Amenamevir, a novel helicase-primase inhibitor, for treatment of herpes zoster: A randomized, double-blind, valaciclovir-controlled phase 3 study.

Amenamevir is a potent helicase-primase inhibitor and a novel class of antiviral agent other than nucleoside compounds, such as aciclovir, valaciclovir and famciclovir. This study is the first randomized, double-blind, valaciclovir-controlled phase 3 study to evaluate the efficacy and safety of amenamevir in Japanese patients with herpes zoster when treated within 72 h after onset of rash. A total of 751 patients were randomly assigned to receive either amenamevir 400 mg or 200 mg p.o. once daily or valaciclovir 1000 mg three times daily (daily dose, 3000 mg) for 7 days. The primary efficacy end-point was the proportion of cessation of new lesion formation by day 4 ("day 4 cessation proportion"). The day 4 cessation proportions for amenamevir 400 and 200 mg and valaciclovir were 81.1% (197/243), 69.6% (172/247) and 75.1% (184/245), respectively. Non-inferiority of amenamevir 400 mg to valaciclovir was confirmed by a closed testing procedure. Days to cessation of new lesion formation, complete crusting, healing, pain resolution and virus disappearance were evaluated as secondary end-points. No significant differences were observed in any of the treatment groups. Amenamevir 400 and 200 mg were well tolerated as well as valaciclovir. The proportions of patients who experienced drug-related adverse events were 10.0% (25/249), 10.7% (27/252) and 12.0% (30/249) with amenamevir 400 and 200 mg and valaciclovir, respectively. In conclusion, amenamevir 400 mg appears to be effective and well tolerated for treatment of herpes zoster in immunocompetent Japanese patients.

Efficacy and toxicity of transarterial chemoembolization therapy using cisplatin and gelatin sponge in patients with liver metastases from uveal melanoma in an Asian population.

BACKGROUND: Although both immune-checkpoint inhibitors and targeted therapies such as MEK inhibitors have been evaluated in metastatic uveal melanoma, the efficacy of these therapies is modest to date. The purpose of this study was to evaluate the efficacy and toxicity of transarterial chemoembolization (TACE) therapy for liver metastasis from uveal melanoma in an Asian population. METHODS: We retrospectively assessed the clinical data of patients with liver metastases from uveal melanoma who received TACE therapy using cisplatin (70 mg/m2) and gelatin sponge between 1997 and 2008. RESULTS: We identified 29 eligible patients. The overall response rate was 21%. The median survival time was 23 months, and the 1-, 2-, and 5-year survival rates were 72.4, 39.4, and 0%, respectively. The favorable prognostic factors were partial response and stable disease, <25% of the tumor volume within the liver at baseline, and normal serum lactate dehydrogenase (LDH) and normal alkaline phosphatase at baseline. Among them, normal LDH at baseline was the only independent prognostic factor in multivariate analysis. The common adverse events (AEs) were liver enzyme elevation (100%), nausea (72.4%), abdominal pain (65.5%), vomiting (55.2%), post-embolization syndrome (34.5% of patients, 9.6% of TACE procedures), and pyrexia (24.1%). Grade ≥3 AEs consisted of aspartate aminotransferase elevation (34.5%), alanine aminotransferase elevation (51.7%), and serum creatinine elevation (3.4%). CONCLUSION: TACE therapy has a certain degree of clinical efficacy with a tolerable toxicity and, therefore, can still be one of the treatment options. However, considering the lack of long-term efficacy of this therapy, further treatment strategies need to be developed.

Treatment satisfaction, willingness to pay and quality of life in Japanese patients with psoriasis.

