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.

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.

Ultrasound-mediated interferon ß gene transfection inhibits growth of malignant melanoma.

We investigated the effects of ultrasound-mediated transfection (sonotransfection) of interferon ß (IFN-ß) gene on melanoma (C32) both in vitro and in vivo. C32 cells were sonotransfected with IFN-ß in vitro. Subcutaneous C32 tumors in mice were sonicated weekly immediately after intra-tumor injection with IFN-ß genes mixed with microbubbles. Successful sonotransfection with IFN-ß gene in vitro was confirmed by ELISA, which resulted in C32 growth inhibition. In vivo, the growth ratio of tumors transfected with IFN-ß gene was significantly lower than the other experimental groups. These results may lead to a new method of treatment against melanoma and other hard-to-treat cancers.

A novel splicing variant of CADM2 as a protective transcript of psoriasis.

CADM2, a candidate gene for psoriasis, was identified by a genome-wide association study using microsatellites in the Japanese population (561 cases and 561 controls). Moreover, haplotype analysis included an additional 68 SNPs and indicated that a 110-kb haplotype block was detected for the protective risk haplotype of psoriasis. We also identified an initial exon of novel splicing variants in this haplotype block. A functional analysis by qRT-PCR using RNAs from the blood of 56 cases and 64 controls significantly demonstrated an inverse correlation between expression frequencies in a novel splicing variant and the number of alleles associated with psoriasis. To confirm these results, we must perform replication studies using other ethnic groups and more functional analysis particularly for skin tissues.

Various skin manifestations of mycosis fungoides: histopathological features and prognosis.

Mycosis fungoides (MF) is a type of T cell lymphoma, and comprises more than one-half of primary cutaneous T cell lymphomas (CTCL). Many variants of MF have been reported to date, although there are only three descriptions of MF variants in the WHO-EORTC classification published in 2005. Herein, we present four cases of MF, namely classical MF, Woringer-Kolopp disease, bullous MF, and folliculotropic MF. These variants of MF were all typical, although they are quite rare. Their unique clinical manifestations arise from characteristic histolopathological changes in the lesions. The location and amount of infiltrating tumor cells in the epidermis seem to be profoundly correlated with the prognosis.

Clinical efficacy of basic fibroblast growth factor (bFGF) for diabetic ulcer.

Basic fibroblast growth factor (bFGF) has been shown to promote wound healing. The present trial evaluated the clinical efficacy of bFGF for diabetic ulcer, a type of refractory skin ulcer, and the dose-response relationship. This was designed as a randomized, double-blind, dose-ranging, placebo-controlled trial. A total of 150 patients with non-ischaemic diabetic ulcers measuring 900 mm2 or less were randomized into a placebo group (n = 51), a 0.001% bFGF group (n = 49) and a 0.01% bFGF group (n = 50), and 148 of these patients received treatment for 8 weeks or less. The efficacy evaluation was carried out on 139 patients who met the protocol in this trial. The primary outcome was the percentage of patients showing 75% or greater reductions in the area of ulcer. The area of ulcer decreased by 75% or more in 57.5% (27/47), 72.3% (34/47), and 82.2% (37/45) in the placebo, 0.001% bFGF and 0.01% bFGF groups, respectively, and differences were significant between the 0.01% bFGF and placebo groups (p = 0.025). The cure rate was 46.8% (22/47), 57.4% (27/47), and 66.7% (30/45) in the placebo, 0.001% bFGF and 0.01% bFGF groups, respectively. The findings obtained in this trial showed wound healing accelerating effects of bFGF on diabetic ulcers.

[Evaluation of dermatological symptom of Yusho patients in the annual examination in 2005-2007].

Yusho is recognized as a poisoning by a mixture of polychlorinated biphenyls (PCBs), dioxins and related compounds. We have continued a follow-up of skin symptoms in patients not only for supporting patients' health but also for understanding the possible prolonged effects of exposure to PCBs and dioxins in humans. We evaluated the severity grades and the skin severity scores of the symptoms who visited the annual examinations of Fukuoka prefecture from 2005 to 2007. Forty years have passed since the Yusho incident, and about 70% of the patients currently present no skin symptoms. In contrast, in about 30% of the patients, characteristic skin symptoms of Yusho, such as pigmentation of skin, black comedones and acneform eruptions, could still be observed. We analyzed statistical correlations between blood levels of PCBs or dioxin and skin severity grades.

Growth inhibition of neurofibroma by ultrasound-mediated interferon γ transfection.

PURPOSE: We have previously shown that ultrasound-mediated transfection (sonotransfection) can be optimized using a concept based on the ultrasound-induced apoptosis produced in our in vitro experiments. At optimized conditions, we have shown, using five cancer cell lines, that sonotransfection is superior to other conventional nonviral methods. Interferon gamma (IFN-γ) transfection using lipofection has been found to markedly inhibit the proliferation of neurofibroma cell lines. In this study, we investigated whether sonotransfection of IFN-γ to neurofibroma cell lines can suppress cell proliferation. METHODS: The ultrasound device used was the SonoPore KTAC-4000, which is capable of various acoustic settings. Ultrasound transducers at an oscillation frequency of 1.011 MHz were used; the potential ideal conditions were an intensity of 0.17 W/cm(2) at a burst frequency of 0.5 Hz, 25% duty factor, and 30-s sonication duration. Cells were assayed at 3 and 5 days after sonication. RESULTS: The transfection efficiency was found to be 12%. The ultrasound-treated cells were successfully transfected with IFN-γ genes as detected by enzyme-linked immunosorbent assay, and the cell growth ratio in the IFN-γ sonotransfection group tended to be lower than that in the other experimental groups. CONCLUSION: These results suggested that IFN-γ sonotransfection could potentially become a nonsurgical method for treating skin lesions such as neurofibromas.

