosthesis in patients with portal hypertension-related complications, with consideration of evolving practices, patient selection, and multidisciplinary co-operation. Further research and patient stratification are necessary to enhance understanding of the optimal use of covered TIPS and to ensure that the right patients receive TIPS at the right time.

AROS is a significant biomarker for both short- and long-term prognosis in non-cirrhotic HCC

Purpose: Despite a low risk of liver failure and preserved liver function, non-cirrhotic HCC has poor prognosis. To improve clinical outcomes of the curative-intent treatment in non-cirrhotic HCC, identification of prognostic factors accompanied by new treatment strategies are needed. In the current study, we evaluated AROS as a prognostic biomarker in non-cirrhotic HCC. Methods: mRNA levels of AROS was measured in tumor and non-tumor tissues derived from 283 non-cirrhotic HCC patients. Relationships between clinical characteristics and AROS expression were analyzed using Chi square and Fisher's exact test. The prognostic significance of AROS expression was analyzed using Kaplan-Meier curves and Cox regression models. Results: AROS was significantly up-regulated in tumors irrespective of tumor stage and BCLC stage. Additionally, recurrent tissues revealed higher average levels of AROS than non-recurrent tissues for follow-up times of 2 years and 5 years and the differences were statistically significant. High mRNA levels of AROS were associated with tumor stage, BCLC stage, AFP level, vascular invasion, tumor size, and portal vein invasion. HCC patients with higher AROS levels showed higher recurrence and shorter DFS for both short-term and long-term compared to those with AROS-low group. Cox regression analysis demonstrated that AROS is a significant predictor for recurrence and DFS along with large tumor size, tumor multiplicity, vascular invasion, and poor tumor differentiation which are the known prognostic factors. Conclusions: Our findings on AROS as a prognostic biomarker could be helpful for designing a strategy for the effective treatment and management of non-cirrhotic HCC.

Preoperative Transjugular Intrahepatic Portosystemic Shunt Placement for Extrahepatic Abdominal Surgery.

Extrahepatic abdominal surgery in patients with portal hypertension is associated with a high rate of perioperative complications and death due to the increased risk of liver failure, perioperative bleeding, and ascites. One proposed method to facilitate surgery in these patients is with preoperative placement of a transjugular intrahepatic portosystemic shunt (TIPS). By decompressing the portal circulation, this presurgical measure would theoretically decrease the potential for bleeding and improve the ability to control ascites in the perioperative and postoperative period. This article reviews the use of TIPS prior to abdominal surgery in patients with portal hypertension.

Effect of preoperative cholangitis on prognosis of patients with hilar cholangiocarcinoma: A systematic review and meta-analysis.

Background:The aim of this study was to compare the clinical outcomes between patients with preoperative cholangitis and noncholangitis patients to determine whether the preoperative cholangitis would be able to serve as an independent predictive factor on hilar cholangiocarcinoma (HCC) outcomes.Methods:A systematic literature search for reported preoperative cholangitis in patients with hilar cholangiocarcinoma was performed in 4 databases: PubMed, Web of Science, Embase, and the Cochrane Library, published from 1979 to 2017.Results:In total, the initial search identified 1228 articles. Of these studies only 9 studies met the inclusion criteria and were included in this analysis. Differences between preoperative cholangitis existing and noncholangitis patients were observed in terms of mortality (RR = 2.29; 95% CI = 1.48–3.52; P = .0002), overall morbidity (RR = 1.15;95% CI = 1.00–1.32; P = .04), Liver failure (RR = 1.15;95% CI = 1.00–1.32; P = .04), Infection (RR = 1.52;95% CI = 1.16–2.00; P = .003), sepsis (RR = 2.40;95% CI = 1.25–4.5; P = .008).Conclusions:The results lend support to the notion that in hilar cholangiocarcinoma patients, the existence of preoperative cholangitis is statistically associated with the higher postoperative mortality and morbidity. Also that it increases the risk of liver failure and infection. therefore, it is very important to properly control the preoperative cholangitis before surgery.

