Excellent outcome in 238 consecutive living donor liver transplantations using the right liver graft in a large volume single center.

BACKGROUND: Using a right liver (RL) graft improves the outcomes in adult living donor liver transplantation (ALDLT). Here we report the recent excellent outcomes of 238 consecutive RL transplantations in ALDLT. METHODS: Between January 2005 and June 2009, 238 consecutive adult recipients underwent RL transplantation; The middle hepatic vein (MHV) was reconstructed using artificial vascular grafts in 209 cases. Among these study subjects, UNOS status 1 and 2A were 12 (5.0 %) and 20 (8.4 %) patients, and the mean medical MELD score, was 19.9. Hepatitis B virus was the most common original liver disease in 184 patients (77.3 %). Hepatocellular carcinoma was diagnosed in 133 patients (56.3 %), and 102 patients (76.1 %) met the radiologic Milan criteria. The mean graft-versus-recipient weight ratio was 1.14 %. The primary endpoint of this study was the patient and graft survival rate. The mean follow-up period was 32 (0-69) months. RESULTS: The most common major complication was biliary complication (n = 62; 26 %). The 1-, 2-, and 5-year patient survival rates were 96, 95, and 94 %, and the graft survival rates were 99, 99, and 98 %. There were 4 hospital deaths (1.6 %). Eighteen late mortalities were observed after recurrence of hepatocellular carcinoma (HCC, n = 17) and one case of lymphoma recurrence. One case of graft failure 33 months after ALDLT was attributed to cholestatic fibrosing hepatitis B saved by re-ALDLT. On multivariate analysis, no drainage of MHV branches and accompanying HCC beyond Milan criteria were the risk factors for poor patients' survival rate (p < 0.05). CONCLUSIONS: Further technical innovation would be required to overcome biliary complications. The technical innovation using right liver draining MHV branches improved both patient and graft survival outcomes of ALDLT. Despite these advances, selection criteria for HCC are still hurdles, even in RL transplantation.

A Phase I/IIa Trial of Yttrium-90 Radioembolization in Combination with Durvalumab for Locally Advanced Unresectable Hepatocellular Carcinoma.

PURPOSE: Synergistic effect of radiotherapy and immunotherapy for the treatment of hepatocellular carcinoma (HCC) has been reported. This phase I/IIa pilot trial evaluated preliminary efficacy and safety of combination of radioembolization with yttrium-90 microspheres (Y90-radioembolization) and durvalumab in patients with locally advanced unresectable HCC. PATIENTS AND METHODS: Patients with Child-Pugh score ≤ 7 and locally advanced HCC, defined as Barcelona Clinic Liver Cancer (BCLC) stage B HCC or BCLC-C disease without extrahepatic metastases, received Y90-radioembolization followed by intravenous durvalumab 1,500 mg 7 to 14 days after Y90-radioembolization and every 4 weeks thereafter. Primary endpoint was time to progression (TTP) assessed by modified RECIST (mRECIST). Secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) determined by mRECIST, and safety. RESULTS: All 24 patients enrolled received Y90-radioembolization and 23 received at least one dose of durvalumab. Median follow-up duration was 19.0 months (range, 2.2-24.2). Median TTP was 15.2 months [95% confidence interval (CI), 6.1-not estimated]. Median OS was not reached and 18-month OS rate was 58.3% (95% CI, 36.4-75.0). Median PFS was 6.9 months (95% CI, 5.4-15.2). Seven (29.2%) patients had a complete response and 13 (54.2%) had a partial response; ORR was 83.3% (95% CI, 62.6-95.3). Eleven (47.8%) patients experienced any-grade treatment-related adverse events. Two (8.7%) patients had grade 3 treatment-related adverse events (neutropenia and fever). None experienced any treatment-related serious adverse events. CONCLUSIONS: In patients with locally advanced unresectable HCC, the combination of Y90-radioembolization and durvalumab demonstrated promising efficacy and safety, warranting further evaluation in large-scale controlled trials.

Efficacy of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide in treatment-naive hepatitis B patients.