Treatment of pigmented lesions of neurofibromatosis 1 with intense pulsed-radio frequency in combination with topical application of vitamin D3 ointment.

Cafe-au-lait spots and pigmented freckling are found in most of patients with neurofibromatosis 1 (NF1). Although many modalities have been used for treating the pigmented lesions, the response to treatment has been variable. Therefore, we performed the treatment of pigmented lesions with NF1 by intense pulsed-radio frequency (IPL-RF) in combination with topical application of vitamin D(3) ointment. Eight patients were treated in this study and the improvement was moderate to good in six cases (75%) although the response was relatively mild. Thus, results from our study indicate that IPL-RF irradiation in combination with topical application of vitamin D(3) ointment would be useful as new modalities, especially for treatment of numerous small pigmented lesions in patients with NF1. Although further studies with large groups of patients should be performed for a better conclusion, it could improve quality of life with NF1 patients who are concerned with serious cosmetic and social problems.

Case of metastatic melanoma in an epitrochlear lymph node arising in a pregnant woman.

We describe a rare case of metastatic melanoma in an epitrochlear lymph node in a 29-year-old female patient. The patient had been aware of a brown macule on her right posterior forearm at puberty. Because the lesion had enlarged rapidly, she was referred to our hospital. Histological examination revealed a malignant melanoma. She underwent wide local excision with 3-cm margins and split thickness skin graft closure, but we were not able to perform sentinel node biopsy. She also received three cycles of systemic chemotherapy with dacarbazine, nimustine, vincristine and interferon-beta. However, an epitrochlear node (interval node) metastasis occurred during pregnancy (seventh week) 2 years after the operation. We emphasize that it is important for clinicians to pay attention to the possibility of epitrochlear node metastasis in patients with malignant melanoma in the upper extremity and that it is necessary to perform sentinel node biopsy to identify uncommon lymph node metastasis.

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.

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.

A case of discoid lupus erythematosus of the eyelid.

A 39-year-old man was first evaluated 12 years ago for erosive erythema of the left lower eyelid. The response to topical therapy was poor. The eyelid lesion was excised on the patient's demand 6 years ago and blepharoplasty was performed. However, recurrence of erythematous plaques at the same site prompted referral to our department. Examination clinically revealed atrophic erythematous plaques and several white papules on the left lower eyelid, in addition to an atrophic erythema of the upper back. The histopathological findings of both plaques and papules were typical of discoid lupus erythematosus. Immunoserological findings suggestive of systemic lupus erythematosus were absent. The lesions improved with administration of low-dose corticosteroids. Discoid lupus erythematosus involving the eyelid is rare, and definitive diagnosis often takes considerable period of time. In patients with lesions of the eyelid such as erythema or papules that are refractory to treatment, skin biopsy and careful physical examination of the entire body for similar lesions are important.

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.

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.

Microvessel density and HIF-1alpha expression correlate with malignant potential in fibrohistiocytic tumors.

Angiogenesis is a central process in the growth of solid tumors. Hypoxia-inducible factor-1alpha (HIF-1alpha) is an oxygen-dependent transcriptional activator, which plays a crucial role in tumor angiogenesis. However, involvement of HIF-1alpha has never been studied in so-called fibrohistiocytic tumors, such as dermatofibroma (DF), dermatofibrosarcoma protuberans (DFSP) and malignant fibrous histiocytoma (MFH). We analyzed the extents of angiogenesis in relation to the expression levels of HIF-1alpha in 26 DF, 13 DFSP and 23 MFH cases. MFH showed significantly higher microvessel density (MVD) compared with DF and DFSP. Immunohistochemically, HIF-1alpha-positive cases constituted 31%, 15% and 98% of DF, DFSP and MFH, respectively, indicating significantly higher HIF-1alpha expression in MFH compared with DF and DFSP. Furthermore, MFH cases expressing high levels of HIF-1alpha showed significantly higher MVD than those with low levels of HIF-1alpha. Thus, higher levels of angiogenesis and HIF-1alpha expression are both closely associated with the malignant potential in so-called fibrohistiocytic tumors, and HIF-1alpha is possibly involved in angiogenesis in MFH.

[Evaluation of dermatological symptoms of Yusho patients in the annual examination in 2003-2004].

We evaluated the severity grades and the skin severity scores of the skin symptoms who visited the annual examinations of Fukuoka prefecture in 2003 and 2004. The severity of skin symptoms improved significantly in the first 20 years; nowadays, however, further improvement can hardly be observed. More than 36 years have passed since the Yusho incident, and about 60% of the patients currently present no skin symptoms. In contrast, in about 40% of the patients, characteristic skin symptoms of Yusho, such as pigmentation of skin, black comedones and acneform eruptions, could still be observed. Using Peason's correlation coefficient test and Spearman's correlation coefficient test, we analyzed correlation between "PCB pattern" and the blood PCB concentration, the skin severity grade and the skin severity scores. However, we could not find out any obvious correlation.

Dermatomyositis with tuberculous fasciitis.

A case of dermatomyositis with tuberculous fasciitis is described. A 69-year-old Japanese man treated with prednisolone for dermatomyositis developed erythema and bilateral swelling of arms and forearms. A diagnosis of tuberculous fasciitis was confirmed by the presence of acid-fast bacilli in a biopsy specimen and the growth of Mycobacterium tuberculosis from tissue cultures. The unusual presenting clinical features resulted in delayed diagnosis. We emphasize that tuberculous fasciitis should be considered in an immunocompromised patient who is treated with steroids, especially if the results of initial treatment are not satisfactory.