The role of ClpX in erythropoietic protoporphyria

Hemoglobin is an essential biological component of human physiology and its production in red blood cells relies upon proper biosynthesis of heme and globin protein. Disruption in the synthesis of these precursors accounts for a number of human blood disorders found in patients. Mutations in genes encoding heme biosynthesis enzymes are associated with a broad class of metabolic disorders called porphyrias. In particular, one subtype – erythropoietic protoporphyria – is caused by the accumulation of protoporphyrin IX. Erythropoietic protoporphyria patients suffer from photosensitivity and a higher risk of liver failure, which is the principle cause of morbidity and mortality. Approximately 90% of these patients carry loss-of-function mutations in the enzyme ferrochelatase (FECH), while 5% of cases are associated with activating mutations in the C-terminus of ALAS2. Recent work has begun to uncover novel mechanisms of heme regulation that may account for the remaining 5% of cases with previously unknown genetic basis. One erythropoietic protoporphyria family has been identified with inherited mutations in the AAA+ protease ClpXP that regulates ALAS activity. In this review article, recent findings on the role of ClpXP as both an activating unfoldase and degrading protease and its impact on heme synthesis will be discussed. This review will also highlight the role of ClpX dysfunction in erythropoietic protoporphyria.

A liver for a kidney: Ethics of trans-organ paired exchange.

Living donation provides important access to organ transplantation, which is the optimal therapy for patients with end-stage liver or kidney failure. Paired exchanges have facilitated thousands of kidney transplants and enable transplantation when the donor and recipient are incompatible. However, frequently willing and otherwise healthy donors have contraindications to the donation of the organ that their recipient needs. Trans-organ paired exchanges would enable a donor associated with a kidney recipient to donate a lobe of liver and a donor associated with a liver recipient to donate a kidney. This article explores some of the ethical concerns that trans-organ exchange might encounter including unbalanced donor risks, the validity of informed consent, and effects on deceased organ donation.

Electrochemical Detection of Acetaminophen with Silicon Nanowires

Acetaminophen (APAP) is an antipyretic, analgesic agent, the overdose of which during medical treatment poses a risk for liver failure. Hence, it is important to develop methods to monitor physiological APAP levels to avoid APAP. Here, we report an efficient, selective electrochemical APAP sensor made from depositing silicon nanowires (SiNWs) onto glassy carbon electrodes (GCEs). Electrocatalytic activity of the SiNW/GCE sensors was monitored under varying pH and concentrations of APAP using cyclic voltammetry (CV) and chronoamperometry (CA). CV of the SiNWs at 0.5 to 13 mmol dm-3 APAP concentrations was used to determine the oxidation and reduction potential of APAP. The selective detection of APAP was then demonstrated using CA at +0.568 V vs Ag/AgCl, where APAP is fully oxidized, in the 0.01 to 3 mmol dm-3 concentration range with potentially-interfering species. The SiNW sensor has the ability to detect APAP well within the detection limits for APAP toxicity, showing promise as a practical biosensor.

Computational Modeling of Oxidative Stress in Fatty Livers Elucidates the Underlying Mechanism of the Increased Susceptibility to Ischemia/Reperfusion Injury

QuestionDonor liver organs with moderate to high fat content (i.e. steatosis) suffer from an enhanced susceptibility to ischemia/reperfusion injury (IRI) during liver transplantation. Responsible for the cellular injury is an increased level of oxidative stress, however the underlying mechanistic network is still not fully understood. MethodWe developed a phenomenological mathematical model of key processes of hepatic lipid metabolism linked to pathways of oxidative stress. The model allows the simulation of hypoxia (i.e. ischemia-like conditions) and reoxygenation (i.e. reperfusion-like conditions) for various degrees of steatosis and predicts the level of hepatic lipid peroxidation (LPO) as a marker of cell damage caused by oxidative stress. Results & ConclusionsOur modeling results show that the underlying feedback loop between the formation of reactive oxygen species (ROS) and LPO leads to bistable systems behavior. Here, the first stable state corresponds to a low basal level of ROS production. The system is directed to this state for healthy, non-steatotic livers. The second stable state corresponds to a high level of oxidative stress with an enhanced formation of ROS and LPO. This state is reached, if steatotic livers with a high fat content undergo a hypoxic phase. Theoretically, our proposed mechanistic network would support the prediction of the maximal tolerable ischemia time for steatotic livers: Exceeding this limit during the transplantation process would lead to severe IRI and a considerable increased risk for liver failure.

