Sofosbuvir plus velpatasvir treatment for hepatitis C virus in patients with decompensated cirrhosis: a Japanese real-world multicenter study

Background

Real-world data on the efficacy and safety of sofosbuvir plus velpatasvir (SOF/VEL) treatment for patients with hepatitis C virus (HCV)-related decompensated cirrhosis are limited in Japan.

Methods

A total of 190 patients with compensated (108) or decompensated (82) cirrhosis who initiated direct-acting antiviral (DAA) treatment between February 2019 and August 2019 were enrolled. Sustained virologic response (SVR) was defined as undetectable serum HCV-RNA at 12 weeks after the end of treatment (EOT).

Results

The SVR12 rates were 92.6% in patients with compensated cirrhosis and 90.2% in patients with decompensated cirrhosis (p = 0.564), and the treatment completion rates were 98.1% and 96.3%, respectively (p = 0.372). In patients with decompensated cirrhosis, 3 patients discontinued treatment and 2 patients died because of liver-related events. In patients with decompensated cirrhosis with SVR12, 50% of patients with Child–Pugh class B at baseline showed improvement to class A at SVR12, and 27% and 9% of patients with Child–Pugh class C at baseline showed improvement to class B and class A at SVR12, respectively. Patients who achieved SVR12 showed elevated serum albumin levels at the EOT, which were further elevated at SVR12, but no elevated serum albumin levels after the EOT were observed in patients with baseline serum albumin levels less than 2.8 g/dl.

Conclusions

Real-world efficacy of SOF/VEL treatment for patients with decompensated cirrhosis was similar to Japanese phase 3 study, although treatment discontinuation and death related to liver disease occurred. In patients with poor hepatic reserve, whether it improves continuously after viral clearance requires further evaluation.

     

Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production

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Large amount of vitamin A has no major effects on thyroidal hormone synthesis in two-stage rat thyroid carcinogenesis model using N-bis(2-hydroxypropyl)nitrosamine and thiourea

In our previous investigation, which focused on two-stage carcinogenicity in the thyroid, rats were administered N-bis(2-hydroxypropyl)nitrosamine (DHPN), followed by thiourea (TU) over an experimental period of 19 weeks. Simultaneous treatment with a high level of vitamin A (VA) enhanced the induction of proliferative lesions that originated from the thyroidal follicular epithelium. To examine whether hormone synthesis in the thyroid could be inhibited by simultaneous treatment with a large amount of VA and TU, all of the rats were initially given a single subcutaneous injection of 2,800 mg DHPN/kg followed by a supply of 0% TU + 0% VA (DHPN only, control group), 0.2% TU in their drinking water (DHPN/TU group), 0.1% VA in their diet (DHPN/VA group), or 0.2% TU + 0.1% VA (DHPN/TU + VA group) during an experimental period of 4 weeks. Results obtained indicate that the iodine uptake and organification, namely iodination of tyrosine residue in thyroglobulin, of the thyroid, were significantly decreased in the DHPN/TU group compared to the DHPN control group. The variation in these values was attributable to the inhibitory effect of TU upon thyroid hormone synthesis. Results obtained from the DHPN/TU + VA and DHPN/TU groups were comparable. Therefore, the possibility that modification of hormone synthesis contributes to the enhancing effect of simultaneous treatment with a large amount of VA on thyroidal tumor induction by TU is considered to be very minimal.     

Infectious background of febrile advanced lung cancer patients who received chemotherapy

The study aimed to determine the diagnostic utility of procalcitonin (PCT) in order to discriminate between infective fever and fever due to inflammation in febrile advanced lung cancer patients treated with cytotoxic chemotherapy. A total of 121 patients with advanced lung cancer, treated with a cytotoxic chemotherapy regimen between September 2007 and September 2008 at Kyoto University Hospital, were recruited. Blood samples were obtained on the first day of the fever. Serum c-reactive protein (CRP) and PCT levels were measured. At least two blood cultures were performed, and sputum was taken for Gram staining and culture. There were 71 episodes in 61 patients in the 12 months of the study, representing 50.4% of our study population. A total of 41 patients (57.7%) were diagnosed with pneumonia using imaging modalities, 6 (8.5%) with bacteremia using blood culture and 4 (5.6%) with urinary tract infections using urine culture. Among the 41 pneumonia cases, culture from sputum revealed pathologic bacteria in 21 (51.2%) and fungal disease in 14 (34.1%) cases. Among the 71 febrile episodes, serum procalcitonin and CRP were measured in 50 episodes. Serum procalcitonin-positive patients showed poor outcomes on antibiotics therapy (Fisher's exact test, p=0.042). Furthermore, serum procalcitonin positivity was able to discriminate infective fever from fever due to inflammation (Chi-square test, p=0.001). We showed the causative organisms of febrile advanced lung cancer patients who received cytotoxic chemotherapy, as well as the possibility of PCT to discriminate infective fever from fever due to inflammation.     

