A study on prevention of bleeding complications using lusutrombopag for safe RFA in patients with hepatocellular carcinoma with low platelet counts: prospective observational study.

BACKGROUND: Platelet (PLT) transfusion was the most practical way to increase patients' PLT counts before invasive hepatic procedures such as radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). A novel drug that raises the PLT count by acting on the thrombopoietin receptor has recently become available. METHODS: Lusutrombopag 3 mg was administered daily for 7 days to patients who underwent RFA for liver tumors with low PLT counts (< 50,000 PLT µL- 1). We collected demographic data concerning the patients' liver function and PLT counts. RESULTS: Lusutrombopag was administered to 91 patients, with a median age of 71 years (range 51-86). Forty-two patients had hepatitis C, 12 had hepatitis B, 21 had alcoholic liver disease, 11 had nonalcoholic steatohepatitis, and five had other diseases. The median Child-Pugh score was 7 (range 5-11). Thirty-seven patients had stage I tumors, 41 had Stage II, 12 had stage III, and one had stage IV. PLT count was elevated from 4.4 × 104 ± 1.4 × 104 to 8.6 × 104 ± 2.5 × 104 PLT µL- 1. Lusutrombopag administration prevented PLT transfusions in 84/91 patients (92%). No patient had bleeding complications after RFA. One had portal thrombosis after lusutrombopag administration. Patients who achieved PLT counts of > 50,000 PLT µL- 1 had higher PLT counts before lusutrombopag administration. The degree of splenomegaly did not affect the rate of PLT count elevation. There was no specific adverse effect by administrating lusutrombopag for patients with PLT counts of around 50,000 µL- 1 but > 50,000 µL- 1. CONCLUSIONS: Lusutrombopag administration before RFA was effective and seemed to be relatively safe for hepatocellular carcinoma patients with low PLT counts. TRIAL REGISTRATION: This study was approved by Japanese Red Cross Medical Center Institutional Reseach Comittie (#862, 07/03/2016), and was registered in a publically accessible primary register (#UMIN000046629, registered date: 14/01/2022).

Effectiveness of direct acting antiviral agents for hepatitis C virus related recurrent hepatocellular carcinoma patients who had multiple courses of recurrence.

Eradication of hepatitis C virus (HCV) using direct acting antiviral agents (DAAs) has been reported to alter liver function and reduce the recurrence rate after curative treatment in naïve hepatocellular carcinoma (HCC) patients. However, it is not well known whether administration of DAAs had favourable effect on HCC patients with multiple courses of recurrence. We retrospectively extracted 146 HCV-related HCC (C-HCC) patients who received curative treatment using radiofrequency ablation (RFA) followed by eradication treatment with DAA between 1 January 2015 and 31 December 2017. We also extracted 184 C-HCC patients who were curatively treated using RFA without HCV eradication treatment between 1 January 2009 and 31 July 2014 as controls. We used propensity score matching method and adjusted following factors between the 2 groups: age, sex, liver function, number of recurrence times, tumour diameter and tumour numbers. We finally enrolled 47 C-HCC patients with eradication of HCV, and 47 C-HCC patients without HCV eradication as controls. Primary end point was time to curative treatment failure. We defined time to curative treatment failure as the interval from curative treatment initiation to premature discontinuation of this type of therapy. Their clinical data, time to curative treatment failure and overall survival were compared. We also assessed the prognostic values of time to curative treatment failure and overall survival using multivariate Cox proportional hazard models. The median age was 74.8 years, 60 patients (63.8%) were male, and 81 patients (86.2%) were Child-Pugh class A. The median tumour number was 1, tumour diameter was 20 mm, and frequency of recurrence was 3 times. There were no significant differences about patients' backgrounds between the 2 groups. The cumulative time to curative treatment failure rates of patients who received DAA were 93.6% and 73.2% at 1 and 3 years, respectively; those of controls were 72.5%, and 37.1% (p < .01). Multivariate analysis indicated that eradication with DAAs (HR 0.23, 95% CI; 0.12-0.43, p < .01) and DCP >50 mAU/ml (HR 2.62, 95% CI; 1.45-4.74, p < .01) as independent factors contributed to time to curative treatment failure. The cumulative overall survival rates of patients who received DAAs were 93.6% and 72.6% at 1 and 3 years, respectively; those of controls were 72.8% and 37.4% (p < .01). Multivariate analysis indicated that eradication with DAAs (HR 0.32, 95% CI; 0.17-0.60, p < .01) and frequency of recurrence times (HR 1.20 per 1 time, 95% CI; 1.01-1.42, p = .038) as independent factors related to overall survival. Eradication of HCV using DAAs prolonged not only time to curative treatment failure but also overall survival even in C-HCC patients with multiple courses of recurrence.

