Eiji Kiyohara

Critical renal adverse event induced by nivolumab therapy in a stage IV melanoma patient

good prognosis and heal after a short duration, as in the present case; however, the stings of social bees, such as Vespinae and Polistinae, are toxic and may be lethal. As the number of stings increases, the severity of the reaction also increases and sometimes results in severe allergic reactions to wasps and honeybees. Although it is not clearly known whether the allergen of large carpenter bees has the same effects, a case of a fatal sting by a large carpenter bee, Xylocopa tranquebarica, has been reported recently. Therefore, although our patient may have little or no chance of receiving another sting from the peaceful Japanese carpenter bee, she should be careful not to stimulate the bee to avoid additional stings.

A Novel Therapy for Melanoma and Prostate Cancer Using a Non-Replicating Sendai Virus Particle (HVJ-E)

The earliest virotherapies involved injection of wild-type viruses and evaluation of their efficacies [1-3]. Ex vivo therapies using autologous irradiated tumors infected with oncolytic viruses were also investigated [12-18]. Deletion mutants of oncolytic viruses [19-24], and recombinant viruses carrying a therapeutic gene [25-32] that induce cancer apoptosis or cancer immunity have been developed and evaluated in the clinical setting.

Novel autoantibody against the β2-glycoprotein I/human leucocyte antigen–DR complex in patients with refractory cutaneous ulcers

DEAR EDITOR, Chronic skin ulcers in the lower legs, feet, toes and digits are sometimes idiopathic and intractable. Although there are many conditions that cause chronic limb ulcers, the reasons why specific patients develop chronic skin ulcers remain unclear. Antiphospholipid syndrome (APS) is an acquired coagulation disorder occurring as vascular thrombosis or pregnancy complications. Patients with APS display various skin manifestations, including livedo reticularis, purpura, cutaneous ulcers, necrotizing vasculitis/pseudovasculitis, digital gangrene and necrosis. Autoantibodies against b2 glycoprotein I (GPI) bound to phospholipids have been considered responsible for the pathogenicity of APS. However, it remains unclear whether b2GPI bound to phospholipid is a natural target for autoantibodies in APS, because patients with clinical manifestations of APS often do not have autoantibodies against b2GPI bound to phospholipid. As cellular misfolded proteins are not generally transported to the cell surface or secreted, these misfolded proteins, transported to the cell surface by HLA class II molecules, may induce autoantibody production as ‘neo-self’ antigen. We have found that endoplasmic reticulum-localized misfolded proteins are transported to the cell surface by human leucocyte antigen (HLA) class II molecules without peptide processing. Furthermore, IgG heavy chains complexed with HLA class II molecules of rheumatoid arthritis-susceptible alleles have been revealed to be the target of rheumatoid factor in patients with rheumatoid arthritis. Similarly, many patients with APS possess autoantibodies against the b2GPI/APS-susceptible HLA–DR complex. Ab epitopes on b2GPI exposed by association with HLA class II molecules seem to be the major autoantibody target in APS and thus autoantibody titres against the b2GPI/HLA-DR complex are more sensitive and specific to APS than anticardiolipin or anti-b2GPI Ab titres, suggesting that b2GPI/HLA-DR is involved in APS pathogenesis. Ab titres against the b2GPI/HLA-DR in 111 patients, not diagnosed with APS, with chronic limb ulcers persisting for > 6 months, were compared with 85 healthy individuals. Twenty-seven per cent of these patients possessed autoantibodies against b2GPI/HLA-DR, and a significant difference in Ab titres was observed between patients with chronic skin ulcers and healthy controls (P < 0 01; Fig. 1a). All patients possessing antib2GPI/HLA-DR Ab were negative for anti-b2GPI Ab, whereas only three patients were positive for anticardiolipin Ab (Fig. 1b). Patients with chronic ulcers were classified according to clinical observations and primary diseases to clarify the pathogenicity of anti-b2GPI/HLA-DR Ab in patients with chronic ulcers (Table 1). Anti-b2GPI/HLA-DR complex Ab was observed at a relatively high frequency in patients with livedo reticularis (n = 9/26). The proportion of anti-b2GPI/HLA-DR Ab-positive patients was also high in suspected polyarteritis nodosa and cutaneous arteritis/pseudovasculitis (n = 4/9). Both livedo reticularis and pseudovasculitis is frequently observed in patients with APS. In particular, anti-b2GPI/HLA-DR Ab was frequently detected in patients with pyoderma with collagen diseases (n = 3/7). Indeed, APS skin ulcers are frequently misdiagnosed as pyoderma gangrenosum. Therefore, these anti-b2GPI/ HLA-DR Ab-positive patients have an APS or an APS-like condition. In addition, there were anti-b2GPI/HLA-DR Ab-positive patients who did not have specific primary diseases (n = 14/ 44). However, the proportion of patients with anti-b2GPI/HLADR Ab was relatively low in those with ischaemic ulcers (n = 2/