There is a range of psoriasis treatments available, from topical applications to biologic therapy, with corresponding cost variations. The efficacy of each treatment is usually evaluated by objective measures such as the Psoriasis Area and Severity Index (PASI) or subjective measures such as the Dermatology Life Quality Index (DLQI). However, the social and economic impacts of psoriasis, including cost-effectiveness, have not been assessed in Japan. The EuroQol 5-Dimension (EQ-5D) is a generic instrument used worldwide to calculate quality-adjusted life years, on which calculations of treatment cost-effectiveness are based. We conducted a pilot study to determine the cost-effectiveness of psoriasis treatment in Japan. We administered a questionnaire to 133 patients with psoriasis (105 men and 28 women) who visited four university hospitals in Fukuoka Prefecture. The questionnaire covered medical costs, satisfaction and willingness to pay (WTP), and we investigated the relationships between these items. PASI was evaluated by physicians. More participants indicated satisfaction with treatment in the group paying less than ¥5000/month. WTP, PASI and EQ-5D showed little correlation. However, the DLQI and EQ-5D showed a moderate correlation (r = 0.472). WTP seemed more dependent on participants' economic backgrounds. We found that it was difficult to reflect the PASI with the EQ-5D. However, the DLQI may be used to estimate the cost-benefit relationship in patients with psoriasis. This is the first study to evaluate the EQ-5D in patients with psoriasis in Japan.

Immunohistochemical demonstration of EphA2 processing by MT1-MMP in invasive cutaneous squamous cell carcinoma.

Erythropoietin-producing hepatocellular receptor-2 (EphA2) overexpression is prevalent in many types of human cancers, and it has been reported that high EphA2 expression is correlated with malignancy. Recent studies revealed that processing of EphA2 by cleaving off the N-terminal portion by membrane-type 1 matrix metalloproteinase (MT1-MMP) promotes invasion via stimulation of Ras in cancer cells in vitro. The objectives of this study were to investigate the presence and role of EphA2 processing in cutaneous squamous cell carcinoma (SCC) tissues. EphA2 (C-terminal and N-terminal) and MT1-MMP expression patterns and levels were analyzed immunohistochemically in SCC (n = 70) and Bowen disease (BD; n = 20). Levels of MT1-MMP and EphA2 expression were evaluated using digital image analysis. Proximity between MT1-MMP and EphA2 in cancer cells and its effect on EphA2 processing were investigated using a combination of in situ proximity ligation assay (PLA) and Western blotting. Immunohistochemical analyses showed that levels of EphA2 N-terminal expression were significantly lower than those of EphA2 C-terminal expression in SCC, whereas levels of EphA2 C- and N-terminal expression were similar in BD. Western blotting showed processed EphA2 fragments in human SCC tissues. Expression levels of MT1-MMP, EphA2, and processed EphA2 fragments were higher in SCC than BD. Proximity between MT1-MMP and EphA2 in SCC was demonstrated by in situ PLA. Our results suggest possible involvement of MT1-MMP processing of EphA2 in invasiveness of cutaneous SCC.

Proactive treatment with calcipotriol reduces recurrence of plaque psoriasis.

Topical calcipotriol is a widely used treatment for plaque-type psoriasis worldwide, and has been shown to improve psoriatic plaques as well as very potent corticosteroids. However, there remains the practical question of whether calcipotriol application should continue on healed pigmentation/depigmentation associated with psoriatic plaques. Therefore, we conducted a pilot clinical study to answer this question. Plaque-type psoriatic patients not receiving systemic treatment were enrolled and treated with calcipotriol for 8 weeks (stage I) to achieve maximum effect. The patients were then divided into two groups: group A continued to apply calcipotriol to the entirety of the previous lesion (including pigmentation/depigmentation) regardless of whether skin was healed or not, while group B applied calcipotriol to the remaining lesion only. Patients were followed for 12 weeks (stage II) and dates of plaque recurrence were recorded. A total of 29 patients (13 men, 16 women) were enrolled. During stage I, reductions in scores for redness, induration and scale occurred in 40%, 47% and 55% of patients, respectively. After stage II was completed, group A (n = 19) showed a significantly better Kaplan-Meier curve of non-recurrence than group B (n = 8, P < 0.01). The mean non-recurrence duration was 76.8 ± 11.8 in group A and 35.0 ± 12.0 in group B. Our study showed that applying topical calcipotriol on seemingly healed psoriatic plaque lesions suppresses recurrence better than applying it only on remaining plaques. This finding may be important for instructing psoriatic patients on topical calcipotriol treatment.