Fructo-oligosaccharides ameliorate steatohepatitis, visceral adiposity, and associated chronic inflammation via increased production of short-chain fatty acids in a mouse model of non-alcoholic steatohepatitis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Within the spectrum of NAFLD, non-alcoholic steatohepatitis (NASH) in combination with hepatic inflammation and fibrosis can lead to liver cirrhosis and hepatocellular carcinoma. Dysbiosis was reported to contribute to NASH pathogenesis. This study aimed to determine the effects of fructo-oligosaccharides (FOS) on steatohepatitis and visceral adiposity in an obese mouse model of NASH. METHODS: Twelve newborn C57BL/6 J male mice were subcutaneously injected with monosodium glutamate (MSG) to induce obesity on a conventional diet. Six mice were also administered 5% FOS via drinking water from 10 weeks of age. At 18 weeks, histological characteristics of the liver and epididymal fat were compared between the groups. Hepatic mRNA expression of lipid metabolism enzymes and SCFA in feces and sera were measured. RESULTS: Hepatic steatosis, inflammatory cell infiltration, and hepatocyte ballooning in the liver and increased hepatic mRNA expression of fatty acid synthase and glycerol-3-phosphate acyltransferase were observed in the MSG-treated mice. FOS treatment improved the liver pathology and blunted the increases in the mRNA expression levels of lipid metabolism enzymes. In addition, FOS inhibited adipocyte enlargement and formation of crown-like structures and reduced the M1 macrophage frequency in the epididymal fat of the MSG mice (39.4% ± 3.0% vs. 22.8% ± 0.7%; P = 0.001). FOS increased not only the fecal concentrations of n-butyric acid (0.04 ± 0.01 vs. 0.38 ± 0.14 mg/g, P = 0.02), propionic acid (0.09 ± 0.03 vs. 0.42 ± 0.16 mg/g, P = 0.02), and acetic acid (0.65 ± 0.16 vs. 1.48 ± 0.29 mg/g, P = 0.03) but also the serum concentration of propionic acid (3.9 ± 0.5 vs. 8.2 ± 0.5 µmol/L, P = 0.001). CONCLUSIONS: FOS ameliorates steatohepatitis, visceral adiposity, and chronic inflammation by increasing SCFA production.

The Coefficient of Variation of Step Time Can Overestimate Gait Abnormality: Test-Retest Reliability of Gait-Related Parameters Obtained with a Tri-Axial Accelerometer in Healthy Subjects.

The aim of this study was to investigate whether variation in gait-related parameters among healthy participants could help detect gait abnormalities. In total, 36 participants (21 men, 15 women; mean age, 35.7 ± 9.9 years) performed a 10-m walk six times while wearing a tri-axial accelerometer fixed at the L3 level. A second walk was performed ≥1 month after the first (mean interval, 49.6 ± 7.6 days). From each 10-m data set, the following nine gait-related parameters were automatically calculated: assessment time, number of steps, stride time, cadence, ground force reaction, step time, coefficient of variation (CV) of step time, velocity, and step length. Six repeated measurement values were averaged for each gait parameter. In addition, for each gait parameter, the difference between the first and second assessments was statistically examined, and the intraclass correlation coefficient (ICC) was calculated with the level of significance set at p < 0.05. Only the CV of step time showed a significant difference between the first and second assessments (p = 0.0188). The CV of step time also showed the lowest ICC, at <0.50 (0.425), among all parameters. Test-retest results of gait assessment using a tri-axial accelerometer showed sufficient reproducibility in terms of the clinical evaluation of all parameters except the CV of step time.