Bilobar Ultramini Percutaneous Hepatolithotomy

Introduction: Hepatolithiasis is defined as the presence of stones in the bile ducts proximal to the confluence of the right and left hepatic ducts, irrespective of the coexistence of stones in the common bile duct and/or gallbladder. The symptoms of hepatolithiasis may include epigastric or right upper quadrant pain, jaundice, fever, and gastrointestinal symptoms. This disease can cause cholestasis, cholangitis, abscesses, postobstructive atrophy, and liver cirrhosis.1 Although the etiology of hepatolithiasis is not exactly known, it is believed that nutrition, environmental and genetic factors, and surgical operations play different roles.2,3 It frequently occurs after a hepatic portoenterostomy (such as a Kasai), with bile stasis and (possibly) bile infections being the main causes of calculi formation. Previous studies have reported a 53% incidence of hepatolithiasis after Kasai operations.3 The aim of hepatolithiasis treatment is to extract the stones and regain biliary drainage. Liver resection as well as less invasive procedures, such as percutaneous transhepatic cholangioscopy, peroral cholangioscopy, and extracorporeal shock wave lithotripsy, may be used for the treatment of hepatolithiasis.4,5 However, these procedures are not always effective, because bile duct anatomy differs, and they may not significantly reduce the intrahepatic stone burden. There is a risk of liver failure after an open liver resection, which is performed if there are multiple large stones, and a stone-free condition cannot be provided for the patient through other treatments. Therefore, an “ultramini percutaneous hepatolithotomy” (UM-PHL) was planned by the Necmettin Erbakan University Stone Diseases Diagnosis and Treatment Center based on decisions made by a urology, interventional radiology, and general surgery clinical team. It was hypothesized that it could provide less morbidity and a higher stone-free condition ratio. Materials and Methods: The patient information details and surgical technique are shown in the video provided. Results and Conclusion: Initially, the left intrahepatic bile ducts were accessed and the obstructing stones were extracted in 126 minutes, whereas the right intrahepatic bile ducts were accessed and treated in 103 minutes. This procedure was performed as one operation, and all of the stones in the patient's intrahepatic bile ducts were removed (stone free). At the 1 month follow-up, liver function tests were performed, which showed normal values, and no stones were seen in the intrahepatic bile ducts through ultrasonography. All of the patient's complaints and symptoms had disappeared, and she did not have any problems during any of her postoperative follow-ups. In postoperative cholangiography and abdominal ultrasonography, there were neither mechanical obstruction findings at the anastomoses nor stones. Pharmacotherapy is not recommended in the evidence-based clinical practice guidelines for cholelithiasis (2016)6 for hepatolithiasis treatment, so this patient was not started on any medications. The previously used methods were not effective in this patient, therefore, UM-PHL was performed. Our hepatolithiasis case is the first case in the literature from whom large stones were extracted using lithotomy with minimal width access, and a complete stone-free state was provided. In hepatolithiasis patients with a high stone burden, an UM-PHL is a safe and effective method for removing stones. No competing financial interests exist. Runtime of video: 9 mins 13 secs

Radioembolization of Colorectal Liver Metastases: Indications, Technique, and Outcomes.

Liver metastases are a major cause of death from colorectal cancer. Intraarterial therapy options for colorectal liver metastases include chemoinfusion via a hepatic arterial pump or port, irinotecan-loaded drug-eluting beads, and radioembolization using 90Y microspheres. Intraarterial therapy allows the delivery of a high dose of chemotherapy or radiation into liver tumors while minimizing the impact on liver parenchyma and avoiding systemic effects. Specificity in intraarterial therapy can be achieved both through preferential arterial flow to the tumor and through selective catheter positioning. In this review, we discuss indications, contraindications, preprocedure evaluation, activity prescription, follow-up, outcomes, and complications of radioembolization of colorectal liver metastases. Methods for preventing off-target embolization, increasing the specificity of microsphere delivery, and reducing the lung-shunt fraction are discussed. There are 2 types of 90Y microspheres: resin and glass. Because glass microspheres have a higher activity per particle, they can deliver a particular radiation dose with fewer particles, likely reducing embolic effects. Glass microspheres thus may be more suitable when early stasis or reflux is a concern, in the setting of hepatocellular carcinoma with portal vein invasion, and for radiation segmentectomy. Because resin microspheres have a lower activity per particle, more particles are needed to deliver a particular radiation dose. Resin microspheres thus may be preferable for larger tumors and those with high arterial flow. In addition, resin microspheres have been approved by the U.S. Food and Drug Administration for colorectal liver metastases, whereas institutional review board approval is required before glass microspheres can be used under a compassionate-use or research protocol. Finally, radiation segmentectomy involves delivering a calculated lobar activity of 90Y microspheres selectively to treat a tumor involving 1 or 2 liver segments. This technique administers a very high radiation dose and effectively causes the ablation of tumors that are too large or are in a location considered unsafe for thermal ablation. The selective delivery spares surrounding normal liver, reducing the risk of liver failure.