Role of sentinel lymph node biopsy in patients with Merkel cell carcinoma: statistical analysis of 403 reported cases.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy with a high rate of nodal metastasis. Sentinel lymph node biopsy (SLNB) is used in MCC and other cancers to identify regional node micrometastases in patients with clinically negative nodes; however, whether SLN status is associated with recurrence or prognosis in MCC is unclear. METHODS: A statistical analysis was performed of 397 published cases of MCC with SLNB results from 22 reports and 6 new cases, in order to elucidate any correlation between SLN status and recurrence, and to determine false-negative rates for SLNB. RESULTS: Of these 403 cases, 128 (31.8 %) had positive SLNs; 16 of these 128 (12.5 %) developed recurrence (6 nodal, 10 distant). Of 275 patients with negative SLNs, 27 (9.8 %) developed recurrence (19 nodal, 8 distant). Patients with positive SLNs had a greater risk of distant metastasis (OR 2.82; P = 0.037; 95 % CI 1.089-7.347). The false-negative rate for SLNB in all 403 patients was 12.9 %. Use of the immunohistochemical approach to diagnosis of micrometastasis with anti-CK20 antibody did not affect the false-negative rate. CONCLUSIONS: Patients with positive SLNs had a greater risk of distant metastasis in MCC; positive SLN was an important prognostic factor in MCC. Further studies using standardized, more-sensitive techniques to examine entire SLNs may decrease the false-negative rate, and improve the significance of SLNB in MCC.

Anthropometric characteristics and comorbidities in Japanese patients with neurofibromatosis type 1: a single institutional case-control study.

Neurofibromatosis type 1 (NF1) is a well-known genetic disorder characterized by café-au-lait spots and neurofibromas, but many other clinical characteristics and associated comorbidities also have been reported. This study aimed to characterize NF1 further by investigating its association with anthropometric characteristics and other diseases. We performed a case-control study of 227 NF1 patients (101 male, 126 female) and a randomly selected age- and sex-matched control group of 681 non-NF1 patients (303 male, 378 female) who visited our institution in Japan. We examined adult (≥20 years) height and body mass index (BMI), and, in the total sample, allergic diseases (bronchial asthma [BA], atopic dermatitis [AD] and allergic rhinitis) and other respiratory cardiovascular and psychiatric disorders. In adults, the mean BMI was lower in the NF1 group than in the control group, and was significantly statistically different among men (P = 0.0238). In the whole sample, the prevalences of BA (P = 0.0184), AD (P = 0.0144) and valvular heart disease (P = 0.0166) were significantly greater in the NF1 group than in the control group. To date, no similar research on the BMI or the prevalence of allergic disease in NF1 patients has been reported. Our results suggest that NF1 patients tend to have lower BMI and may have alterations in specific metabolic pathways and altered allergic immunity.

Edaravone, a free radical scavenger, accelerates wound healing in diabetic mice.

UNLABELLED: Refractory wound healing is a major complication of diabetes, which restricts wound healing by interfering with the inflammatory response, decreasing granulation, causing peripheral neuropathy, and inhibiting angiogenesis. Oxidative stress has been proposed as an important pathogenic factor in diabetic wound complications. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a strong free radical scavenger that suppresses the effect of oxidative stress. MATERIAL AND METHODS: Streptozotocin-induced diabetes was established in adult C57BL/6 mice, and full-thickness skin was then removed from the dorsomedial back using an 8-mm biopsy punch. Edaravone or vehicle alone was applied to the wound on day 0 and day 4 after wound creation. The wound was monitored with a digital camera and analyzed on days 0, 4, and 7 after wound creation. RESULTS: This study investigated whether accelerated wound closure occurred in the edaravone group (n = 24) compared with the vehicle-alone group (n = 15). On day 7, wound closure between the 2 groups was statistically different (P = 0.0019). Angiogenesis and lymphangiogenesis were markedly promoted. The possibility of an inhibitory effect of edaravone characterized by suppression of oxidative stress was explored. Edaravone-induced upregulation of endothelial nitric oxide synthase (eNOS) mRNA expression, and eNOS protein was immunohistochemically detected. CONCLUSION: Edaravone upregulates eNOS expression and accelerates wound healing.

Possible association of hepatitis C virus infection with late-onset psoriasis: a hospital-based observational study.