[Successful Hepatic Arterial Injection Chemotherapy for Hepatocellular Carcinoma with Inferior Vena Cava Invasion and Extrahepatic Spread in a Patient with Child-Pugh Class BLiver Cirrhosis].

A 65-year-old woman who had liver cirrhosis(Child-Pugh class B)due to hepatitis C infection was diagnosed with hepatocellular carcinoma with hepatic vein invasion, portal vein tumor invasion, and lung metastasis. No recommended treatment was noted in the clinical practice guidelines for hepatocellular carcinoma with vascular invasion in patients with Child- Pugh class B liver cirrhosis. After initiating arterial injection chemotherapy, marked decreases in tumor size of lung metastasis, vascular invasion, and primary liver cancer were observed. Based on our experience and previous reports, hepatic arterial infusion chemotherapy was considered valuable for hepatocellular carcinoma with vascular invasion, even in patients with Child-Pugh class B liver cirrhosis.

N-glycan-dependent cell-surface expression of the P2Y2 receptor and N-glycan-independent distribution to lipid rafts.

P2Y2 receptor (P2Y2R) is a G-protein-coupled receptor (GPCR) that couples with Gαq/11 and is stimulated by ATP and UTP. P2Y2R is involved in pain, proinflammatory changes, and blood pressure control. Some GPCRs are localized in lipid rafts for interaction with other signaling molecules. In this study, we prepared N-glycan-deficient mutants by mutating the two consensus Asn residues for N-glycosylation to Gln to examine intracellular localization and association with lipid rafts. Western blotting of the wild type (WT) protein and mutants (N9Q, N13Q, N9Q/N13Q) in COS-7 cells showed that both Asn residues were glycosylated in the WT. Fluorescent microscopy analysis showed that WT, N9Q and N13Q were expressed in the endoplasmic reticulum (ER), Golgi body, and cell membrane, but N9Q/N13Q was only found in the ER. WT, N9Q and N13Q moved from the cell surface to endosomes within 15 min after UTP stimulation. WT and the N9Q/N13Q glycosylation-deficient mutant appeared in the detergent insoluble membrane fraction, lipid raft. These findings suggest that P2Y2R is localized in lipid rafts in the ER during biosynthesis, and that N-glycosylation is required for subsequent expression in the cell membrane. In the presence of epoxomicin, a proteasome inhibitor, there was a significant increase in the level of N9Q/N13Q, which suggests that N-glycan-deficient P2Y2R undergoes proteasomal degradation.

Emergency endoscopic variceal ligation following variceal rupture in patients with advanced hepatocellular carcinoma and portal vein tumor thrombosis: a retrospective study.

BACKGROUND: The outcomes of treatment of ruptured varices in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) are unclear. We therefore evaluated the long- (rebleeding and death) and short-term (immediate death within 24 h of variceal bleeding diagnosis) outcomes of patients with PVTT who underwent emergency variceal band ligation. METHODS: Data on 62 patients with PVTT and endoscopically proven esophageal or gastric variceal bleeding from 2007 to 2012 were studied. In most cases, the varices were treated using endoscopic variceal band ligation (EVL). We assessed the patients' rebleeding-free and overall survival using the Kaplan-Meier method, and a Cox proportional hazard model was used to analyze effect of independent factors on rebleeding-free and overall survival times. RESULTS: Most patients had decompensated cirrhosis and were classified as Child-Pugh class B (56%) or C (36%). A total of 35 patients (56%) had PVTT in the main portal trunk. Among all patients, 58 (94%) and 4 (6%) had esophageal and gastric variceal bleeding, respectively. Bleeding was managed using EVL in all, but one patient (98%) who was treated with a Sengstaken-Blakemore tube. A total of 24 patients (39.3%) experienced rebleeding, and these patients had a median overall survival time of 36 days. A PVTT in the main portal trunk was predictive of rebleeding (hazard ratio 3.706, p = .0223), and α-fetoprotein-L3 levels <37.4% (hazard ratio 0.464, p = 0.015) and Child-Pugh class A/B (hazard ratio 0.398, p = 0.007) were associated with overall survival. We observed 95 bleeding events in 62 patients. EVL achieved hemostasis in 92 of the 95 bleeding events, whereas seven immediate deaths occurred due to variceal bleeding (7/92, 7.6%). All three bleeding events treated with modalities other than EVL resulted in immediate deaths. CONCLUSIONS: EVL is a safe and effective treatment of variceal ruptures in patients with HCC and PVTT. After successful hemostasis, alleviation of the underlying liver function impairment and tumor control are equally important for a good prognosis.