Antagonistic activity of Y-25130 on 5-HT3 receptors.

This paper describes the 5-hydroxytryptamine3 (5-HT3) receptor antagonism of Y-25130 ((+-)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dih yd ro- 2H-1,4-benzoxazine-8-carboxamide monohydrochloride) in the rat cerebral cortex, isolated rabbit heart and isolated guinea pig ileum. In an in vitro binding assay, Y-25130 inhibited the specific binding of [3H]quipazine to 5-HT3 receptors at the synaptic membranes of the rat cerebral cortex with a Ki value of 2.9 nM, the same as that of ondansetron. Metoclopramide, 5-HT and 2-methyl-5-HT also showed an inhibitory effect, but their affinities for 5-HT3 receptors were lower than that of Y-25130. Y-25130 showed low affinity for histamine H1 receptors (IC50 = 4.4 microM) but it could not reveal any affinities for the other receptors (5-HT1A, 5-HT2, dopamine D1, dopamine D2, alpha 1-adrenoceptor, alpha 2-adrenoceptor, muscarine and benzodiazepine) even at a 10 microM concentration. In the isolated rabbit heart, Y-25130 antagonized the indirect sympathomimetic responses to 5-HT (pA2 value = 10.06) and this effect was more potent than that of metoclopramide. In the isolated longitudinal smooth muscle of the guinea pig ileum, concentration-contraction effect curves for 5-HT were biphasic in the presence of ketanserin. Y-25130 shifted to the right only in the second phase of concentration-effect curves for 5-HT (pA2 value = 7.04) and its activity was more potent than that of metoclopramide. These results indicate that Y-25130 is a potent and selective 5-HT3 receptor antagonist.     

Visualization of pancreaticobiliary reflux in anomalous pancreaticobiliary junction by secretin-stimulated dynamic magnetic resonance cholangiopancreatography

PURPOSE: To assess the utility of secretin-stimulated dynamic MR cholangiopancreatography (MRCP) for the visualization of pancreaticobiliary reflux in patients with anomalous pancreaticobiliary junction (PBJ). MATERIAL AND METHODS: Ten controls and seven patients diagnosed as having anomalous PBJ were prospectively examined by dynamic MRCP after secretin injection using a breath-hold, single-shot turbo spin-echo T2-weighted sequence. The optimal MRCP section was repeated 35 times at approx. 10-second interval after secretin injection; the acquisition time was 4 s per image. The signal intensity (SI) changes of the extrahepatic and intrahepatic bile ducts, presence or absence of intraluminal signal void, caliber change of the bile duct, duodenal filling, and peak time of the SI ratio of the extrahepatic bile duct after secretin injection were compared between the controls and patients. RESULTS: In the controls, the extrahepatic and intrahepatic bile ducts showed neither enhancement nor caliber change over the observation period, providing no apparent peak time. Of the seven patients, the extrahepatic bile duct showed retrograde enhancement and sequential delay in occurrence of the peak time from its distal third to its proximal third (n = 6) with a signal void in its distal part (n =4); its caliber increased subsequently to pancreatic secretion (n = 5); the intrahepatic bile ducts showed a slight enhancement following SI increase of the proximal extrahepatic bile duct (n = 6); duodenal filling grade tended to be lower in the patients than volunteers (P<.005). CONCLUSION: In patients with anomalous PBJ pancreaticobiliary reflux were demonstrated by dynamic secretin-stimulated MRCP.     