Psoriasis is a chronic inflammatory disease mainly involving the skin and joints, mediated by pro-inflammatory cytokine tumor necrosis factor (TNF)-α. In hepatitis C, continuous inflammation mediated by TNF-α leads to liver cirrhosis and diabetes mellitus. Hence, psoriasis and hepatitis C have pathophysiological factors in common. An epidemiological association between the two conditions has been reported, but no detailed research has yet been performed. Frequency of hepatitis C virus (HCV) infection was assessed in 717 patients with psoriasis and 38 057 with all other dermatological diseases who visited Fukuoka University Hospital in 1998-2011. HCV⁺ and HCV⁻ psoriatic patients were further compared. Frequency of HCV infection was significantly higher in psoriasis (7.5%) than in controls (3.3%) in overall ages. When stratified by age at the first visit, the frequency was significantly higher in patients with psoriasis than in controls aged in their 60s (11.8% vs 6.6%, respectively, P = 0.0215) and 70s (19.5% vs 7.3%, P < 0.0001). HCV⁺ psoriatic patients were significantly older at onset than HCV⁻ ones (median, 54 vs 39 years), stronger male predominance (male/female ratio, 4.4:1), similar family history of psoriasis, higher association of diabetes mellitus and hypertension, and significantly lower body mass index (22.4 ± 2.73 vs 24.2 ± 4.61), in age-stratified (≥ 40 years) analysis. HCV⁺ psoriatic patients were less obese, but still had a higher frequency of diabetes mellitus and hypertension, possibly due to chronic inflammation in the liver and other organs. HCV infection may trigger psoriasis, especially late-onset psoriasis, possibly via overproduction of TNF-α, a common mediator of the two conditions.

Narrowband ultraviolet B irradiation increases the serum level of vitamin D3 in patients with neurofibromatosis 1.

The serum vitamin D3 levels in patients with neurofibromatosis 1 has been reported to be significantly lower than that in control subjects, and the level of vitamin D3 reversely correlates with the severity of neurofibroma formation. We found that narrowband ultraviolet B (NB-UVB) irradiation increased the serum level of 1,25(OH)2 vitamin D3 in patients with neurofibromatosis 1. The difference in the 1,25(OH)2 vitamin D3 levels between patients who had received irradiation for more than 18 months and those who had no irradiation was highly significant. Time-course analyses of the serum vitamin D3 levels in the patients who were enrolled after informed consent revealed that the levels became higher significantly after 6 months of irradiation. It is suggested that NB-UVB irradiation is effective for increasing the serum level of vitamin D3 in patients with neurofibromatosis 1, which may be of benefit for skin symptoms such as pigmented macules or neurofibromas.

In vitro responses of neurofibroma fibroblasts, mast cells and Schwann cells obtained from patients with neurofibromatosis 1 to 308-nm excimer light and/or vitamin D3.

Fibroblasts, mast cells and Schwann cells were isolated from neurofibromas of patients with neurofibromatosis 1, and their responses to 308-nm excimer light irradiation and/or vitamin D3 or an analog (tacalcitol; 1,24-dihydroxyvitamin D3 ) were examined in vitro. Excimer light irradiation (300 mJ/cm(2) ) suppressed the growth of all three cell types. Exposure to 10(-7)  mol/L of 1α,25(OH)2 D3 (VD3 ) or tacalcitol suppressed the growth of fibroblasts and mast cells, but not Schwann cells. These results suggest that the different neurofibroma cell types show different responses to VD3 . A combination of excimer light irradiation and VD3 is necessary to suppress the growth of neurofibroma cells in vivo.

Case report of anti-transcription intermediary factor-1-γ/α antibody-positive dermatomyositis associated with gastric cancer and immunoglobulin G4-positive pulmonary inflammatory pseudotumor.