[Development of Rapid Assay of Transthyretin in Whole Blood].

Transthyretin (TTR), a rapid turnover protein with a half-life of 2 days, which is shorter than that of albumin, is considered to be a sensitive indicator of a patient's nutritional status. We have newly developed a rapid assay of TTR by immunochromatography (IC) using samples of whole blood as well as serum at volumes of 10 µL. The fundamental performance was evaluated using control sera. In addition, whole blood samples were measured by IC and the results were compared with measured levels of plasma samples by turbidimetry and those of sera by nephelometry. The limit of quantification was 8.3 mg/dL. The linearity was 8.7-35.4 mg/dL. The reproducibility was 6.1-8.6% coefficient of variation. Bilirubin, hemolysis, chyle, and rheumatoid factor did not influence the measured levels. An increase of 1% in hematocrit resulted in a decrease of 1% in the measured levels. The correlation between IC (y) and nephelometry (x) was determined to be y = 0.927x+2.62 (r = 0.935, n = 64). The newly developed IC showed good performance and it was suggested that IC would be useful for nutrition monitoring as point of care test.

A Case of Rheumatoid Meningitis Diagnosed with FLAIR Images and Anti-cyclic Citrullinated Peptide Antibodies Levels.

Rheumatoid meningitis (RM) is a rare but serious extra-articular manifestation of rheumatoid arthritis. Due to the absence of specific biomarkers, imaging findings, or guidelines for its detection, the diagnosis of RM is difficult. This report describes a patient of RM diagnosed with an open biopsy and discusses the utility of anticyclic citrullinated peptide antibodies (ACPA) levels in the serum and cerebrospinal fluid (CSF), and contrast-enhanced (CE) fluid-attenuated inversion recovery (FLAIR) images for screening and monitoring RM. A 65-year-old woman presented with a 2-month history of headaches. Imaging studies showed asymmetric meningeal and leptomeningeal involvement seen on brain magnetic resonance imaging (MRI). An open biopsy of the meninges and leptomeninges depicted palisaded and necrotizing granulomatous inflammation, which suggests rheumatoid nodules. Treatment with prednisolone and tocilizumab led to symptom improvement and reduced lesion intensity on follow-up MRI. Throughout the treatment, the ACPA index in her serum and CSF, and the findings of CE-FLAIR images, rather than the CE T1WI, reflected disease activity. For 6 months, the patient has been stable without symptom recurrence. The ACPA index and the CE-FLAIR images were useful for the diagnosis and monitoring of RM. To validate these findings, further studies are necessary.

Subarachnoid Hemorrhage Confirmed by Magnetic Resonance Imaging in a Patient with Brain Death owing to Hypoxic Encephalopathy Following Suicide by Hanging.

