Cytokine biomarkers to predict antitumor responses to nivolumab suggested in a phase 2 study for advanced melanoma.

Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor antibody against the programmed death-1 protein, were suggested in previous phase 1 studies. The present phase 2, single-arm study (JAPIC-CTI #111681) evaluated the antitumor activities of nivolumab and explored its predictive correlates in advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg was given repeatedly at 3-week intervals to 35 of 37 patients enrolled from December 2011 to May 2012 until they experienced unacceptable toxicity, disease progression, or complete response. Primary endpoint was objective response rate. Serum levels of immune modulators were assessed at multiple time points. As of 21 October 2014, median response duration, median progression-free survival, and median overall survival were 463 days, 169 days, and 18.0 months, respectively. The overall response rate and 1- and 2-year survival rates were 28.6%, 54.3%, and 42.9%, respectively. Thirteen patients remained alive at the end of the observation period and no deaths were drug related. Grade 3-4 drug-related adverse events were observed in 31.4% of patients. Pretreatment serum interferon-γ, and interleukin-6 and -10 levels were significantly higher in the patients with objective tumor responses than in those with tumor progression. In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients, strongly suggesting the usefulness of nivolumab for advanced melanoma and the usefulness of pretreatment serum cytokine profiles as correlates for predicting treatment efficacy.

Transplanted bone marrow-derived circulating PDGFRα+ cells restore type VII collagen in recessive dystrophic epidermolysis bullosa mouse skin graft.

Recessive dystrophic epidermolysis bullosa (RDEB) is an intractable genetic blistering skin disease in which the epithelial structure easily separates from the underlying dermis because of genetic loss of functional type VII collagen (Col7) in the cutaneous basement membrane zone. Recent studies have demonstrated that allogeneic bone marrow transplantation (BMT) ameliorates the skin blistering phenotype of RDEB patients by restoring Col7. However, the exact therapeutic mechanism of BMT in RDEB remains unclear. In this study, we investigated the roles of transplanted bone marrow-derived circulating mesenchymal cells in RDEB (Col7-null) mice. In wild-type mice with prior GFP-BMT after lethal irradiation, lineage-negative/GFP-positive (Lin(-)/GFP(+)) cells, including platelet-derived growth factor receptor α-positive (PDGFRα(+)) mesenchymal cells, specifically migrated to skin grafts from RDEB mice and expressed Col7. Vascular endothelial cells and follicular keratinocytes in the deep dermis of the skin grafts expressed SDF-1α, and the bone marrow-derived PDGFRα(+) cells expressed CXCR4 on their surface. Systemic administration of the CXCR4 antagonist AMD3100 markedly decreased the migration of bone marrow-derived PDGFRα(+) cells into the skin graft, resulting in persistent epidermal detachment with massive necrosis and inflammation in the skin graft of RDEB mice; without AMD3100 administration, Col7 was significantly supplemented to ameliorate the pathogenic blistering phenotype. Collectively, these data suggest that the SDF1α/CXCR4 signaling axis induces transplanted bone marrow-derived circulating PDGFRα(+) mesenchymal cells to migrate and supply functional Col7 to regenerate RDEB skin.

Prognostic indicators in 35 patients with extramammary Paget's disease.

BACKGROUND: Extramammary Paget's disease (EMPD) is an uncommon skin tumor that usually occurs in the genital area. Few studies on EMPD have been conducted. OBJECTIVE: To evaluate the clinical and pathologic features, treatments, recurrence, survival rates, and prognostic factors of EMPD. METHODS: A total of 35 (27 men and 8 women) patients with EMPD was analyzed. The average age of the patients was 73.4 years. RESULT: Twenty nine Of the 35 patients had lesions in the genital area, one in the genital and perianal area, three in the axillary area and two in the perianal area. Eighteen patients had in situ lesions, five had inguinal lymph node metastases and two had distant metastases at the time of diagnosis. Surgical resection was performed in 30 cases and radiation therapy, was administered in three cases. Six patients died of EMPD, and the overall 5 year survival rate was 75%. CONCLUSION: The presence of a nodule on the primary lesion, clinically palpable lymph nodes, the level of tumor invasion, and lymph node metastases were found to be significant prognostic factors in the 35 EMPD cases at our institution.

Two cases of male nipple leiomyoma: idiopathic leiomyoma and gynecomastia-associated leiomyoma.