Individualized Adaptive Stereotactic Body Radiotherapy for Liver Tumors in Patients at High Risk for Liver Damage

Patients with preexisting liver dysfunction could benefit the most from personalized therapy for liver tumors to balance maximal tumor control and minimal risk of liver failure. We designed an individualized adaptive trial testing the hypothesis that adapting treatment based on change in liver function could optimize the therapeutic index for each patient. To characterize the safety and efficacy of individualized adaptive stereotactic body radiotherapy (SRBT) for liver tumors in patients who have preexisting liver dysfunction. From 2010 to 2014, 90 patients with intrahepatic cancer treated with prior liver-directed therapy were enrolled in this large phase 2, single-arm, clinical trial at an academic medical center. All patients had at least 1 year of potential follow-up. Using indocyanine green retention at 15 minutes (ICGR15) as a direct biomarker of liver function and a Bayesian adaptive model, planned SBRT was individually modified midway through the course of therapy to maintain liver function after the complete course. The primary outcome was local control; the secondary outcome was safety and overall survival. Patients were 34 to 85 years of age, and 70% (63) were male. Ninety patients (69 [77%] with hepatocellular carcinoma, 4 [4%] with intrahepatic cholangiocarcinoma, and 17 [19%] with metastatic) received treatment to 116 tumors. Sixty-two patients (69%) had cirrhosis, 21 (23%) were Child-Pugh (CP) grade B. The median tumor size was 3 cm; 16 patients (18%) had portal vein involvement. Sixty-two (69%) received all 5 fractions (47 full dose, 15 dose-reduced owing to rising ICGR15). Treatment was well tolerated, with a lower than expected complication rate without adaptation: 6 (7%) experienced a 2-point decline in CP 6 months post-SBRT. The 1- and 2-year local control rates were 99% (95% CI, 97%-100%) and 95% (95% CI, 91%-99%), respectively. We demonstrated that the treatment strategy of individualized adaptive therapy based on a direct biomarker of liver function can be used to achieve both high rates of local control and a high degree of safety without sacrificing either. Individualized adaptive radiotherapy may represent a new treatment paradigm in which dose is based on individual, rather than population-based, tolerance to treatment. clinicaltrials.gov Identifier: NCT01522937.

Nomogram for individualised prediction of liver failure risk after hepatectomy in patients with resectable hepatocellular carcinoma: the evidence from ultrasound data.

This study sought to develop a clinical nomogram for predicting post-hepatectomy liver failure (PHLF) among patients with resectable hepatocellular carcinoma (HCC). The nomogram was established based on data obtained from a prospective study on 136 consecutive patients with resectable HCC undergoing hepatectomy from January 2015 to December 2015 in our centre. Another 80 patients in our centre served as an independent internal validation set. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index), calibration curve and compared with commonly predictive systems. PHLF occurred in 30.9% of patients in the derivation set, including 36 and six patients with Grades A and B, respectively. The statistical nomogram built on the basis of platelet count, serum bilirubin, serum GGT, clinical signs of portal hypertension and shear wave elastography had good calibration and discriminatory abilities, with C-indices of 0.85. These models showed satisfactory goodness-of-fit and discrimination abilities in the independent validation set with C-indices of 0.824 for PHLF. The areas under the receiver-operator characteristic (ROC) curve using our methods were greater than those of conventional predictive systems in the validation patients (corresponding C-indices, 0.572-0.701). This novel nomogram provides good preoperative prediction of PHLF in patients with resectable HCC. • The nomogram was built by platelet count, bilirubin, GGT, CSPH and SWE. • The nomogram showed good calibration and discriminatory abilities in the different sets. • Compared with other models, the nomogram indicated better discriminatory capability.

