Protective Effects of a Mixed Medicinal Herb Extract (NUC1) on Collagenase-Induced Osteoarthritis in Rabbits.

NUC1 (Nutraceutical compound 1) is an ethanol extract composed of a formulation based on medicinal herbs traditionally used for the treatment of arthritis in Korea and China. This study investigated the therapeutic effects of NUC1 on osteoarthritis (OA). The protective effect of NUC1 on OA was tested in a rabbit model of collagenase-induced arthritis (CIA) for 4 weeks. Results were compared among four groups (n = 9 per group): the normal group (untreated), the CIA group (vehicle control), the NUC1 group (CIA rabbits treated with 200 mg/kg NUC1), and the JOINS group (positive control, CIA rabbits treated with 200 mg/kg JOINS tablet). NUC1 significantly inhibited NO production (p < 0.05 at 125 µg/ml, p < 0.01 at 250 µg/ml, and p < 0.001 at 500 µg/ml) and iNOS expression in macrophages, in a concentration-dependent manner. NUC1 also inhibited the release and protein expression of MMP-1, 3, and 13, in TNF-α-induced chondrosarcoma cells in a concentration-dependent manner. In vivo, the MMP-1 and MMP-3 levels in synovial fluids were significantly (p < 0.05) lower in NUC1 group (77.50 ± 20.56 and 22.50 ± 7.39 pg/ml, respectively) than in the CIA group (148.33 ± 68.58 and 77.50 ± 20.46 pg/ml, respectively). Also, in histopathological, NUC1 ameliorated articular cartilage damage in OA by increasing the abundance of chondrocytes and proteoglycan in the articular cartilage. Thus, NUC1 showed promise as a potential therapeutic agent, and it can be generalized to a broader study population in different OA animal models.

Anti-Obesity and Lipid Metabolism Effects of Ulmus davidiana var. japonica in Mice Fed a High-Fat Diet.

The root bark of Ulmus davidiana var. japonica (Japanese elm) is used in Korea and other East Asian countries as a traditional herbal remedy to treat a variety of inflammatory diseases and ailments such as edema, gastric cancer and mastitis. For this study, we investigated the lipid metabolism and anti-obesity efficacy of ethyl alcohol extract of Ulmus davidiana var. japonica root bark (UDE). First, HPLC was performed to quantify the level of (+)-catechin, the active ingredient of UDE. In the following experiments, cultured 3T3-L1 pre-adipocytes and high-fat diet (HFD)-fed murine model were studied for anti-obesity efficacy by testing the lipid metabolism effects of UDE and (+)-catechin. In the test using 3T3-L1 pre-adipocytes, treatment with UDE inhibited adipocyte differentiation and significantly reduced the production of adipogenic genes and transcription factors PPARγ, C/EBPα and SREBP-1c. HFD-fed, obese mice were administered with UDE (200 mg/kg per day) and (+)-catechin (30 mg/kg per day) by oral gavage for 4 weeks. Weight gain, epididymal and abdominal adipose tissue mass were significantly reduced, and a change in adipocyte size was observed in the UDE and (+)-catechin treatment groups compared to the untreated control group (***p < 0.001). Significantly lower total cholesterol and triglyceride levels were detected in UDE-treated HFD mice compared to the control, revealing the efficacy of UDE. In addition, it was found that lipid accumulation in hepatocytes was also significantly reduced after administration of UDE. These results suggest that UDE has significant anti-obesity and lipid metabolism effects through inhibition of adipocyte differentiation and adipogenesis.

Sequential transcatheter arterial chemoembolization and portal vein embolization before right hemihepatectomy in patients with hepatocellular carcinoma.

BACKGROUND: Recent studies showed that sequential selective transcatheter arterial chemoembolization (TACE) and portal vein embolization (PVE) provided better future liver remnant (FLR) regeneration rate and disease-free survival following surgery compared with PVE alone. The present study aimed to clarify whether preoperative sequential TACE and PVE before right hemihepatectomy can reduce postoperative hepatocellular carcinoma (HCC) recurrence and improve long-term disease-free and overall survival. METHODS: Recurrence and survival outcomes were retrospectively evaluated in 205 patients with HCC who underwent right hemihepatectomy by a single surgeon from November 1993 to November 2017. Patients were divided into four groups according to the procedure performed before the surgery: sequential TACE and PVE (TACE-PVE), PVE-only, TACE-only, or naïve control groups. The baseline patient and tumor characteristics, postoperative outcomes, recurrence-free survival and overall survival were analyzed. RESULTS: Baseline patient and tumor characteristics upon diagnosis were similar in all four groups, while sequential TACE and PVE were well tolerated. The TACE-PVE group had a higher mean increase in percentage FLR volume compared with that of the PVE-only group (17.46% ± 6.63% vs. 12.14% ± 5.93%; P = 0.001). The TACE-PVE group had significantly better overall and disease-free survival rates compared with the other groups (both P < 0.001). CONCLUSIONS: Sequential TACE and PVE prior to surgery can be an effective therapeutic strategy for patients with HCC scheduled for major hepatic resection. The active application of preoperative sequential TACE and PVE for HCC would allow more patients with marginal FLR volume to become candidates for major hepatic resection by promoting compensatory FLR hypertrophy without the deterioration of basal hepatic functional reserve or tumor progression.