We describe 2 cases of male nipple leiomyoma. A 70-year-old man had a painful subcutaneous tumor on his left nipple of 6 months duration. Histopathology disclosed dermal spindle cells with oval-shaped nuclei forming interlacing bundles with irregular pattern. Glandular elements were absent. The spindle cells were positive to α-smooth muscle actin, desmin, and vimentin. Estrogen receptor (ER) and progesterone receptor (PrR) were negative. We diagnosed this case as male leiomyoma of the nipple. Another patient was a 61-year-old man with gynecomastia induced by spironolactone of 6 months duration. He also had a painful nodule on his left nipple and histopathology disclosed spindle-shaped tumor cells as in the previous patient. The tumor was accompanied by glandular elements in the deep dermis and subcutaneous tissue, which showed apocrine secretion and were positive for α-smooth muscle actin, ER, and PrR. These glandular elements were interpreted as mammary gland. But ER and PrR stain did not show positive results for leiomyoma in the upper dermis. To the best of our knowledge, this is the first report of male idiopathic and gynecomastia-induced leiomyoma with ER and PrR staining.

Epidemiological survey of the quantity and anatomical position of facial pigmented spots in relation to age in 454 Japanese women.

Facial pigmented spots are one of the phenotypes of skin aging, but no quantitative analysis of spot features such as color intensity, size, anatomical position, and number on the cheek has yet been performed. In the current study, we conducted an epidemiological survey of 454 Japanese women in their 20s to 70s and analyzed age-related changes and site differences of facial pigmented spots. Using image analysis of high-resolution digital facial photographs, 4912 individual pigmented spots were quantified according to color, size, anatomical position, and total number on the cheek. As a result of color analysis, the color intensity of individual pigmented spots increased with aging, significantly so between ages 30s and 50s. The age-related increase in melanin index of facial spots was confirmed in all sites but did not significantly differ between facial subregions. Regarding the size of pigmented spots, the frequency of large spots increased with age, and large spots were detected in all facial sites. The total number of pigmented spots on the entire cheek increased with aging, significantly so between the 20s and 40s. The number of pigmented spots tended to increase from the region near the canthi to the lower cheeks. The number of spots was markedly increased in the buccal regions compared with the infraorbital and zygomatic regions. The data and methodology presented in the current study can link the state of facial pigmentation with the various factors involved in the histological development of pigmented spots, opening new possibilities in the fields of skin pharmacology and dermatology.

Patients with palmoplantar pustulosis have increased IL-17 and IL-22 levels both in the lesion and serum.

Recent findings about the pathogenesis of pustulosis palmaris et plantaris (PPP), also known as palmoplantar pustulosis, suggest that IL-17 expression in the acrosyringium as well as infiltration of IL-17 positive cells, e.g. Langerhans cells may play important roles. However, to date, it has not been established whether circulating IL-17 related cytokines are involved in PPP. We studied the circulating IL-17 related cytokines as well as the mRNA levels in lesional skin. IL-17 related cytokine mRNAs were increased in the PPP lesions compared with the control tissues (five patients vs five controls). The serum levels of TNF-alpha, IL-17, IL-22 and IFN-gamma also were significantly increased in PPP, but not IL-23 and IL-8 (48 patients vs 20 controls). Our findings document that not only the serum IL-17 but also tissue IL-17 are elevated in PPP and may be in the pathogenesis of this disorder.

Tight junctions in the stratum corneum explain spatial differences in corneodesmosome degradation.

To maintain stratum corneum integrity while simultaneously desquamating at a steady rate, degradation of corneodesmosomes must proceed in a controlled manner. It is unknown why corneodesmosomes are present only at the cell periphery in the upper stratum corneum. To explore this, we studied distributions of three major corneodesmosomal components, corneodesmosin, desmoglein 1 and desmocollin 1 in normal adult human epidermis. Immunofluorescent microscopy studies of skin surface corneocytes detected all three components only at the cell edges. Immunoelectron microscopy revealed selective loss of these components at the central areas starting from the deep cornified layers. We hypothesized that tight junctions (TJs) formed in the superficial granular layer may prevent protease access by functioning as a barrier between the peripheral and the central intercellular spaces in the stratum corneum. Ultrastructural examination demonstrated TJs up to the junctions between the seventh and the eighth deepest cornified layers. Immunoelectron microscopy also detected clusters of occludin and claudin-1 immunolabels at the cell periphery, and kallikrein 7 immunolabels outside of TJs in the lower cornified layers. With colloidal lanthanum nitrate perfusion assay of stripped stratum corneum, the tracer was excluded from TJ domains. Taken together, we propose that TJs inhibit access of proteases to the peripheral corneodesmosomes forming the structural basis for the basket-weave-like appearance of the stratum corneum.

