Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis.

Enhanced de novo lipogenesis mediated by sterol regulatory element-binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage-activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment.

Intrahepatic Tumor Burden as a Novel Factor Influencing the Introduction of Second-line Chemotherapy for Hepatocellular Carcinoma.

BACKGROUND/AIM: To examine the factors influencing the introduction of the second-line chemotherapy and discuss the selection of first-line agent for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We retrospectively studied 154 patients with HCC who received sorafenib therapy. RESULTS: A total of 109 (70.8%) patients, maintained Child-Pugh grade A and Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 upon sorafenib discontinuation. Multivariate analysis revealed that the up-to-seven criteria status in the hepatic lesion [p=0.019; odds ratio=OR, 2.685], albumin-bilirubin (ALBI) grade (p=0.002; OR=3.589), and macroscopic vascular invasion (MVI) (p=0.008; OR=2.972) were significant factors at sorafenib initiation that influenced the maintenance of Child-Pugh grade A and ECOG-PS ≤1 upon therapy discontinuation. CONCLUSION: Not only ALBI grade and MVI, but also up-to-seven criteria status in the hepatic lesion influence the introduction of second-line therapy, and could affect the selection of the first-line therapy.

Current status and future prospects of chemotherapy for advanced hepatocellular carcinoma.

Sorafenib is the only drug that demonstrates a survival benefit for advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is limited, so development of a more effective treatment method and second-line treatments is needed. Since the advent of sorafenib, clinical studies have been conducted with a variety of drugs and treatment methods, mainly with molecular targeted therapy, but almost all trials have ended in failure. The reasons for the difficulty in the development of a novel drug or treatment method include the diversity of mechanisms in the carcinogenesis and development of HCC, as well as the presence of background liver diseases such as chronic hepatitis and cirrhosis. Trials with immune-checkpoint inhibitors, which have an entirely different anti-tumor mechanism from that of molecular targeted drugs or cytotoxic drugs, have recently begun. Based on the results to date, clinical trials are now being conducted with enriched target subjects. In the future, providing more individualized treatment approaches for patients with advanced HCC will be essential.

Thalamic deep brain stimulation for posttraumatic action tremor.

We report a case of thalamic deep brain stimulation (DBS) for treatment of posttraumatic tremor. An 18-year-old right-handed man developed a disabling and medically refractory action tremor in the right upper extremity 9 months after sustaining diffuse axonal injury in a motor vehicle collision. DBS of the left ventral intermediate nucleus of the thalamus (Vim) suppressed the tremor without complication and should be considered as an option for the management of intractable posttraumatic tremor.

Bilateral stimulation of the subthalamic nucleus in Parkinson's disease: surgical efficacy and prediction of outcome.

OBJECTIVE: Over the last decade neurosurgery has reemerged as a valid therapy for patients with advanced Parkinson's disease. Previously, we have addressed safety and efficacy of subthalamic nucleus (STN) deep brain stimulation (DBS). In this study, we extended these observations and analyzed factors that affect surgical outcome and its predictive value. METHODS: Thirty-nine patients were enrolled in an open-label prospective protocol designed to evaluate safety and efficacy of bilateral STN DBS in patients with advanced Parkinson's disease between January 1999 and July 2002. Electrodes were stereotactically implanted with electrophysiological conformation of the target location. All patients were evaluated in the medication 'off' and 'on' state preoperatively and at 3, 6, and 12 months after surgery in medication 'on' and 'off' as well as in the stimulation 'off' and 'on' state. Tests included Unified Parkinson's Disease Rating Scales (UPDRS) as well as timed tests. All data was analyzed by means of Analysis of Variance. For outcome prediction, correlation and linear regression analyses were utilized. Stimulation produced significant improvements in all 'off' mediation conditions, resulting in a 42% improvement in UPDRS III score at 12 months compared to the preoperative status. Stimulation in conjunction with medication did not produce any significant change when compared to the preoperative medication 'on' state. Dyskinesia, motor fluctuations, and duration of 'off' periods were significantly reduced with stimulation. Significant outcome predictor variables were age, preoperative percent change of UPDRS III score from medication 'off' to medication 'on' state, and the duration of disease. CONCLUSIONS: Bilateral STN DBS produces robust improvements in parkinsonian motor symptoms. Surgical outcome can reliably be predicted.