Although true subarachnoid hemorrhage (SAH) is an atypical complication owing to suicide by hanging, pseudo-SAH can often develop because of hypoxic encephalopathy. Therefore, differentiating pseudo-SAH from true SAH using brain computed tomography (CT) is often challenging. In Japan, an individual's cause of brain death must be determined to be eligible for organ donation, regardless of whether true SAH is involved or not. Herein, we report a case of SAH confirmed by magnetic resonance imaging (MRI) in a patient with brain death owing to hypoxic encephalopathy following suicide by hanging. A 48-year-old man attempted suicide by hanging. Upon arrival at the hospital, he developed pulseless electrical activity with apnea. Although spontaneous circulation returned within a few minutes of his arrival, spontaneous breathing did not recover. The patient was in deep comatose state without response to pain stimulation, brainstem reflexes, or electrical activities on an electroencephalogram. Consequently, the patient met diagnostic criteria for clinical brain death based on the Japanese organ transplantation law. Brain CT revealed global hypoxic injury and high density in the basal cisterns and subarachnoid space. Brain MR T2*-weighted imaging revealed low intensity at the left Sylvian fissure underlying the hematoma. These findings indicated brain death owing to hypoxic encephalopathy following hanging, and incidental true SAH was confirmed by MRI. Donor surgery and organ transplantation were performed. Spontaneous SAH can often develop secondary to hanging, and brain MRI can effectively determine whether the cause of brain death involves true SAH.

Endovascular embolization and needle aspiration of a life-threatening cervical hematoma due to a neurofibromatosis type 1-associated arteriovenous fistula: illustrative case.

BACKGROUND: In cases of neurofibromatosis in which the bleeding source is considered strongly related to a neurofibroma, an open surgical approach could risk uncontrollable bleeding from the vascular wall infiltration by neurofibroma. The case of a neurofibromatosis type 1 (NF1)-associated arteriovenous fistula presenting with a life-threatening cervical hematoma that was successfully treated with alternative treatment is described. OBSERVATIONS: A 68-year-old woman diagnosed with NF1 presented with sudden onset of a spontaneous right cervical mass. Neck imaging on admission showed a massive subcutaneous hematoma with tracheal deviation and abnormal vascular structure in the hematoma. Digital subtraction angiography showed that an arteriovenous fistula (AVF) fed from a vertebral artery located within the hematoma cavity was the primary source of bleeding and feeding arteries from the occipital artery to the neurofibroma. Embolization of the cervical neurofibroma, as well as the AVF, was performed to reduce the secondary risk of bleeding, and was accomplished. After endovascular treatment, needle aspiration of the cervical hematoma was performed to reduce the mass effect. LESSONS: When performing open surgery via tissues with neurofibromatosis proliferation, uncontrollable bleeding can occur. Therefore, endovascular embolization and needle aspiration of the hematoma should be considered in this setting.

Percutaneous ethanol injection for hepatocellular carcinoma: 20-year outcome and prognostic factors.

BACKGROUND: Ethanol injection is the best-known image-guided percutaneous ablation for hepatocellular carcinoma (HCC) and a well-tolerated, inexpensive procedure with few adverse effects. However, there have been few reports on its long-term results. AIMS: We report a 20-year consecutive case series at a tertiary referral centre. METHODS: We performed 2147 ethanol injection treatments on 685 primary HCC patients and analysed a collected database. RESULTS: Final computed tomography demonstrated complete ablation of treated tumours in 2108 (98.2%) of the 2147 treatments. With a median follow-up of 51.6 months, 5-, 10- and 20-year survival rates were 49.0% [95% confidence interval (CI) = 45.3-53.0%], 17.9% (95% CI = 15.0-21.2%) and 7.2% (95% CI = 4..5-11.5%) respectively. Multivariate analysis demonstrated that age, Child-Pugh class, tumour size, tumour number and serum alpha-fetoprotein level were significant prognostic factors for survival. Five-, 10- and 20-year local tumour progression rates were 18.2% (95% CI = 15.0-21.4%), 18.4% (95% CI = 15.2-21.6%) and 18.4% (95% CI = 15.2-21.6%) respectively. Five-, 10- and 20-year distant recurrence rates were 53.5% (95% CI = 49.4-57.7%), 60.4 (95% CI = 56.3-64.5%) and 60.8% (95% CI = 56.7-64.9%) respectively. There were 45 complications (2.1%) and two deaths (0.09%). CONCLUSIONS: Ethanol injection was potentially curative for HCC, resulting in survival for more than 20 years. This study suggests that new ablation therapies will achieve similar or even better long-term results in HCC.

Construction of super-rapid brain MRA using oblique transverse acquisition phase contrast angiography with tilted optimized non-saturated excitation pulse.