Effects of serine palmitoyltransferase inhibitor ISP-I on the stratum corneum of intact mouse skin.

Serine palmitoyltransferase (SPT) is involved in the ceramide synthesis pathway. We investigated the effects of ISP-I, a potent inhibitor of SPT, on the stratum corneum (SC) of hairless mouse skin. Application of ISP-I for one week resulted in a significant decrease in the amount of ceramide, which was associated with a decrease in SC hydration. However, there was an increase in the number of SC layers and less transepidermal water loss than control. Transmission Electron Microscopy observation revealed that the number of desmosome-like structures in the layers immediately above the stratum granulosum (SG) was significantly increased in ISP-I-treated skin compared to vehicle-treated skin. The activity of serine protease-an enzyme associated with the process of desquamation-was lower in the SC of ISP-I-treated skin than control. Furthermore, immunoelectronmicroscopy revealed that glucosylceramide and corneodesmosin tended to remain in corneocytes and were not secreted into the intercellular spaces of the SC in the ISP-I-treated skin. These results indicate that the application of ISP-I decreases ceramide and skin hydration, while at the same time increases the number of SC layers. The accumulation of corneocyte layers may originate from an aberrant desquamation process related to the decrease in the serine protease activity as well as an alteration in the transport of desquamation-related proteases by lamellar bodies.

Cost-efficacy and pharmacoeconomics of scalp lesions of psoriatic patients in current Japanese health-care insurance system.

Psoriatic scalp lesion is occasionally recalcitrant to topical or systemic treatments including biologic agents. The combined active vitamin D3 /corticosteroids are more expensive despite their marked efficacy. The aim of the present study is to evaluate total costs as well as costs versus efficacy of topical scalp psoriasis treatments under the current Japanese health-care insurance system. A prospective study was performed from the database of an outpatient clinic. The medical costs of scalp psoriasis patients were evaluated in a prospective manner in each case over a total 12-month duration from July 2017 until August 2019. The total cost of the combined active vitamin D3 /corticosteroid gel (combined gel) was higher (¥79 350) than that of topical corticosteroid lotion (¥22 970). The cost versus efficacy of the combined gel was lower (¥2026/cost for the reduction of 1 Psoriasis Scalp Severity Index [1PSSI] score) than that of topical corticosteroid lotion (¥2316/1PSSI). The reduction of PSSI score was observed by changing from topical corticosteroid lotion to topical combined gel. The combined gel showed the best cost efficacy in terms of medical economic burden in the current Japanese insurance system.

Toxic epidermal necrolysis with prominent facial pustules: a case with reactivation of human herpesvirus 7.

A 37-year-old Japanese man presented with confluent erythemas and progressive erosive lesions on the almost entire body including the oral mucosa and genitalia. This was accompanied with prominent facial pustules. Although a lymphocyte stimulation test was positive only for acetaminophen, he took other agents including carbamazepine for his depression. He was diagnosed as having toxic epidermal necrolysis with prominent facial pustules and treated by methylprednisolone pulse therapy, which resulted in a good response. During the course, human herpesvirus 7 (HHV-7) DNA was detected in his peripheral blood. The HHV-7 reactivation might be related to facial pustulosis, which is occasionally observed in drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms.

Safety, tolerability and efficacy of repeated intravenous infusions of KHK4083, a fully human anti-OX40 monoclonal antibody, in Japanese patients with moderate to severe atopic dermatitis.

BACKGROUND: KHK4083, a fully human anti-OX40 monoclonal antibody, is a potential novel therapeutic option for moderate to severe atopic dermatitis (AD), targeting the immunopathogenic pathways. OBJECTIVE: Assess the safety and tolerability of repeated doses of KHK4083 in patients with moderate to severe AD, and investigate the pharmacokinetics and immunogenicity of KHK4083. Additionally, assess the clinical efficacy and pharmacodynamics as exploratory objectives. METHODS: In this phase 1, single-center, open-label, repeated-dose study, a total of 22 patients received KHK4083 10 mg/kg IV on Day 1, Day 15 and Day 29, and were followed until Day 155. RESULTS: There were no deaths, serious adverse events (SAEs), or discontinuations due to adverse events (AEs). Common treatment-emergent AEs were mild or moderate pyrexia (11 patients, 50.0 %), and chills (8 patients, 36.4 %). No clinically meaningful changes in the laboratory values, vital signs, and electrocardiogram recordings were observed. The Cmax was 267 ± 53 µg/mL and the t1/2 was 303 ± 88 h at Day 29. The overall assessment of antibodies against KHK4083 (immunogenicity) showed low positive responses. Continued improvement in the Eczema Area and Severity Index (EASI) and Investigator's Global Assessment (IGA) scores were observed throughout the study. The mean and median percent changes in thymus and activation-regulated chemokine (TARC) continued to decrease over time to -70.4 and -78.8 % until Day 155. CONCLUSION: Repeated intravenous infusion of KHK4083 had an acceptable safety profile in patients with moderate to severe AD. Sustained improvement in the symptoms of AD was observed after completion of KHK4083 treatment.