Impairment of natural killer cell and dendritic cell functions by the soluble form of MHC class I-related chain A in advanced human hepatocellular carcinomas

BACKGROUND/AIMS: MHC class I-related chain A (MICA), a human ligand of natural killer (NK) cell stimulatory receptor NKG2D, is expressed in human hepatocellular carcinomas (HCC). Earlier research demonstrated that the soluble form of MICA (sMICA) is released from some types of tumors, but its presence and role in HCC was not determined. METHODS: Serum sMICA was studied in 26 patients with HCC. In vitro experiments were performed to examine the impact of sMICA on NK cell expression of NKG2D and subsequent dendritic cell (DC) activation. RESULTS: The levels of sMICA were frequently elevated in patients with advanced HCC. The elevation of sMICA was associated with down-regulated NKG2D expression and impaired activation of NK cells. In vitro experiments revealed that sMICA derived from advanced HCC was responsible for down-modulation of NKG2D expression and NK cell functions. NK cells upon stimulation of human hepatoma cells induced maturation of DC and enhanced the allostimulatory capacity of DC; maturation and activation of DC were completely abolished when NK cells were pre-treated with sMICA-containing serum. CONCLUSIONS: sMICA is present in sera of patients with advanced HCC and may serve as a tumor evasion mechanism by negatively modulating both innate and adaptive immunity.     

Phase II study of pemetrexed as first-line treatment in elderly (≥75) non-squamous non-small-cell lung cancer: Kyoto Thoracic Oncology Research Group Trial 0901

Background

Single-agent chemotherapy with third-generation non-platinum agents, such as docetaxel, vinorelbine, is a standard therapeutic option for elderly patients with non-small-cell lung cancer (NSCLC). Subset analysis of a previous phase III study comparing pemetrexed with docetaxel in the second-line setting showed the superiority of pemetrexed in an elderly (≥70) population in both efficacy and toxicity.

Patients and methods

This was a single-arm phase II study of pemetrexed in elderly (≥75) Japanese patients with advanced non-squamous NSCLC. Patients received four cycles of pemetrexed (500 mg/m²) every 3 weeks. The primary endpoint was the response rate, and secondary endpoints were safety and survival.

Results

Twenty-eight patients were enrolled between January 2010 and April 2012. The median age of the patients was 77 years (range 75–88). All but one patient had adenocarcinoma histology. The median number of chemotherapy cycles administered was 4 (range, 1–12). Seventeen (60 %) patients completed four cycles of chemotherapy. Partial response was achieved in 7 patients (response rate: 25 %) and stable disease in 11 patients (disease control rate: 64 %). Median progression-free survival and overall survival were 3.3 and 17.5 months, respectively. Grade 3/4 neutropenia and thrombocytopenia were observed in 8 patients (29 %) and 2 (7 %), respectively. Non-hematologic toxicities were generally mild, and there were no treatment-related deaths.

Conclusions

Although this study did not meet our primary endpoint, pemetrexed showed favorable antitumor activity with mild toxicity in elderly patients with non-squamous NSCLC. Further investigations of pemetrexed in this population are warranted (UMIN-CTR number, 000002452).     

Plasma and pleural fluid pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with non-small-cell lung cancer with pleural effusion

Background: Erlotinib is orally active and selectively inhibits the tyrosine kinase activity of the epidermal growth factor receptor. The pleural space penetration and exposure of erlotinib is poorly understood. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in non–small-cell lung cancer (NSCLC) of malignant pleural effusion (MPE). Patients and Methods: We analyzed the PK of erlotinib and OSI-420 on days 1 and 8 after beginning erlotinib therapy in 9 patients with MPE. Their concentrations were determined by high-performance liquid chromatography with ultraviolet detection. Blood samples were obtained five times per day: before administration, and 2, 4, 8, and 24 hours after administration. Pleural effusions were obtained once per day, 2 hours after administration on day 1, and before administration on day 8. The exceptions were cases 2 and 4, which had pleural effusions obtained just before drug administration, and 2, 4, 8, and 24 hours after administration. Results: The mean percentage of penetration from plasma to pleural effusion for erlotinib was 18% on day 1 and 112% on day 8, while these values for OSI-420 were 9.5% on day 1 and 131% on day 8. The area under the drug concentration-time curve of pleural fluid for erlotinib was 28,406 ng-hr/mL for case 2 and 45,906 ng-hr/mL for case 4. Conclusions: There seems to be a significant accumulation of both erlotinib and OSI-420 in MPE with repeated dosing. Although larger studies will be necessary to determine the true impact of erlotinib MPE accumulation on plasma PK and safety, erlotinib can be administered safely to patients with MPE with respect to efficacy and side effects.