Pyoderma gangrenosum-like lesions in the setting of IgA cutaneous vasculitis: Favourable response to adalimumab.

Pyoderma gangrenosum is a rare inflammatory skin disease classified within the group of neutrophilic dermatoses, and clinically characterised by painful, rapidly evolving cutaneous ulcers with undermined, irregular, erythematous-violaceous edges. Underlying diseases include rheumatoid arthritis, inflammatory bowel disease, haematopoietic malignancy, and aortitis syndrome. However, there was a limited number of cases of concomitant pyoderma gangrenosum and IgA vasculitis. Herein, we report a case presenting persistent large skin wounds as a diagnosis of pyoderma gangrenosum in the setting of IgA cutaneous vasculitis, which was successfully treated by a TNF-α inhibitor. A 67-year-old obese female presented palpable purpura on her lower extremities. A skin biopsy taken from the purpuric eruption showed leukocytoclastic vasculitis with IgA and C3 depositions in the vessel walls of the upper dermis, leading to the diagnosis of IgA vasculitis. Small skin ulcers rapidly expanded in several days, eventually developing perforating skin ulcers with irregular erythematous and violaceous edges on both lower extremities following the tapered oral prednisolone at a dose of 25 mg per day. Based on the clinical manifestation and histological analysis, we diagnosed her skin wound as pyoderma gangrenosum. After the adalimumab administration, the spreading ulceration was dampened, leading to the acceleration of wound epithelialisation.

A Case of Pan-TRK Positive Dermatofibrosarcoma Protuberans Located on the Nose.

Dermatofibrosarcoma protuberans (DFSP) is a rare and infiltrative soft tissue tumor. Our report details a distinctive case of DFSP with pan-TRK positivity in the right nasal dorsum of a 46-year-old female. Histological analysis identified NTRK fusion gene involvement in this patient, detectable through pan-TRK immunostaining. The case underscores the significance of comprehensive management for pan-TRK-positive DFSP in challenging facial locations, indicating the potential efficacy of TRK inhibitors.

Congenital Langerhans Cell Histiocytosis With the Skin and Lung Involvement: A Case and Literature Review.

Langerhans cell histiocytosis (LCH) is a clonal proliferative disease of immature Langerhans cells that expand in various organs, leading to organ and tissue dysfunction. Although LCH is most commonly seen in children under the age of three, a small number of cases of congenital LCH have been described. With a review of the literature on congenital LCH with lung and skin lesions, we present a case of congenital LCH with involvement of skin and lung, which was effectively treated with chemotherapy without recurrence for 3 years during the observational period. In addition, we summarized previously published case studies of congenital LCH with skin and lung involvement.

Cardiac Arrest Due to Kounis Syndrome Following Cephazolin Administration During Surgery Under Local Anesthesia.

The Kounis syndrome is described as the co-occurrence of allergic responses brought on by mast cell activation and acute coronary syndromes. We present a case of Kounis syndrome leading to cardiac arrest following the cephazolin sodium administration during the surgical resection of basal cell carcinoma. An 87-year-old woman was diagnosed with basal cell cancer. She received surgical excision of the tumor while anesthetized with lidocaine hydrochloride and 1% epinephrine. This patient began to itch around five minutes after cefazolin (CEZ) administration and eventually experienced cardiac arrest following diffuse rashes that spread throughout her body and edema in her eyelids. In line with the response, the electrocardiogram (ECG) also showed an elevated ST segment in V1-6, leading to possibly the diagnosis of Kounis syndrome. We also review the literature on Kounis syndrome following CEZ administration.

The Efficacy of Platinum Chemotherapy in a Japanese Malignant Melanoma Patient With a BRCA2 Mutation Identified by Gene Panel Testing.