Focal adhesion kinase as an immunotherapeutic target.

BACKGROUND: Focal adhesion kinase (FAK) is a ubiquitously expressed non-receptor tyrosine kinase involved in cancer progression and metastasis that is found overexpressed in a large number of tumors such as breast, colon, prostate, melanoma, head and neck, lung and ovary. Thus, FAK could be an attractive tumor associated antigen (TAA) for developing immunotherapy against a broad type of malignancies. In this study, we determined whether predicted T cell epitopes from FAK would be able to induce anti-tumor immune cellular responses. METHODS: To validate FAK as a TAA recognized by CD4 helper T lymphocytes (HTL), we have combined the use of predictive peptide/MHC class II binding algorithms with in vitro vaccination of CD4 T lymphocytes from healthy individuals and melanoma patients. RESULTS: Two synthetic peptides, FAK(143-157) and FAK(1,000-1,014), induced HTL responses that directly recognized FAK-expressing tumor cells and autologous dendritic cells pulsed with FAK-expressing tumor cell lysates in an HLA class II-restricted manner. Moreover, since the FAK peptides were recognized by melanoma patient's CD4 T cells, this is indicative that T cell precursors reactive with FAK already exist in peripheral blood of these patients. CONCLUSIONS: Our results provide evidence that FAK functions as a TAA and describe peptide epitopes that may be used for designing T cell-based immunotherapy for FAK-expressing cancers, which could be used in combination with newly developed FAK inhibitors.

A randomized double-blind trial of intravenous immunoglobulin for pemphigus.

BACKGROUND: Pemphigus is a rare life-threatening intractable autoimmune blistering disease caused by IgG autoantibodies to desmogleins. It has been difficult to conduct a double-blind clinical study for pemphigus partly because, in a placebo group, appropriate treatment often must be provided when the disease flares. OBJECTIVE: A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of a single cycle of high-dose intravenous immunoglobulin (400, 200, or 0 mg/kg/d) administered over 5 consecutive days in patients relatively resistant to systemic steroids. METHODS: We evaluated efficacy with time to escape from the protocol as a novel primary end point, and pemphigus activity score, antidesmoglein enzyme-linked immunosorbent assay scores, and safety as secondary end points. RESULTS: We enrolled 61 patients with pemphigus vulgaris or pemphigus foliaceus who did not respond to prednisolone (> or =20 mg/d). Time to escape from the protocol was significantly prolonged in the 400-mg group compared with the placebo group (P < .001), and a dose-response relationship among the 3 treatment groups was observed (P < .001). Disease activity and enzyme-linked immunosorbent assay scores were significantly lower in the 400-mg group than in the other groups (P < .05 on day 43, P < .01 on day 85). There was no significant difference in the safety end point among the 3 treatment groups. LIMITATION: Prednisolone at 20 mg/d or more may not be high enough to define steroid resistance. CONCLUSION: Intravenous immunoglobulin (400 mg/kg/d for 5 d) in a single cycle is an effective and safe treatment for patients with pemphigus who are relatively resistant to systemic steroids. Time to escape from the protocol is a useful indicator for evaluation in randomized, placebo-controlled, double-blind studies of rare and serious diseases.

Recognition of prostate and melanoma tumor cells by six-transmembrane epithelial antigen of prostate-specific helper T lymphocytes in a human leukocyte antigen class II-restricted manner.