Dermatomyositis is a rare connective tissue disease often associated with internal malignancy and interstitial pneumonitis. Serologically, various auto-antibodies (Ab) are associated with dermatomyositis. Anti-transcription intermediary factor-1-γ/α (TIF-1-γ/α) Ab was recently identified as an auto-Ab and was observed mostly in cancer-associated dermatomyositis. IgG4-related disease is a newly described entity characterized by increased serum IgG4 levels and IgG4-positive plasma cell infiltration with fibrosis in organs such as the pancreas and parotid gland. IgG4-related disease also includes inflammatory pseudotumors in various organs. We report herein a 59-year-old Japanese man who had dermatomyositis complicated with a gastric cancer and an IgG4-related pulmonary inflammatory pseudotumor. He manifested typical classical Gottron's papules on the fingers, V-sign erythema on the chest, flagellate erythema on the back, nail fold bleeding and facial erythema. Serum levels of anti-TIF-1-γ/α Ab were positive as assessed by immunoprecipitation assay. He also had bilateral swelling of the parotid gland, and an excised specimen of the lung showed inflammatory pseudotumor with IgG4-positive plasma cells. As far as we know, this case is the first to report the association of IgG4-related disease and TIF-1-γ/α-positive dermatomyositis. Further accumulation of such cases is required to elucidate the mechanism of this association.

Vitamin D-dependent cathelicidin inhibits Mycobacterium marinum infection in human monocytic cells.

BACKGROUND: 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) up-regulates the production of human cathelicidin antimicrobial peptide (CAMP) from monocytes/macrophages infected with Mycobacterium tuberculosis (M. tbc). CAMP facilitates the co-localization of autophagolysosomes with M. tbc, promoting the antimicrobial activity of monocytes. Mycobacterium marinum (M. marinum) is an acid-fast bacillus that causes less severe granulomatous skin lesions compared with M. tbc. OBJECTIVE: We investigated whether autophagic antimicrobial activity is promoted by 1,25(OH)2D3 or C-terminal of cathelicidin LL-37 in human monocytes upon infection with M. marinum. METHODS: Human monocytes (THP-1) were infected with M. marinum. Effects of simultaneous treatments of 1,25(OH)2D3, exogenous LL-37 peptide, autophagolysosome inhibitors, 3-methyladenine or chloroquine, were examined. RESULTS: CAMP was strongly induced by adding 1,25(OH)2D3 to the culture of THP-1 cells. In the absence of 1,25(OH)2D3 M. marinum infection alone did not induce CAMP, however, simultaneous addition of 1,25(OH)2D3 to M. marinum infection accelerated CAMP production more than 1,25(OH)2D3 alone. Proliferation of M. marinum was markedly decreased in the presence of 1,25(OH)2D3 or exogenous LL-37 in THP-1 cells. Co-localization of CAMP with autophagolysosome was evident in 1,25(OH)2D3 and LL-37 treated THP-1 cells after M. marinum infection. Autophagolysosome inhibitors abrogated the antimicrobial effects of 1,25(OH)2D3 and exogenous LL-37 against M. marinum infection in THP-1 cells. CONCLUSIONS: Human monocytic cells, whose CAMP production is up-regulated by 1,25(OH)2D3-vitamin D receptor pathway, accelerate antimicrobial function of autophagolysosome in M. marinum infection.

Profile of patients with psoriasis associated with hepatitis C virus infection.

Psoriasis is a chronic inflammatory skin disease associated with various complications such as arthritis, diabetes mellitus and hypertension. Hepatitis C is caused by chronic infection of hepatitis C virus (HCV), and eventually leads to liver cirrhosis and hepatocellular carcinoma. Although an association between psoriasis and HCV has been reported, there have been no large case series to date. The aim of the present study was to outline the profiles of HCV-positive psoriatic patients. Patients with a diagnosis of psoriasis who visited Fukuoka University from 1991-2011 were sought in the database, and their medical records were manually checked for detailed information about serum liver enzymes, anti-HCV antibodies, medical history, and treatments and outcomes of both psoriasis and hepatitis. There were 54 (7.5%) anti-HCV antibody-positive patients among the 717 psoriatic patients detected. Male predominance (male/female ratio, 44:10) and late onset (median age, 55 years) were the characteristics of the 54 patients. HCV infection preceded the onset of psoriasis definitely in 80% and probably in 11%. Interferon therapy exacerbated 70% of pre-existing psoriasis cases, and induced de novo psoriasis in eight patients. Complication with diabetes mellitus was found in 35% of the patients. Our observations suggest that HCV infection can be an inducing factor for psoriasis. In hepatitis C patients, elevated tumor necrosis factor-α is known to cause progression of hepatic disease and possibly induces psoriasis in patients with a certain predisposition.