A BRCA2 mutation increases the chance of developing cancer and has been linked to several diseases, including hereditary breast, ovarian, pancreatic, and prostate cancers. We present a case of advanced malignant melanoma treated with platinum-containing chemotherapy and demonstrate a momentarily favorable clinical outcome as determined by a Next Generation Sequencer (NGS) gene panel testing. A 54-year-old female with BRAF wild-type of anal primary melanoma received adjuvant immunotherapy with nivolumab following surgical resection. Novel distant lung metastasis was identified four months after the adjuvant therapy. Multi-gene panel testing figured out another potential treatment strategy using a sample from a distant metastatic tumor and identified a BRCA2 mutation in the tumor. Based on the sensitivity to platinum agents in BRCA2 mutation-positive tumors, DAC-Tam therapy (Dacarbazine, Nimustine, Cisplatin, and Tamoxifen) was administrated and showed tumor size reduction. After five rounds of DAC-Tam treatment, the metastatic lesion decreased from 17 mm to 5 mm. The parent was treated with platinum and Dacarbazine alone because of deteriorated renal function and grade 3 myelosuppression. In addition, the tumor showed resistance to the platinum plus Dacarbazine chemotherapy. Her chemotherapy-induced renal failure and bone marrow suppression did not improve well. Additionally, she felt significant weakness due to poor dietary intake and did not want to receive additional chemotherapy. To relieve her symptoms, she and her family desired the best supporting care and moved her to another hospital. The patient died 12 months after submitting the gene panel.

Ixekizumab-induced urticarial drug eruption.

Biological agents targeting inflammatory skin diseases have dramatically overcome many of the limitations of older oral therapeutic options. Among the various biological agents, ixekizumab is a humanised monoclonal antibody that blocks the biological activity of IL-17A, which exhibited high efficacy against psoriasis. Although there are a limited number of cutaneous adverse reactions, biologic-induced type I allergic reactions are rare. Herein, we report a case of ixekizumab-induced urticaria.

Survival rates of systemic interventions for psoriasis in the Western Japan Psoriasis Registry: A multicenter retrospective study.

Psoriasis affects approximately 0.3% of the Japanese population. Recently, various effective systemic drugs have become available, and the continuation of a given treatment has become critical because of the chronic nature of psoriasis. Factors affecting drug survival (the time until treatment discontinuation) in psoriasis treatment include efficacy, safety, ease of use, and patient preference. In the present study, the authors retrospectively surveyed a multifacility patient registry to determine the real-world evidence of the survival rate of systemic interventions for psoriasis treatment. Patients with psoriasis who visited 20 facilities in the Western Japan area between January 2019 and May 2020 and gave written consent were registered as study participants, and their medical history of systemic interventions for psoriasis (starting from 2010) was retrospectively collected and analyzed. The drugs investigated were adalimumab, infliximab, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, cyclosporine, and apremilast. When drugs were discontinued, the reasons were also recorded. A total of 1003 patients with psoriasis including 268 with psoriatic arthritis (PsA) were enrolled. In biologics, more recently released drugs such as interleukin 17 inhibitors showed a numerically higher survival rate in the overall (post-2010) analysis. However, in the subset of patients who began treatment after 2017, the difference in the survival rate among the drugs was smaller. The reasons for discontinuing drugs varied, but a loss of efficacy against dermatological or joint symptoms were relatively frequently seen with some biologics and cyclosporine. The stratification of drug survival rates based on patient characteristics such as bio-naive or experienced, normal weight or obese, and with or without PsA, revealed that bio-experienced, obese, and PsA groups had poorer survival rates for most drugs. No notable safety issues were identified in this study. Overall, the present study revealed that the biologics show differences in their tendency to develop a loss of efficacy, and the factors that negatively impact the survival rate of biologics include the previous use of biologics, obesity, and PsA.

Identification of Multiple Bowen's Disease Skin Lesions by Careful Physical Examination in a Patient With Fanconi Anemia.

Because Fanconi anemia is a hereditary bone marrow failure disease caused by DNA repair dysfunction, malignant skin tumors have been recognized in patients with Fanconi anemia. Herein, we report a 32-year-old male with Fanconi anemia presenting multiple Bowen's disease skin lesions. He first recognized skin eruption in his scrotum, which was diagnosed with Bowen's disease by dermoscopy examination and histological analysis. Due to the elevated risk of skin cancers in Fanconi anemia, we conducted additional meticulous examinations using dermoscopy on the entire body's skin, revealing another skin tumor on his back. A skin biopsy confirmed the diagnosis of another site of Bowen's disease. Therefore, additional thorough examinations using dermoscopy might aid in identifying multiple skin tumors in high-risk cases of skin malignancies, such as Fanconi anemia.

STING expression is an independent prognostic factor in patients with mycosis fungoides.

