Yuichiro Ohshima

c-RET Molecule in Malignant Melanoma from Oncogenic RET-Carrying Transgenic Mice and Human Cell Lines

Malignant melanoma is one of the most aggressive cancers and its incidence worldwide has been increasing at a greater rate than that of any other cancer. We previously reported that constitutively activated RFP-RET-carrying transgenic mice (RET-mice) spontaneously develop malignant melanoma. In this study, we showed that expression levels of intrinsic c-Ret, glial cell line-derived neurotrophic factor (Gdnf) and Gdnf receptor alpha 1 (Gfra1) transcripts in malignant melanomas from RET-transgenic mice were significantly upregulated compared with those in benign melanocytic tumors. These results suggest that not only introduced oncogenic RET but also intrinsic c-Ret/Gdnf are involved in murine melanomagenesis in RET-mice. We then showed that c-RET and GDNF transcript expression levels in human malignant melanoma cell lines (HM3KO and MNT-1) were higher than those in primary cultured normal human epithelial melanocytes (NHEM), while GFRa1 transcript expression levels were comparable among NHEM, HM3KO and MNT-1. We next showed c-RET and GFRa1 protein expression in HM3KO cells and GDNF-mediated increased levels of their phosphorylated c-RET tyrosine kinase and signal transduction molecules (ERK and AKT) sited potentially downstream of c-RET. Taken together with the finding of augmented proliferation of HM3KO cells after GDNF stimulation, our results suggest that GDNF-mediated c-RET kinase activation is associated with the pathogenesis of malignant melanoma.

CD109 expression levels in malignant melanoma.

Yoshiki Tokura Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan *Corresponding author at: Department of Dermatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawara, Sakyo, Kyoto 606-8507, Japan. Tel.: +81 75 7513310/93 6917445; fax: +81 75 7613002/93 6910907 E-mail address: kaba@kuhp.kyoto-u.ac.jp (Kenji Kabashima).

Treatment of patients with acquired idiopathic generalized anhidrosis.

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Effectiveness of Iontophoresis with Alternating Current (AC) in the Treatment of Patients with Palmoplantar Hyperhidrosis

Conventionally, iontophoresis employing direct current (DC) has been used in the treatment of palmoplantar hyperhidrosis, but this is accompanied by side effects such as pain and burns. In the present study, a prototype apparatus using alternating current (AC) was constructed, and iontophoresis with AC was performed in palmoplantar hyperhidrosis patients to determine its effectiveness. The average amount of perspiration of the palmoplantar hyperhidrosis patients was significantly reduced after the third session when iontophoresis treatments were performed once per week. By the eighth treatment, perspiration was reduced to nearly the normal level, and there were no particular side‐effects during the treatment period. This treatment therefore appears to be both safe and effective. The treatment effect tended to appear sooner when alternating current iontophoresis was combined with the administration of anticholinergic drugs than when alternating current iontophoresis was used alone. Alternating current iontophoresis is an effective treatment for palmoplantar hyperhidrosis. Guidelines for this treatment for patients with palmoplantar hyperhidrosis will need to be established in the future.

Therapeutic effectiveness of botulinum toxin type A based on severity of palmar hyperhidrosis

A dose of 60 units (U) of botulinum toxin type A (BT‐A) has been confirmed to have efficacy for patients with palmoplantar hyperhidrosis. However, the effectiveness of this dose is limited in severe cases defined as sweat production of 2 mg/cm2 per min or more (measured by the ventilated capsule method) and a Hyperhidrosis Disease Severity Scale (HDSS) grade of 3 or 4. An increased dose of 90 U of BT‐A was found to reduce sweating for approximately 7 months. In a comparison of patients with sweat production of more than 2.5 mg/cm2 per min and an HDSS grade of 4 and patients with sweat production of 2.5 mg/cm2 per min or less and an HDSS grade of 3, there was no difference in the reduction of sweat production at 5 months, but the duration of the reduced sweating was shorter for the former group. This suggests that there are limits to the efficacy of BT‐A for severe forms of the disease with sweat production of more than 2.5 mg/cm2 per mL.

Histological localization of aluminum in topical aluminum chloride treatment for palmar hyperhidrosis

Primary or secondary hyperhidrosis is excessive sweating beyond that required for returning body temperature to normal. It can be focal or generalized and commonly affects the underarms, Al specific binding fluorescence reagent and we investigated the mechanism of the antiperspirant action of AC. Palmar hyperhidorosis patients (n = 127) were topically treated with 20% AC solution without occlusion once a day for 1 month. Collection of subjects from patients was based on informed consent and declaration of Helsinki principles received approval of the ethical committee in Aichi Medical University School of Medicine (No. 11-014). First, sweat production was measured by palms, soles or face [1]. The disease often significantly affects the patient’s quality of life. Treatment options include topical aluminum chloride (AC), iontophoresis, botulinum toxin A, oral anticholinergics, and endoscopic sympathectomy. Topical AC is a well-established therapy for hyperhidrosis and is the first-line therapy for mild to moderate disease [2]. The mechanism of the action of aluminum (Al) salt in the forearm or axilla has been investigated in a few studies [3,4]. However, there has been no report on the mechanism of the antiperspirant action of AC for treatment of palmoplantar hyperhidrosis. In this study, we investigated the histological localization of Al for palmar hyperhidorosis by using an