[Background] Magnetic resonance angiography (MRA) is one of the most important sequences to estimate a cerebrovascular disease. We often encounter poor image quality due to slow arterial flow related to aging and motion artifact caused by disturbance of consciousness. We focused on phase contrast angiography (PCA) to overcome these difficulties. PCA can reduce scan time drastically by combining transverse acquisition and partial slab setting covering entire brain arteries. However, transverse acquisition in PCA has a large difference in signal intensity between proximal and distal vessels. Therefore, we apply tilted optimized non-saturated excitation (TONE) to improve image quality. [Purpose] The purpose of this study to investigate the usefulness of TONE for PCA. [Method] We estimated the efficacy of TONE in transverse acquisition PCA using measurement of signal intensity in arteries. We compared image quality among 1 min PCA with/without TONE and time-of flight (TOF)-MRA, by visual. [Result] TONE improved the signal inhomogeneity in entire brain arteries. PCA with TONE (5°-9°) demonstrated the highest image quality. [Conclusion] Oblique transverse acquisition PCA with TONE provides superior image quality compared with TOF with similar scan time. TONE improved image quality by the homogenizing signal intensity of vessels from proximal to distal in oblique transvers acquisition PCA. Our MRA can be performed in about 1 min and provides sufficient quality to estimate brain vessels.

Small Sphenoid Ridge as a Factor Associated with Laterally Deviated Proximal Sylvian Fissure in Patients Undergoing Pterional Craniotomy.

BACKGROUND: During the pterional-transsylvian approach, we sometimes encounter the proximal Sylvian fissure (SF) deviating laterally beyond the fold of the sphenoidal ridge (SR) and experience difficulty dissecting the SF due to the deep and oblique dissection plane. In the present study, we explored the association between the height of the SR and lateral deviation of the SF during the pterional-transsylvian approach. METHODS: The association between the height of the SR on axial computed tomography and the presence of a laterally deviated SF was evaluated by reviewing patients who had undergone pterional craniotomy. RESULTS: Among the 52 patients included, lateral deviation of the SF was observed in 8 patients (13.4%). The median height of the SR was significantly smaller in patients with laterally deviated SF (6.0 mm) than in patients with non-deviating SF (13.4 mm; P < 0.0001). The oculomotor nerves and middle fossa were observed at the edge of the dissection plane of the SF in all patients with a laterally deviating SF, while medial structures such as the internal carotid artery or optic nerve were observed in patients with non-deviating SF. CONCLUSIONS: Small SR was associated with lateral deviation of the proximal SF.

[Successful treatment of a gastrointestinal stromal tumor with liver metastases in a case that tolerated imatinib administration, by radiofrequency ablation using contrast-enhanced ultrasonography].

We report a case of gastrointestinal stromal tumor (GIST) with liver metastases which was undetectable by B-mode ultrasonography, effectively treated by radiofrequency ablation using contrast-enhanced ultrasonography US. A 43-year-old woman was admitted for the treatment of 6 lesions up to 4cm in diameter, which had emerged from necrotic sites within the liver after imatinib treatment. The recurrent lesions were not detected on B-mode US, and it was difficult to perform radiofrequency ablation (RFA) treatment. Using a contrast-enhanced agent (sonazoid), the recurrent lesions were detected and treated by RFA. RFA is considered to be an effective treatment for GIST with liver metastases that tolerate imatinib administration.

Improvement in gait function after carotid endarterectomy is associated with postoperative recovery in perfusion and neurotransmitter receptor function in the motor-related cerebral cortex: a 123I-iomazenil SPECT study.