Mycosis fungoides is recognized as an indolent cutaneous malignant T-cell lymphoma. In contrast, there are few therapeutic options for advanced forms of mycosis fungoides. Since immunotherapy is desirable as an alternative therapeutic option, identifying candidate molecules is an important goal for clinicians. Although tumor-derived negative immunomodulatory molecules, such as PD-1/PD-L1, have been identified in various malignancies, the useful positive immunological drivers of mycosis fungoides are largely unknown. We found that the stimulator of interferon (IFN) genes (STING) was highly upregulated in early-stage mycosis fungoides. Immunohistochemical examination revealed different STING staining patterns in patients with mycosis fungoides. Although there were no significant differences in clinical factors' characteristics, STING expression was associated with the survival of patients with mycosis fungoides. The survival rate was significantly poor in patients with low STING-expressing mycosis fungoides. Univariate and multivariate analyses revealed that low STING expression was associated with an increased hazard ratio. Our results indicate that STING expression independently influences the prognosis of mycosis fungoides.

Vedolizumab Attenuates Immune-Checkpoint-Therapy-Induced Infliximab-Refractory Colitis.

Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, have drastically changed treatments of advanced melanoma. However, ICI-related enterocolitis is often the most common adverse event, and represents the main reason for ICI discontinuation and mortalities. Here, we report the case of a metastatic melanoma treated with vedolizumab for ICI-induced colitis. A 67-year-old man treated with ipilimumab and nivolumab developed ICI-induced colitis and grade 3 diarrhea refractory to methylprednisolone and infliximab. After his third dose of vedolizumab, oral prednisolone ceased, and the colitis had completely resolved with no recurrence. This case report supports vedolizumab use in treating severe colitis which failed to resolve with first- and second-line immunosuppressive therapy.

Psoriasis epidemiology screening tool (PEST) is useful for the detection of psoriatic arthritis in the Japanese population.

Psoriasis is a chronic inflammatory skin disease that involves various systemic organs and tissues and is characterized by scaly erythematous skin. Among the different types of psoriasis, psoriatic arthritis (PsA) is frequently reported, and occasionally develops into severe arthritis leading to joint dysfunction. There are various tools, especially questionnaires, to identify the presence of PsA in European and American populations; however, little is known about the utility of these tools in the Asian population. In this study, we investigated the utility of a representative tool, the psoriasis epidemiology screening tool (PEST) questionnaire, to identify PsA among Japanese patients with psoriasis. A total of 143 patients with psoriasis were enrolled in this study. Among them, 29 patients were diagnosed with PsA. The frequency of PsA was significantly increased in patients with PEST scores > 3, with a sensitivity of 93.1% and a specificity of 78.9%. Among the questions in the PEST questionnaire, "Have you ever had a swollen joint?" showed the highest frequency to answer "Yes" among patients with PsA. Univariate and multivariate analyses revealed that high PEST scores (> 3) was an independent variable in PsA patients. Taken together, our study suggests that the PEST questionnaire is a useful tool to identify PsA among Japanese patients with psoriasis.

A Positive Dermcidin Expression Is an Unfavorable Prognostic Marker for Extramammary Paget's Disease.

Extramammary Paget's disease is recognized as an apocrine-origin cutaneous tumor and is localized in the intraepithelial skin lesion. However, its advanced form is intractable, and there is currently no therapeutic option with a satisfactory level of clinical outcome. Therefore, it is of great importance to identify a potential biomarker to estimate tumor advancement in extramammary Paget's disease. Dermcidin is an antimicrobial peptide derived from the eccrine gland and is identified as a biomarker in various malignancies. To investigate the potential of dermcidin in extramammary Paget's disease, we investigated dermcidin expression in tumors using the immunostaining technique. Although previous studies have reported that extramammary Paget's disease has no positive staining against dermcidin, 14 out of 60 patients showed positive staining of dermcidin in our study. To clarify the characteristics of positive dermcidin in extramammary Paget's disease, we investigated the clinical characteristics of positive dermcidin extramammary Paget's disease patients. Positive dermcidin patients showed a significantly high frequency of lymph node metastasis. We next investigated the impact of positive dermcidin on overall survival. Univariate analysis identified that positive dermcidin showed a significantly increased hazard ratio in overall survival, suggesting that dermcidin might be a prognostic factor for extramammary Paget's disease.