Antitumor effect of sorafenib and mammalian target of rapamycin inhibitor in liver transplantation recipients with hepatocellular carcinoma recurrence.

Both sorafenib and mammalian target of rapamycin inhibitor (mTORi) have antitumor effects. This study aimed to evaluate their antitumor effects in liver transplantation (LT) recipients with hepatocellular carcinoma (HCC) recurrence. We performed a laboratory study using sorafenib and mTORi and subsequently validated their survival benefit in a clinical LT setting. In the laboratory study, the HepG2.2.15 liver tumor cell line and 5 patient-derived graft HCC cell lines were used for in vitro cytotoxic studies. After treatment with everolimus and sorafenib, cell viability and apoptosis assays revealed noticeable cytotoxic effects with individual agents and augmented effects by combination therapy. An in vivo mouse study also demonstrated similar cytotoxic outcomes. In the clinical study including 232 LT recipients with HCC recurrence, the 3-month medication drop-out rate was 35.6% for sorafenib administration and 23.5% for mTORi administration. Postrecurrence survival rates were not different according to sorafenib administration (P = 0.17) but were significantly improved following mTORi administration (P < 0.001). In mTORi subgroups with and without sorafenib, there was no difference in the overall postrecurrence patient survival period (P = 0.26), indicating an absence of synergistic or additional antitumor effect from sorafenib. The median progression-free and overall survival period was 6.4 and 11.8 months, respectively, after sorafenib administration. Time of tumor recurrence and use of mTORi were independent risk factors. In conclusion, our laboratory study demonstrated synergistic antitumor effects of sorafenib and mTORi, but this was not reproduced in our clinical LT study. Our clinical result of mTORi administration showed improved postrecurrence survival, thus administering mTORi in LT recipients with HCC recurrence appears worthwhile. However, the antitumor effect of sorafenib on posttransplant recurrence was not determined in this retrospective study, thus requiring further studies with early start of sorafenib administration. Liver Transplantation 24 932-945 2018. © 2018 AASLD.

Beneficial effect of low caloric intake in the early period after orthotopic liver transplantation: a new concept using graft weight.

BACKGROUND/AIMS: Although various factors are correlated with early graft function after orthotopic liver transplantation (OLT), caloric supplementation is not considered in postoperative period. This retrospective study investigated the correlation between caloric intake and early graft function and compared calorie/ body weight ratio (CBWR) and calorie/graft weight ratio (CGWR) as standards for nutritional provision. METHODOLOGY: Patients were divided into the low caloric group (<18 kcal/kg/day) and eucaloric group (≥18 kcal/kg/day) according to caloric intake until 48 hours post-OLT. Graft function was assessed according to aminotransferase level, bilirubin level, and international normalised ratio (INR) on postoperative days (POD) 0, 2, and 7. The variables associated with caloric intake were compared to identify the superiority between CBWR and CGWR. RESULTS: There were 32 and 8 patients in the low caloric and eucaloric groups. INR on POD 2 was significantly lower in the low caloric group (p = 0.018). CGWR was more strongly correlated with INR than CBWR on POD 2 (r = 0.08, p = 0.63 vs. r = 0.36, p = 0.024). CONCLUSIONS: Low caloric intake has a beneficial effect on the restoration of early graft function. CGWR is superior to CBWR as a standard for nutritional supplementation.

Spatholobus suberectus inhibits osteoclastogenesis and stimulates chondrogenesis.