OBJECTIVE: Carotid endarterectomy (CEA) often restores cerebral perfusion and neurotransmitter receptor function, which is seen on early and late images, respectively, on brain I-iomazenil single-photon emission computed tomography (SPECT). The reliability of gait-related parameters obtained using a triaxial accelerometer, a portable device for gait assessment, has been confirmed with test-retest measurements. The purpose of the present prospective cohort study was to determine whether improvement in gait function after CEA is associated with postoperative recovery in perfusion and neurotransmitter receptor function in the motor-related cerebral cortex. METHODS: Gait testing using a triaxial accelerometer was performed preoperatively and 6 months postoperatively in 64 patients undergoing CEA for ipsilateral internal carotid artery stenosis (≥70%). I-iomazenil SPECT was also performed with scanning within 30 min (early images) and at 180 min (late images) after tracer administration before and after surgery. SPECT data were analyzed using a three-dimensional stereotactic surface projection, and motor (Brodmann 4) and premotor (Brodmann 6) cortexes in each hemisphere were combined and defined as the motor-related cortex. RESULTS: Based on preoperative and postoperative gait testing, seven patients (11%) showed postoperative improved gait. Logistic regression analysis revealed that postoperative increase in I-iomazenil uptake in the motor-related cortex ipsilateral to surgery on early [95% confidence interval (CI), 4.32-365.21; P = 0.0477) or late (95% CI, 9.45-1572.57; P = 0.0173) images was an independent predictor of postoperative improved gait. CONCLUSIONS: Improvement in gait function after CEA is associated with postoperative recovery in perfusion and neurotransmitter receptor function in the motor-related cerebral cortex.

Impact of Adverse Events on the Progression-Free Survival of Patients with Advanced Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Retrospective Study.

BACKGROUND AND OBJECTIVE: Experience of the use of lenvatinib (LEN) in the clinical setting remains limited. We conducted this study to elucidate the factors associated with progression-free survival (PFS) in patients with advanced HCC treated with LEN. METHODS: In this multicenter retrospective study, we analyzed data on patient characteristics, treatment outcomes, and adverse events (AEs) for 77 patients with advanced hepatocellular carcinoma (HCC). We also analyzed PFS and factors that influence PFS. RESULTS: The response rate to LEN was 29.9% and the disease control rate was 77.9%. Patients who achieved relative dose intensities of more than 70% had better outcomes (response rate 45.2% vs. 11.4%, P < 0.01). Appetite loss, fatigue, diarrhea, hypertension, and thyroid dysfunction were the most frequent AEs. Twenty-three patients (29.9%) had grade 3 or 4 AEs. Fifty-two patients (67.5%) required a dose reduction and 47 (61.0%) stopped taking the drug due to AEs. The PFS rates at 3, 6, and 12 months were 81.2%, 49.8%, and 34.8%, respectively. The median PFS was 5.6 months. Multivariate analysis showed that thyroid dysfunction of grade ≥ 2 (hazard ratio [HR] 4.57, 95% confidence interval [CI] 2.05-10.2, P < 0.01), appetite loss (HR 3.58, 95% CI 1.72-7.52, P < 0.01), and tumor diameter ≥ 40 mm (HR: 2.27, 95% CI 1.17-4.40, P = 0.015) were independent factors associated with poor PFS. On the other hand, Child-Pugh class 5A (HR 0.41, 95% CI 0.19-0.90, P = 0.027) and complete or partial response (HR 0.40, 95% CI 0.17-0.95, P = 0.039) were independent factors associated with better PFS. CONCLUSIONS: Thyroid dysfunction and appetite loss after the administration of LEN were independent factors associated with shorter PFS, so these AEs should be carefully managed after administering LEN.

Ramucirumab after prior sorafenib in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein: Japanese subgroup analysis of the REACH-2 trial.