BACKGROUND AND AIMS: Antiviral agents for chronic hepatitis B (CHB) reduced the risk of hepatocellular carcinoma (HCC) development. The outcomes of entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) were compared in patients with CHB. METHODS: Between 2017 and 2019, treatment-naïve patients with CHB treated with ETV, TDF, and TAF were recruited from three Korean tertiary institutes. The cumulative incidences of HCC and orthotopic liver transplantation (OLT) or mortality were calculated and compared using Kaplan-Meier analysis before and after trimatch. RESULTS: Among recruited 2082 patients, 43 patients developed HCC, whereas 66 developed OLT or mortality. Before trimatch, the cumulative incidence of HCC was statistically similar among patients treated with three antiviral agents (p = 0.340). However, the cumulative probability of OLT or mortality development in patients treated with ETV or TDF was significantly higher than that of patients with TAF before trimatch (all p < 0.05). On multivariate analysis, male sex [hazard ratio (HR) 2.990] and older age (HR 1.044) were independently associated with an increased risk of HCC development, whereas higher platelet count (HR 0.993) was independently associated with a decreased risk (all p < 0.05). The type of antiviral agents did not significantly influence the risk of HCC and OLT or mortality development (all p > 0.05). After trimatch, no significant difference in the cumulative probability for HCC and OLT or mortality according to antiviral agents was found (all p > 0.05). CONCLUSIONS: The outcomes of ETV, TDF, and TAF on the risk of HCC and OLT or mortality were statistically similar in treatment-naïve patients with CHB.

Central Diabetes Insipidus Associated with Orbital Apex Syndrome.

Orbital apex syndrome (OAS) manifests as multiple cranial nerve palsies caused by an abnormal nerve response to inflammation or other processes. Central diabetes insipidus (CDI) is characterized by deficient synthesis or secretion of antidiuretic hormone. A 62-year-old woman underwent myringotomy for otitis media with effusion. Two months after the procedure, symptoms of hearing loss had not improved, and she underwent left tympanoplasty and mastoidectomy. After surgery, she presented with left ocular pain and visual loss. Neurologic examination revealed ptosis, total ophthalmoplegia, and a relative afferent pupillary defect on the left eye. Magnetic resonance imaging showed an asymmetric contrast-enhancing lesion in the left orbital apex and left cavernous sinus, with adjacent dural thickening and enhancement. OAS was diagnosed, and steroid treatment was started. During the regular follow-up period, she reported polyuria, and CDI was diagnosed. Treatment with intranasal desmopressin 10 µg twice daily was started, and symptoms greatly improved. The mechanism underlying the association of CDI with OAS is unclear, and further research is needed. The present case suggests that polyuria in OAS should alert neurologists and ophthalmologists to possible CDI.

A phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86-9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma.

PURPOSE: There is an unmet need for treatment options in hepatocellular carcinoma (HCC). Sorafenib is currently the only approved systemic treatment for HCC. Refametinib, an oral, allosteric MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in vitro and in vivo. A phase II study evaluated efficacy and safety of refametinib plus sorafenib in Asian patients with HCC (NCT01204177). EXPERIMENTAL DESIGN: Eligible patients received twice-daily refametinib 50 mg plus twice-daily sorafenib 200 mg (morning)/400 mg (evening), with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade ≥ 2 hand-foot skin reaction, fatigue, or gastrointestinal toxicity occurred. Primary efficacy endpoint: disease control rate. Secondary endpoints: time to progression, overall survival, pharmacokinetic assessment, biomarker analysis, safety, and tolerability. RESULTS: Of 95 enrolled patients, 70 received study treatment. Most patients had liver cirrhosis (82.9%) and hepatitis B viral infection (75.7%). Disease control rate was 44.8% (primary efficacy analysis; n = 58). Median time to progression was 122 days, median overall survival was 290 days (n = 70). Best clinical responders had RAS mutations; majority of poor responders had wild-type RAS. Most frequent drug-related adverse events were diarrhea, rash, aspartate aminotransferase elevation, vomiting, and nausea. Dose modifications due to adverse events were necessary in almost all patients. CONCLUSIONS: Refametinib plus sorafenib showed antitumor activity in patients with HCC and was tolerated at reduced doses by most patients. Frequent dose modifications due to grade 3 adverse events may have contributed to limited treatment effect. Patients with RAS mutations appear to benefit from refametinib/sorafenib combination.