This study was carried out to investigate the effect of Spatholobus suberectus Dunn (SS) on the protection of chondral defect and inhibition of osteoclastogenesis. To examine these effects, we measured the matrix metalloproteinase (MMP) levels in SW1353 chondrosarcoma cells and performed tartrate-resistant acid phosphatase (TRAP) staining in bone marrow macrophage (BMM)-derived osteoclasts. To investigate the anti-osteoarthritis (OA) effects, we assessed TNF-α-induced MMP-1, -3, -9 and tissue inhibitors of matrix metalloproteinase (TIMP) expression levels in SW1353 cells. We observed that SS extract significantly inhibited MMP and TIMP expression in SW1353 cells. Also, SS extract inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation. These results suggest that SS extract may have a potential in the treatment of bone loss and chondral defect by suppressing osteoclast differentiation and decreasing the expression of OA factors. Therefore, clarification of the mechanism of the action of SS extract and its active components is needed.

Stereotactic body radiation therapy as an alternative treatment for small hepatocellular carcinoma.

BACKGROUND: Even with early stage hepatocellular carcinoma (HCC), patients are often ineligible for surgical resection, transplantation, or local ablation due to advanced cirrhosis, donor shortage, or difficult location. Stereotactic body radiation therapy (SBRT) has been established as a standard treatment option for patients with stage I lung cancer, who are not eligible for surgery, and may be a promising alternative treatment for patients with small HCC who are not eligible for curative treatment. MATERIALS AND METHODS: A registry database of 93 patients who were treated with SBRT for HCC between 2007 and 2009 was analyzed. A dose of 10-20 Gy per fraction was given over 3-4 consecutive days, resulting in a total dose of 30-60 Gy. The tumor response was determined using dynamic computed tomography or magnetic resonance imaging, which was performed 3 months after completion of SBRT. RESULTS: The median follow-up period was 25.6 months. Median size of tumors was 2 cm (range: 1-6 cm). Overall patients' survival rates at 1 and 3 years were 86.0% and 53.8%, respectively. Complete and partial tumor response were achieved in 15.5% and 45.7% of patients, respectively. Local recurrence-free survival rate was 92.1% at 3 years. Most local failures were found in patients with HCCs > 3 cm, and local control rate at 3 years was 76.3% in patients with HCC > 3 cm, 93.3% in patients with tumors between 2.1-3 cm, and 100% in patients with tumors ≤ 2 cm, respectively. Out-of-field intrahepatic recurrence-free survival rates at 1 and 3 years were 51.9% and 32.4%, respectively. Grade ≥ 3 hepatic toxicity was observed in 6 (6.5%). CONCLUSIONS: SBRT was effective in local control of small HCC. SBRT may be a promising alternative treatment for patients with small HCC which is unsuitable for other curative therapy.

Anti-inflammatory and anti-osteoarthritis effects of fermented Achyranthes japonica Nakai.

ETHNOPHARMACOLOGICAL RELEVANCE: Achyranthyes japonica Nakai (AJN) has been traditionally used to control pain and improve dysfunction in osteoarthritis (OA) patients. AIM OF THE STUDY: The objectives of the present study were to investigate anti-inflammatory and anti-osteoarthritis activities of fermented AJN (FAJN). MATERIALS AND METHODS: Anti-inflammatory activity of non-fermented AJN (NFAJN) and FAJN was evaluated by in vitro assay using LPS-induced RAW 264.7 cells. In addition, their cartilage protective effects were also determined in vitro assay using SW1353 cell and in vivo model system using collagenase-induced arthritis (CIA) in rabbits. Moreover, we isolated and identified 20-hydroxyecdysone (20-HES) as a marker component in FAJN. RESULT: FAJN showed stronger anti-inflammatory activity than NFAJN through inhibiting production of NO and PGE2 in LPS-induced RAW 264.7, and lowering levels of MMP-3 release in SW1353 cells treated with TNF-a. FAJN contained higher levels of 20-HES, as a marker component, than AJN. FAJN ameliorates the progress of OA by inhibiting local inflammation. It does this by regulating levels of TNF-a and IL-4, and protecting articular cartilage by preventing destruction of proteoglycan, collagens, and also preventing injury to chondrocytes. CONCLUSION: Therefore, FAJN is a potential therapeutic agent for reduction of cartilage damage that occurs in OA.

Predicting survival after living and deceased donor liver transplantation in adult patients with acute liver failure.