Pallidal deep brain stimulation for longstanding severe generalized dystonia in Hallervorden-Spatz syndrome. Case report.

Generalized dystonia is one of the most disabling movement disorders. Ablative stereotactic surgery such as pallidotomy has been performed for medically refractory dystonia. Recently, deep brain stimulation (DBS) has appeared as an alternative to ablative procedures. Nevertheless, there have been few published reports detailing improvement in dystonia with DBS. This 36-year-old man with Hallervorden-Spatz syndrome suffered from intractable primary generalized dystonia for 28 years. He was completely dependent for activities of daily living and wheelchair bound because of continuous severe dystonic movements in the face, tongue, neck, trunk, and upper and lower extremities while at rest. The Burke-Fahn-Marsden (BFM) Dystonia Rating Scale score was 112 (maximum 120 points). Bilateral DBS of the globus pallidus internus was performed and resulted in marked improvement in motor functioning and dystonic symptoms with a significant reduction in disability. The BFM score improved to 22.5 points (80% improvement) at 3 months postsurgery and the patient's dystonia was still well suppressed 1 year after surgery. Bilateral pallidal stimulation is an effective and safe treatment for intractable generalized dystonia in Hallervorden-Spatz syndrome, even if the disability is severe and longstanding.

Deep brain stimulation for movement disorders: morbidity and mortality in 109 patients.

OBJECT: Deep brain stimulation (DBS) has been advocated as a more highly effective and less morbidity-producing alternative to ablative stereotactic surgery in the treatment of medically intractable movement disorders. Nevertheless, the exact incidence of morbidity and mortality associated with the procedure is not well known. In this study the authors reviewed the surgical morbidity and mortality rates in a large series of DBS operations. METHODS: The authors retrospectively analyzed surgical complications in their consecutive series of 179 DBS implantations in 109 patients performed by a single surgical team at one center between July 1998 and April 2002. The mean follow-up period was 20 months. There were 16 serious adverse events related to surgery in 14 patients (12.8%). There were two perioperative deaths (1.8%), one caused by pulmonary embolism and the second due to aspiration pneumonia. The other adverse events were two pulmonary embolisms, two subcortical hemorrhages, two chronic subdural hematomas, one venous infarction, one seizure, four infections, one cerebrospinal fluid leak, and one skin erosion. The incidence of permanent sequelae was 4.6% (five of 109 patients). The incidence of device-related complications, such as infection or skin erosion, was also 4.6% (five of 109 patients). CONCLUSIONS: There is a significant incidence of adverse events associated with the DBS procedure. Nevertheless, DBS is clinically effective in well-selected patients and should be seriously considered as a treatment option for patients with medically refractory movement disorders.

Thalamic deep brain stimulation for disabling tremor after excision of a midbrain cavernous angioma. Case report.

Thalamic deep brain stimulation (DBS) has been demonstrated to be effective for the treatment of parkinsonian or essential tremor. To date, however, few data exist to support the application of this method to treat midbrain tremor. A 24-year-old right-handed man underwent radiosurgery and subsequent resection of a recurrently hemorrhaging cavernous angioma located in the left side of the midbrain. The surgery exacerbated severe choreoathetotic resting and action tremors of his right extremities and trunk. The patient underwent placement of a deep brain stimulator into the left ventral intermediate nucleus of the thalamus (Vim). Postoperatively, decreased truncal ataxia and right-sided choreoathetotic tremor were demonstrated, with a 57% increase in dexterity as measured by task testing. The authors demonstrate that DBS can be an effective treatment modality for disabling tremor after resection of a midbrain cavernous angioma.