BACKGROUND: The global, randomized, phase 3 REACH-2 study (ClinicalTrials.gov identifier: NCT02435433) found significantly longer overall survival (OS) for second-line ramucirumab versus placebo (hazard ratio [HR]: 0.710, 95% confidence interval [CI] 0.531-0.949, P = 0.0199) in patients with advanced hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP) ≥ 400 ng/mL. This prespecified subgroup analysis evaluated the efficacy and safety of ramucirumab in the Japanese patients enrolled in the study. METHODS: Patients with advanced HCC and AFP ≥ 400 ng/mL after first-line sorafenib were randomized 2:1 to ramucirumab (8 mg/kg intravenously) or placebo every 2 weeks. Hazard ratios for progression-free survival (PFS) and OS (primary endpoint of the overall study) were estimated using the stratified Cox regression model. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with AFP ≥ 400 ng/mL. RESULTS: In the Japanese REACH-2 subpopulation, there were improvements for ramucirumab (n = 41) versus placebo (n = 18) in PFS (HR 0.282, 95% CI 0.144-0.553) and OS was numerically prolonged (HR 0.599, 95% CI 0.303-1.187), consistent with the significant benefit seen in the overall REACH-2 study population. In the ramucirumab and placebo arms, respectively, the objective response rate was 7.3% and 0%, and the disease control rate was 70.7% and 33.3%. The most frequently reported grade ≥ 3 treatment-emergent adverse event was hypertension (ramucirumab: 15%; placebo: 11%). CONCLUSIONS: Ramucirumab after prior sorafenib improved PFS and OS compared with placebo, with a manageable safety profile, in the Japanese REACH-2 subpopulation, consistent with the overall REACH-2 study results. Ramucirumab is the first agent to demonstrate clinical benefit for Japanese patients with HCC in the second-line setting.

Hepatic Arterial Infusion Chemotherapy versus Sorafenib in Patients with Advanced Hepatocellular Carcinoma.

BACKGROUND: Prior to the approval of sorafenib, hepatic arterial infusion chemotherapy (HAIC) was offered to patients with advanced hepatocellular carcinoma (HCC) in East Asia, particularly Japan. According to the Japanese guidelines, HAIC is recommended as one of the treatment options in patients without extrahepatic metastasis (EHM). METHODS: The present cohort study compared the use of HAIC and sorafenib on outcomes of patients with advanced HCC. Consecutive patients with advanced HCC who received HAIC or sorafenib as a first-line systemic therapy were enrolled from 10 Japanese institutions. The primary outcomes were overall survival (OS) in patients with macrovascular invasion (MVI), but without EHM, and OS in patients without both MVI and EHM. RESULTS: Between 2009 and 2016, 2,006 patients were enrolled (541 HAIC patients, 1,465 sorafenib patients). After propensity score matching, the OS of patients with MVI but without EHM was significantly longer in the HAIC group compared with the sorafenib group (10.1 vs. 9.1 months for the HAIC and sorafenib groups, respectively; n = 170 for each group; hazard ratio [HR] 0.668; 95% confidence interval [95% CI] 0.475-0.935; p = 0.018). There was no significant difference in OS between patients without both MVI and EHM (12.2 vs. 15.4 months for the HAIC and sorafenib groups, respectively; n = 76 in each cohort after propensity score matching; HR 1.227; 95% CI 0.699-2.155; p = 0.475). CONCLUSION: HAIC is a potential front-line treatment choice in a subpopulation of patients with advanced HCC with MVI but without EHM.

Treatment strategy for hepatocellular carcinoma: expanding the indications for radiofrequency ablation.

BACKGROUND: Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is ordinarily indicated for those with three or fewer nodules, none of which exceeds 3 cm in diameter. This study investigated whether an apparent threshold exists in the diameter and number of nodules in terms of the prognosis of patients with HCC. METHODS: We enrolled 663 naïve patients with HCC who were treated with RFA at our hospital between 1999 and 2005. We analyzed the patients' prognosis using multivariate Cox proportional regression with the diameter and number of nodules as covariates and Child-Pugh class as a stratification factor. The diameter and number were categorized as 5 cm and 1, 2-3, 4-5, and >5, respectively. RESULTS: The adjusted hazard ratio of patients whose largest nodule was 5 cm was 1, 1.51, 2.56, 2.25, and 2.71, respectively. The adjusted hazard ratio of patients with one, two or three, four or five, and more than five nodules was 1, 1.35, 1.70, and 2.12, respectively. Therefore, patients with three or fewer nodules, none of which exceeds 5 cm in diameter, have a 5-year survival of 40%. CONCLUSIONS: The prognosis of the patients worsened gradually as the diameter and number of nodules increased. No apparent threshold in the diameter or number of HCC nodules was detected. RFA can be applied beyond the conventional indications.