BACKGROUND: Post-transplant outcomes for acute liver failure (ALF) are unsatisfactory, and there are debates about the most suitable type of graft. Given the critical shortage of donor organs, accurate assessment of post-transplant outcome in ALF patients is crucial to avoid a futile liver transplantation (LT). METHODS: A database of 160 consecutive adult ALF patients who underwent primary LT between 2000 and 2009 in a tertiary LT center was analyzed. RESULTS: The most common causes of ALF were hepatitis B virus infection (30%) and herbal/folk medicine use (30%). Thirty-six (22.5%) and 124 (77.5%) patients underwent deceased-donor LT (DDLT) and adult-to-adult living-donor LT (LDLT), respectively. During a median follow-up period of 38 (range 1-132) months, the DDLT and LDLT groups showed similar patient (P = 0.99) and graft (P = 0.97) survival rates. The overall 1- and 3-year patient survival rates were 78.8 and 74.6%, respectively. Five predictors of patient survival were identified by bootstrapping and multivariate analysis: vasopressor requirement, estimated glomerular filtration rate, serum sodium concentration, recipient age, and donor age, at the time of transplant. By summing scores weighted in each of these predictor categories, we designed a prognostic scoring system (scores from -2 to 20) that estimated 1-year post-transplant mortality from 0 to 100% (c statistic 0.79). CONCLUSIONS: Long-term outcomes after LDLT and DDLT were comparable in adult patients with ALF. A simple prognostic scoring system that includes 5 predictive variables at the time of LT may help estimate post-transplant survival in ALF patients, regardless of the type of transplant.

Radiotherapy plus transarterial chemoembolization for hepatocellular carcinoma invading the portal vein: long-term patient outcomes.

PURPOSE: We have evaluated the clinical outcomes of patients after transarterial chemoembolization (TACE) and 3-dimensional conformal radiotherapy for hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). METHODS AND MATERIALS: A registry database of 412 patients treated with TACE and three-dimensional conformal radiotherapy for HCC with PVTT between August 2002 and August 2008 were analyzed retrospectively. The radiotherapy volume included the PVTT, with a 2- to 3-cm margin to cover adjacent HCC. Intrahepatic primary HCC was managed by TACE before or after radiotherapy. RESULTS: Median patient age was 52 years old, and 88.1% of patients were male. Main or bilateral PVTT was observed in 200 (48.5%) patients. Median radiation dose was 40 Gy (range, 21-60 Gy) delivered in 2- to 5-Gy fractions. We found that 3.6% of patients achieved a complete response and that 24.3% of patients achieved a partial response. The response and progression-free rates of PVTT were 39.6% and 85.6%, respectively. Median patient survival was 10.6 months, and the 1- and 2-year survival rates were 42.5% and 22.8%, respectively. Significant independent variables associated with overall survival included advanced tumor stage, alpha-fetoprotein level, degree of PVTT, and response to radiotherapy. Forty-one patients (10.0%) showed grade 3-4 hepatic toxicity during or 3 months after completion of radiotherapy. Grades 2-3 gastroduodenal complications were observed in 15 patients (3.6%). CONCLUSIONS: Radiotherapy is a safe and effective treatment for PVTT in patients with HCC. These results suggested that the combination of TACE and radiotherapy is a treatment option for relieving and/or stabilizing PVTT in patients with advanced HCC.

Postoperative chemoradiotherapy for extrahepatic bile duct cancer.

PURPOSE: To evaluate the effect of postoperative concurrent chemoradiotherapy using three-dimensional conformal radiotherapy and to identify the prognostic factors that influence survival in patients with extrahepatic bile duct cancer. METHODS AND MATERIALS: We retrospectively analyzed the data from 101 patients with extrahepatic bile duct cancer who had undergone postoperative concurrent chemoradiotherapy using three-dimensional conformal radiotherapy. Of the 101 patients, 52 (51%) had undergone complete resection (R0 resection) and 49 (49%) had microscopic or macroscopic residual tumors (R1 or R2 resection). The median radiation dose was 50 Gy. Also, 85 patients (84%) underwent concurrent chemotherapy with 5-fluorouracil. RESULTS: The median follow-up period was 47 months for the surviving patients. The 5-year overall survival rate was 34% for all patients. A comparison between patients with R0 and R1 resection indicated no significant difference in the 5-year overall survival (44% vs. 33%, p=.2779), progression-free survival (35% vs. 22%, p=.3107), or locoregional progression-free survival (75% vs. 63%, p=.2784) rates. An analysis of the first failure site in the 89 patients with R0 or R1 resection indicated isolated locoregional recurrence in 7 patients. Elevated postoperative carbohydrate antigen 19-9 level was an independent prognostic factor for overall survival (p=.001) and progression-free survival (p=.033). A total of 3 patients developed Grade 3 or greater late toxicity. CONCLUSION: Adjuvant concurrent chemoradiotherapy using three-dimensional conformal radiotherapy appears to improve locoregional control and survival in extrahepatic bile duct cancer patients with R1 resection. The postoperative carbohydrate antigen 19-9 level might be a useful prognostic marker to select patients for more intensified adjuvant therapy.