Gene Therapy of Melanoma Using Inactivated Sendai Virus Envelope Vector (HVJ-E) with Intrinsic Anti-Tumor Activities

Despite the development of various cancer treatments, including surgical treatment, radiation, and anti-cancer reagents, cancer cells are not completely eliminated from the body in many cases, which allows the tumors to recur. Disease recurrence is the most difficult problem in cancer treatment. Much attention has been paid to cancer immunotherapy as a strategy to eliminate cancer cells from patients (1). However, numerous failures of cancer immunotherapy have indicated the difficulty of achieving anti-cancer immunity (1, 2). Cancer tissues produce factors that attenuate anti-tumor immunity and eventually induce immunotolerance against cancers in tumor-bearing individuals (3, 4). Therefore, to successfully eradicate cancer, first the tumor mass must be reduced as much as possible through surgery, radiation and chemotherapy; then, immunotherapy should be provided to increase the immune-activation signals and decrease the immune-suppression signals (5-7). Thus, multi-lateral strategies are needed in cancer treatment. Gene therapy has been anticipated to be a new tool for cancer treatment (8). Much attention has been also paid to immuno-gene therapy (9). However, it is still very difficult to achieve long-term remissions in cancer patients (10). Based on the concept of multi-lateral strategies, the control of multiple pathways of cancer growth is also necessary in gene therapy. We have developed a hemagglutinating virus of Japan envelope (HVJ-E) vector by using inactivated Sendai virus as a pseudovirion for gene and drug delivery (11). This vector can deliver siRNA, DNA, proteins, and anti-cancer drugs to cells in vitro and in vivo (12). We previously reported that HVJ-E itself has a strong anti-tumor effect against mouse tumors, such as colon carcinoma and renal carcinoma, by the activation of cytotoxic T lymphocytes and natural killer cells and the suppression of regulatory T cells (13, 14). Recently, we also determined the direct tumor-killing activity of HVJ-E through the induction of type I interferon on hormone-resistant human prostate cancer cells and human glioblastoma cells (15, 16). Thus, HVJ-E is a versatile gene and drug delivery vector with

Physician-initiated clinical study of limb ulcers treated with a functional peptide, SR-0379: from discovery to a randomized, double-blind, placebo-controlled trial