The six-transmembrane epithelial antigen of prostate (STEAP) protein is an attractive candidate for T cell-based immunotherapy because it is overexpressed in prostate cancer and various other tumor types. Several peptide epitopes capable of stimulating CTLs that killed STEAP-expressing tumor cells have been described. Our goal was the identification of helper T lymphocyte (HTL) epitopes of STEAP for the optimization of T cell-based immunotherapies against STEAP-expressing malignancies. Candidate HTL epitopes for STEAP were predicted using in silico algorithms for HLA class II-binding peptides and were tested for their ability to elicit HTL responses by in vitro peptide vaccination of CD4 T lymphocytes from healthy individuals and prostate cancer patients. Two peptides (STEAP(102-116) and STEAP(192-206)) were effective in stimulating in vitro antitumor HTL responses in both normal individuals and prostate cancer patients. Notably, both STEAP HTL peptides behaved as promiscuous T-cell epitopes because they stimulated T cells in the context of more than one MHC class II allele. These newly described STEAP HTL epitopes could be of value for the design and optimization of T cell-based immunotherapy against STEAP-expressing tumors.

Cost-efficacy and pharmacoeconomics of psoriatic patients in Japan: Analysis from a single outpatient clinic.

Compared with topical corticosteroids, topical combined active vitamin D3 /corticosteroids and especially biologics are more expensive despite their marked efficacy in the treatment of psoriasis. The aim of the present study is to evaluate total costs as well as costs versus efficacy of various psoriasis treatments under the current Japanese health-care insurance system. A prospective study was performed from the database of a single clinic located in Hokkaido Prefecture. Cost and quality of life of psoriatic patients were evaluated in a prospective manner during a total of 12 months from March 2017 until June 2018. Quality-adjusted life year (QALY) of biologics was the highest among all treatments. Among the topical treatments, the cost versus efficacy of combined active vitamin D3 /corticosteroid was lowest (¥10 557/1 Psoriasis Area and Severity Index). Furthermore, incremental cost-effectiveness ratio (ICER) of combined active vitamin D3 /corticosteroid was ¥1 024 031/QALY when compared with topical corticosteroid treatment alone. The topical combined active vitamin D3 /corticosteroid treatment showed the best cost-efficacy in terms of medical economic burden.

Multiple papules and nodules on the face and neck caused by the larvae of an unknown nematode: A noncreeping type eruption.

Cutaneous larva migrans is caused by various nematodes. Skin manifestations may include superficial or creeping eruptions, folliculitis, and migratory subcutaneous nodules. We report a 52-year-old man with asymptomatic, multiple eruptive papules and nodules on the face and neck caused by the larvae of an unknown nematode. The patient never had any creeping or migratory eruptions. Our case is very unusual and differs from previously reported cases of cutaneous larva migrans.

Primary cutaneous anaplastic large cell lymphoma successfully treated with local thermotherapy using pocket hand warmers.

Apart from for cutaneous deep fungal or mycobacterial infections, thermotherapy has been used for various malignant tumors. We report a case of primary cutaneous anaplastic large cell lymphoma, which responded quite well to topical thermotherapy using chemical pocket hand warmers. The treatment resulted in an immediate tumor regression without recurrence. This method is simple and might be a useful tool against solitary cutaneous lymphoma, especially of elderly patients with poor performance status or with various systemic complications.

Epidemiological survey from 2009 to 2012 of psoriatic patients in Japanese Society for Psoriasis Research.

Since 1982, the Japanese Society for Psoriasis Research has conducted annual epidemiological surveys of patients with psoriasis. Kawada et al. have reported data for 1982-2001 and Takahashi et al. have reported data for 2002-2008. The present study evaluated 9290 psoriatic cases according to age and sex (2009-2012). The male : female ratio was 2.08:1 (6281 male patients [67.6%] to 3009 female patients [32.4%]). The most prevalent type was psoriasis vulgaris (85.6% of all cases), which was followed by psoriasis arthropathica (6.0%), psoriasis guttate acuta (3.2%), Zumbusch-type generalized pustular psoriasis (1.8%) and psoriasis erythroderma (1.5%). Psoriasis vulgaris was the most prevalent type for all ages, while psoriasis arthropathica and psoriasis guttate acuta were most prevalent among patients aged less than 65 years. The present survey detected an increased number of cases with comorbid diabetes and/or arthritis symptoms compared with the previous surveys. We found that treatments frequently involved topical corticosteroids (89.7% of cases) and vitamin D3 ointments (78.0% of cases), with a notable increase in the use of vitamin D3 ointments. Systemic treatments were used in 33.3% of cases, including cyclosporin (33.6%), etretinate (19.5%), methotrexate (8.6%), infliximab (11.4%), adalimumab (10.9%) and ustekinumab (6.2%). Phototherapy was used in 30.9% of cases. Although psoralen plus ultraviolet A therapy was the predominant phototherapy during previous studies, the present survey revealed that narrowband ultraviolet B therapy was used in 84.5% of phototherapy-treated cases. Thus, the present survey revealed major changes in treatment trends.