Hypophosphatemia after Hepatectomy or Pancreatectomy: Role of the Nicotinamide Phosphoribosyltransferase

Postoperative hypophosphatemia is common and is associated with a lower risk of liver failure after hepatectomy, but higher morbidity after pancreatectomy. Whether different physiologic mechanisms underlie the hypophosphatemia associated with these very different clinical outcomes is unclear. This study aims to evaluate the underlying mechanism in postoperative hypophosphatemia. We prospectively enrolled 120 patients who underwent major hepatectomy (n= 30), minor hepatectomy (n= 30), pancreatectomy (n= 30), and laparotomy without resection (control group, n= 30). Preoperative and postoperative serum and urinary phosphorus, calcium, and creatinine, as well as phosphaturic factors, including serum nicotinamide phosphoribosyltransferase (NAMPT), fibroblast growth factor-23, and parathyroid hormone were measured. In addition, we evaluated urinary levels of nicotinamide catabolites, N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-3-carboxamide. We found that significant hypophosphatemia occurred from postoperative day (POD) 1 to POD 2 in all 4 groups and was preceded by hyperphosphaturia from preoperative day to POD 1. Phosphate level alterations were associated with a significant increase in NAMPT levels from preoperative day to POD 2 in all 3 resected groups, but not in the control group. The fibroblast growth factor-23 levels were significantly decreased postoperatively in all 4 groups, and parathyroid hormone levels did not change in any of the 4 groups. Urine levels of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-3-carboxamide decreased significantly in all 4 groups postoperatively. This study demonstrates that the mechanism of hypophosphatemia is the same for both liver and pancreas resections. Postoperative hypophosphatemia is associated with increased NAMPT. The mechanism that upregulates NAMPT and its role on disparate clinical outcomes in postoperative patients warrant additional investigation.

Postoperative Liver Failure Risk Score: Identifying Patients with Resectable Perihilar Cholangiocarcinoma Who Can Benefit from Portal Vein Embolization

Major liver resection for perihilar cholangiocarcinoma (PHC) is associated with a 22% to 33% postoperative liver failure incidence. The aim of this study was analyze the predictive value of future liver remnant (FLR) volume for postoperative liver failure after resection for PHC and to develop a risk score to improve patient selection for portal vein embolization. A consecutive series of 217 patients underwent major liver resection for PHC between 1997 and 2014 at 2 Western centers; FLR volumes were calculated with CT volumetry; other variables included jaundice at presentation, immediate preoperative bilirubin, and preoperative cholangitis. The FLR volume was categorized as <30%, 30% to 45%, or >45%. A risk score for postoperative liver failure (grade B/C according to the International Study Group of Liver Surgery criteria) was developed using multivariable logistic regression with 5 predefined variables. Postoperative liver failure incidence was 24% and liver failure-related mortality was 12%. Risk factors for liver failure were FLR volume <30% (odds ratio 4.2; 95% CI 1.77 to 10.3) and FLR volume 30% to 45% (odds ratio 1.4; 95% CI 10.6 to 3.4). In addition, jaundice at presentation (odds ratio 3.1; 95% CI 1.1 to 9.0), immediate preoperative bilirubin >50 μmol/L (>2.9 mg/dL) (odds ratio 4.3; 95% CI 1.7 to 10.7), and preoperative cholangitis (odds ratio 3.4; 95% CI 1.6 to 7.4) were risk factors for liver failure. These variables were included in a risk score that showed good discrimination (area under the curve 0.79; 95% CI 0.72 to 0.86) and ranking patients in 3 risk sub-groups with predicted liver failure incidence of 4%, 14%, and 44%. The selection of patients for portal vein embolization using only liver volume is insufficient, considering the other predictors of liver failure in PHC patients. The proposed risk score can be used for selection of patients for portal vein embolization, for adequate patient counseling, and identification of other modifiable risk factors besides liver volume.