Yutaka Horie

BACKGROUND: Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria. RESULTS: A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions. CONCLUSIONS: Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.).

BACKGROUND: Percutaneous ethanol injection therapy has been used widely for small hepatocellular carcinoma. This study was undertaken to determine factors predictive of local recurrence or new nodular recurrence in patients with small hepatocellular carcinoma treated with percutaneous ethanol injection. METHODS: The authors studied 73 nodules treated with percutaneous ethanol injection in 49 patients with small hepatocellular carcinoma. The usefulness of predictive factors for recurrence was assessed with the Kaplan-Meier method. The clinicopathologic variables examined included age, gender, Child-Pugh classification, number of tumors (single vs. multiple), tumor size, degree of tumor differentiation, ultrasonographic findings such as peripheral hypoechoic band (so-called 'halo'), intratumoral echo pattern, tumor staining on enhanced computed tomography, combination therapy with transcatheter arterial embolization, and serum alpha-fetoprotein level. RESULTS: The local recurrence rates were 19%, 27%, 33%, 33%, and 33%, respectively, and the new nodular recurrence rates were 19%, 51%, 74%, 83%, and 83%, respectively, at 1, 2, 3, 4, and 5 years after percutaneous ethanol injection therapy. The frequency of local recurrence was associated with the histologic differentiation of more than moderately differentiated (P < 0.001), presence of a sonographic halo (P < 0. 005), an intratumoral heterogeneous echo pattern (P < 0.001), and positive tumor staining on enhanced computed tomography (P < 0.01). Multivariate analysis showed that the presence of a halo and an intratumoral heterogeneous echo pattern were the most important variables for predicting local recurrence. The frequency of new nodular recurrences was related to the presence of multiple tumors (P < 0.01) and a high serum alpha-fetoprotein level (P < 0.001). Multivariate analysis showed that a high serum alpha-fetoprotein level was a reliable predictor of new nodular recurrence. CONCLUSIONS: This study showed that the presence of a halo and an intratumoral echo pattern on ultrasonography were useful predictors for local recurrence after percutaneous ethanol injection therapy for small hepatocellular carcinoma, and that a high serum alpha-fetoprotein level was associated with a higher frequency of new nodular recurrences.

Pedunculated hepatocellular carcinoma (HC) is rarely found in the United States and Europe. There have been several cases in Japan. The diagnosis of pedunculated HC is said to be very difficult. This article describes three cases of pedunculated HC which were diagnosed preoperatively and were resected successfully. Celiac angiography and CT scan were useful diagnostic procedures. World literature is reviewed, and 15 documented cases of pedunculated HC have been found, including the three cases presented. It may be assumed that pedunculated HC may arise from the accessory lobe of the liver or ectopic liver tissue.