Cell Adhesion Molecule 1 (CADM1) Is an Independent Prognostic Factor in Patients with Cutaneous Squamous Cell Carcinoma.

Cell adhesion molecular 1 (CADM1) is a multifunctional cell adhesion molecule belonging to the immunoglobulin superfamily, which suppresses malignant solid tumor development. However, the correlation between CADM1 expression and prognosis in cutaneous squamous cell carcinoma (cSCC) patients remains unclear. In a retrospective analysis of 88 patients diagnosed with cSCC at our institution between January 2006 and December 2016, the degree of CADM1 expression in tumor cells was evaluated by immunostaining. Fifty-five and 33 patients had tumors with high and low CADM1 expression, respectively. Low CADM1 expression on the tumor was associated with poor differentiation, whereas the Kaplan-Meier curve and log-lank test indicated a favorable prognosis with high CADM1 expression. Multivariate analysis excluding the effect of the degree of differentiation and clinical stages showed that the hazard ratio (HR) of survival was significantly increased with low CADM1 expression. Thus, CADM1 expression is an independent prognostic factor for cSCC patients.

Immunotherapy with 4-1BBL-Expressing iPS Cell-Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma.

We have established an immune cell therapy with immortalized induced pluripotent stem-cell-derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expression of CD86 was upregulated in iPS-ML-41BBL more than that in control iPS-ML. Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured with iPS-ML or iPS-ML-41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPS-ML-41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice compared to that of iPS-ML. Furthermore, the numbers of antigen-specific CD8+ T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPS-ML-41BBL compared to those treated with control iPS-ML. The number of CXCR6-positive T cells were increased in the tumor tissues after treatment with iPS-ML-41BBL compared to that with control iPS-ML. These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological "cold tumor" to "hot tumor".

High S100A2 expression in keratinocytes in patients with drug eruption.

Telaprevir used as a protease inhibitor against hepatitis C virus is frequently associated with cutaneous adverse reactions. To explore a histological biomarker of cutaneous adverse events induced by telaprevir, we systematically searched for genes that were dysregulated by telaprevir in normal human epidermal keratinocytes (NHEKs). Microarray analysis and real-time polymerase chain reaction (PCR) revealed the significant increase in the expression of S100 calcium-binding protein A2 (S100A2) gene following treatment of NHEKs with telaprevir. Immunohistochemical analysis demonstrated that the expression of S100A2 was dominant in the spinous layer of the epidermis in patients with telaprevir-mediated severe-type drug eruptions and limited to the basal layer of the epidermis in healthy subjects. Furthermore, S100A2 expression increased after treatment with trichloroethylene and other medications, and the degree of S100A2 expression correlated with the severity of cutaneous adverse events. S100A2 expression also significantly increased in the skin of patients with atopic dermatitis and psoriasis. Taken together, S100A2 is highly expressed in the epidermis under inflammatory conditions and drug eruptions and may serve as a marker for keratinocyte damage in response to any inflammatory or toxic condition.

Matrin-3 plays an important role in cell cycle and apoptosis for survival in malignant melanoma.

BACKGROUND: A previous study revealed that matrin-3 is an essential component in maintaining fibroblast growth factor 2 (FGF2)-mediated undifferentiation of neural stem cells (NSCs) using a proteomics approach. Malignant melanoma (MM) arises from melanocytes that originate from neural crest stem cells during development. Additionally, it has been reported that the expression of FGF2 is positively correlated with the progression of MM. OBJECTIVE: We expected that matrin-3, as a downstream component of FGF2, might be associated with the aggressiveness or differentiation of MM. METHODS: Matrin-3 expression was measured in human melanoma patient tissues and human MM cell lines. We analyzed the effect of matrin-3 siRNA on the proliferation of human MM cell lines and focused on cell cycle progression and apoptosis. We carried out in vivo xenograft tumor experiments by implanting A375 cells transfected with matrin-3 shRNA. RESULTS: Matrin-3 was highly expressed in MM, and matrin-3 knockdown inhibited the proliferation of melanoma cellsin vivo and in vitro. Furthermore, we found that matrin-3 knockdown led to an accumulation of cells in the G1 phase and an increase in apoptotic cell number. CONCLUSION: Our results suggest that matrin-3 could be a new therapeutic target for the treatment of MM.