Living donor liver transplantation.

PURPOSE OF REVIEW: The widening gap between the growing number of liver transplant candidates and the supply of deceased donor organs became a strong motivation for the development of living donor liver transplantation (LDLT). LDLT has gone through its developmental phase and become an established life-saving procedure. RECENT FINDINGS: Despite the challenging nature of the technique of LDLT, there have been continuous innovations. A better understanding of complex surgical anatomy and physiologic differences of partial hepatic allografts has helped to avoid graft congestion, small-for-size syndrome, or graft hypoperfusion from portal flow steal. LDLT for patients with high Model for End-Stage Liver Disease score can achieve comparable results with deceased donor liver transplantation (DDLT). Size limitation of partial grafts can be overcome with dual grafts. The extended application of LDLT for hepatocellular carcinoma beyond Milan criteria seems feasible but at the cost of slightly compromised survival. More information has become available for prospective donors about the consequences of living liver donation in terms of psychosocial impact. SUMMARY: Although LDLT is still evolving, it has become the most effective alternative to DDLT. Proven or potential benefit of LDLT include the superior quality of the allograft despite the smaller size, selection of proper timing for transplantation and a reduced waiting time, which prevents waiting list mortality.

Sorafenib for recurrent hepatocellular carcinoma after liver transplantation.

OBJECTIVE: Sorafenib is the only drug that has shown a survival benefit in patients with hepatocellular carcinoma in randomized Phase 3 trials. The efficacy and safety of sorafenib in the treatment of recurrent hepatocellular carcinoma after liver transplantation, however, has not been determined. METHODS: We retrospectively analyzed 13 patients who were treated with sorafenib for recurrent hepatocellular carcinoma after liver transplantation. RESULTS: The median time to recurrence from liver transplantation was 12.3 months (95% confidence interval: 8.5-16.1 months). Six of 10 evaluable patients showed stable disease, which was the best response and the median duration of stabilization was 3.9 months (95% confidence interval: 1.6-6.2 months). At a median follow-up duration of 3.7 months (range: 0.3-10.9 months) in surviving patients, the median time to progression and the median overall survival from commencement of sorafenib were 2.9 months (95% confidence interval: 0.0-6.8 months) and 5.4 months (95% confidence interval: 3.7-7.0 months), respectively. Grade 3 neutropenia was observed in one patient, which was the only high-grade hematologic toxicity observed. Grade 3 hand-foot skin reactions were observed in three patients. Adverse events could be managed with dose adjustment. CONCLUSIONS: These findings suggest that sorafenib may be a feasible treatment option regarding its efficacy and safety for recurrent hepatocellular carcinoma after liver transplantation.

Severe lactic acidosis and thiamine deficiency during total parenteral nutrition--case report.

We encountered a case of total parenteral nutrition-associated lactic acidosis that did not respond to sodium bicarbonate or other conventional emergency treatments. He was characterized by minimal food intake before surgery, delayed gastric emptying after pylorus-preserving pancreatoduodenectomy due to pancreas head cancer and long-term total parenteral nutrition without food intake and vitamin supplements after surgery. After thiamine administration, the patient very quickly recovered with dramatic reestablishment of the acid-base balance. We emphasize the need to supplement total parenteral nutrition with thiamine-containing vitamins for the patients whose food intake does not meet nutritional requirements and to intravenously replenish using high-dose thiamine simultaneously with the manifestation of signs and symptoms of severe lactic acidosis with unknown cause. In conclusion, thiamine deficiency should be included in the differential diagnosis of lactic acidosis for the patients who received total parenteral nutrition without food intake and vitamin supplements.

Retroperitoneal abscess complicated by acupuncture: case report.

With acupuncture treatment becoming an increasingly popular analgesic, there have been increasing reports on its associated complications. Although pneumothorax is the most frequently reported injury caused by acupuncture needles, infectious complications may not be uncommon. Most infectious complications show less serious clinical manifestations than pneumothorax, but retroperitoneal or intraabdominal abscess caused by acupuncture may be much more serious conditions. We experienced a 56-yr-old male diabetic patient presenting with serious retroperitoneal abscess after acupuncture treatments. Emergency operative drainage with adequate antibiotic therapy was performed. Bacterial culture of blood and closed pus specimens recovered Klebsiella pneumoniae. In addition to application of better knowledge on anatomy, appropriate antiseptic practice by practitioners will reduce many serious complications associated with acupuncture.