Changes in Na+, K+ concentrations in perspiration and perspiration volume with alternating current iontophoresis in palmoplantar hyperhidrosis patients

Various treatments are currently available for palmoplantar hyperhidrosis. We have treated palmoplantar hyperhidrosis patients effectively with the use of alternating current (AC) iontophoresis. However, much remains unknown about the physiological changes that occur with AC iontophoresis, and its mechanism of action. We measured the changes in Na+, K+ concentration in perspiration and perspiration volume with AC iontophoresis in palmoplantar hyperhidrosis patients. We found that hyperhidrosis patients have significantly higher perspiration volume and Na+ concentration in perspiration than healthy controls. Looking at the temporal changes with AC iontophoresis, we found a significant decrease in perspiration volume and Na+ concentration in perspiration after six iontophoresis treatments. This result is further evidence that Na+ concentration in perspiration is closely involved with perspiration volume. However, looking at the changes in perspiration volume and Na+ concentration in perspiration before and after a single AC iontophoresis treatment, we found that while perspiration volume did not decrease in hyperhidrosis patients after a single treatment, there was a significant decrease in Na+ concentration. In healthy controls as well, Na+ concentration in perspiration decreased significantly after a single treatment. These findings suggest that the effect of AC iontophoresis may be due to a complex mechanism involving changes in reabsorption of ductal Na+.

Classification of Systemic and Localized Sweating Disorders

Hyperhidrosis can be subdivided into generalized hyperhidrosis, with increased sweating over the entire body, and focal hyperhidrosis, in which the excessive sweating is restricted to specific parts of the body. Generalized hyperhidrosis may be either primary (idiopathic) or secondary. Secondary generalized hyperhidrosis may be caused by infections such as tuberculosis, hyperthyroidism, endocrine and metabolic disturbances such as pheochromocytoma, neurological disorders, or drugs. Focal hyperhidrosis may also be primary (idiopathic) or secondary. Freys syndrome is one form of secondary focal hyperhidrosis that occurs during eating together with reddening of the area in front of the ear following parotid gland surgery or injury. Primary focal hyperhidrosis is particularly common on the palms and soles of the feet, in the axilla, and on the head. Anhidrosis may be either congenital/genetic or acquired. Some of the most typical forms of congenital/genetic anhidrosis include hypohidrotic ectodermal dysplasia, congenital insensitivity to pain and anhidrosis, and Fabry disease. Acquired anhidrosis is classified as secondary anhidrosis, which may be due to an underlying disorder such as a neurological disorder, an endocrine or metabolic disturbance, or the effect of drugs, or idiopathic anhidrosis for which the pathology, cause, and mechanism are unknown. Idiopathic anhidrosis is classified into acquired idiopathic generalized anhidrosis (AIGA), idiopathic segmental anhidrosis, and Ross syndrome. AIGA is divided into three categories according to differences in the site of disturbance: (1) sudomotor neuropathy, (2) idiopathic pure sudomotor failure, and (3) sweat gland failure.

Thioredoxin upregulation by 5-aminolaevulinic acid-based photodynamic therapy in human skin squamous cell carcinoma cell line

Background/purpose: 5‐aminolaevulinic acid‐based photodynamic therapy (ALA‐PDT) is widely performed in the clinical setting for superficial skin cancers, giving favorable results, but residual tumor and recurrence occur occasionally. Thioredoxin is a common antioxidant that suppresses apoptosis and facilitates cell growth. We investigated the expression of thioredoxin following ALA‐PDT in human skin squamous cell carcinoma cell line, HSC‐5.

Evaluation of the correlation between severity of acquired idiopathic generalized anhidrosis and quality of life scores

Symptoms of acquired idiopathic generalized anhidrosis (AIGA) include heat retention and/or heat stroke due to the effects of the disorder on the perspiration ability of the whole body under thermal environmental changes or exercise. Additionally, cholinergic urticaria can also occur in these patients. AIGA has a major impact on everyday life. However, the effects of AIGA severity on the quality of life (QOL) of the patients have not been sufficiently defined. The objective of this study was to evaluate the correlation between AIGA severity and QOL. Study subjects comprised 44 patients diagnosed with AIGA at three registered institutions. AIGA severity assessment was conducted and the Dermatology Life Quality Index (DLQI) questionnaire was administered. Correlations between AIGA severity and DLQI, as well as severity by DLQI subscale, were assessed. We found a positive correlation between total score of AIGA severity criteria and DLQI total scores (R = 0.720, P = 0.001). The impairment increased with the increase in AIGA severity (P < 0.01). In relation to the DLQI subscales, leisure (social and sporting activities) impairment was significantly higher for patients with severe AIGA than those with mild AIGA (P < 0.01). Comparing QOL for AIGA patients with that of patients with other dermatological disorders, it is possible that QOL impairment for AIGA patients is as severe as that for patients with atopic dermatitis. AIGA severity and DLQI are correlated and AIGA patients experience disruption of everyday life more broadly than conventionally perceived.