SR-0379 is a functional peptide that has wound healing effect with anti-microbial action, making it an ideal drug to prevent infection. To evaluate the safety, efficacy, and pharmacokinetics of SR-0379 for the treatment of leg ulcers, a physician-initiated, phase I/IIa, first-in-patient clinical study was designed. A multi-center, double-blind, randomized clinical study was conducted from October 2015 to September 2016. The inclusion criteria for leg ulcers were (1) diabetes or critical limb ischemia and (2) wound size <6 cm in diameter. Twelve patients were randomized into four groups and administered 0.02%, 0.1%, or 0.5% SR-0379 or placebo treatment on skin ulcers once per day for 28 days. Efficiency was evaluated by determining the rate of wound size reduction as a primary endpoint at 4 weeks after the first treatment compared with the pre-treatment wound size. As a secondary endpoint, the DESIGN-R score index, time to wound closure, and the 50% wound size reduction ratio were also evaluated. The safety of SR-0379 was evaluated during the study period. In the evaluation of efficiency, the skin ulcer reduction rates at the last evaluation were 44.73% for the 0.02% SR-0379 group, 68.25% for the 0.1% group, and 71.61% for the 0.5% group, compared with 9.95% for the placebo group. Six adverse events were reported in four patients, of which one occurred in the placebo group, and causal relationships to study drugs were denied for all six events. Treatment with SR-0379 for chronic leg ulcers was safe, well tolerated, and effective.Dermatology: peptide drug development for skin ulcersChronic leg ulcers result in substantial impairment of patient quality of life with a socioeconomic impact both in terms of medical care and missed work days. A teams led by Hironori Nakagami at Osaka University originally identified a functional peptide, SR-0379, and evaluated the safety and efficacy of SR-0379 for the treatment of leg ulcers in a physician-initiated, first-in-patient, a multi-center, double-blind, randomized clinical study. In the evaluation of efficiency, the skin ulcer reduction rates were improved for the SR-0379 treated groups in a dose-dependent manner, compared for the placebo group with no causal adverse events. Since treatment with SR-0379 for chronic leg ulcers was safe, well tolerated, and effective in this initial clinical trial, the clinical trial on next stage will be designed toward peptide drug development.

Anti‐RNA polymerase III antibody positive limited cutaneous systemic sclerosis with cryoglobulin‐induced digital gangrene

Systemic sclerosis (SSc) is a rheumatological disorder characterized by excessive fibrosis and microvascular damage of the skin and various internal organs. The pathogenesis of SSc remains unknown, but systemic autoimmunity is one of the central features of the disease. Antinuclear antibodies (ANAs) are detected in > 90% of patients with SSc. Subgrouping patients with SSc based on ANA type can be useful for diagnosis, and for predicting organ involvement and prognosis. Patients who are positive for anti-RNA polymerase (anti-RNAP) III antibodies have been reported to have an increased risk of diffuse cutaneous involvement, scleroderma renal crisis and cancer. However, the pathogenesis of low-prevalence digital gangrene in anti-RNAP III antibody-positive patients with SSc has not been fully investigated. We report a case of anti-RNAP III antibody-positive SSc complicated by digital gangrene induced by cryoglobulinaemia. A 77-year-old Japanese woman presented with 1-year history of oedematous erythema of the fingers, but only during the winter months. She had first presented to her primary care doctor with the condition 1 year previously,

A rare case of mucinous carcinoma of the skin with multiple organ metastases

Mucinous carcinoma of the skin (MCS), which was first reported by Lennox [1], is an adnexal neoplasm considered to originate from the secretory coil of eccrine sweat glands [2]. It is a rare skin malignancy as only approximately 200 cases have so far been reported [3]. Its most common location is the head and neck [4]. Although local recurrences are frequent, only a few cases of distant metastases have been so far reported [5, 6]. We present herein an extremely rare case of MCS metastasizing to [...]

A case of adult T-cell leukemia/lymphoma presenting with erythema gyratum repens-like eruptions

Dear Editor, Adult T‐cell leukemia/lymphoma (ATLL) is a peripheral T‐cell malignancy caused by human T‐lymphotropic virus type I (HTLV‐1). Cutaneous involvement is common in ATLL with variable manifestations, including multiple papules, nodules, plaques, erythrodermas, and purpuric lesions. Erythema gyratum repens (EGR) is characterized by serpiginous “wood‐grain” or “zebra‐like” erythema, usually associated with an underlying malignancy. Here, we report a case of acute‐type ATLL presentingwith distinct EGR‐like eruptions, whichwas improved by combination therapywith injected interferon‐gamma and etretinate.