Establishment of a trastuzumab-resistant extramammary Paget disease model: loss of PTEN as a potential mechanism.

BACKGROUND/OBJECTIVES: Extramammary Paget disease (EMPD) is a rare, cutaneous intraepithelial adenocarcinoma typically treated with wide local excision. Unfortunately, a number of patients with metastases show poor responses to chemotherapy. While some studies have explored trastuzumab's effectiveness against EMPD positive for human epidermal growth factor receptor 2 (HER2), trastuzumab resistance (TR) may emerge after anti-HER2 therapy. METHODS/SUBJECTS: In this study, we established TR EMPD patient-derived xenografts (PDX) that replicated the histological and HER2 expression traits of naive EMPD tumours. RESULTS: Cancer gene analyses revealed a loss of the PTEN gene in TR tumours, which was further confirmed by immunohistochemical staining and immunoblotting to test for protein expression levels. Reduced PTEN levels correlated with increased protein kinase B (Akt) phosphorylation and p27 downregulation, suggesting a potential mechanism for trastuzumab resistance in EMPD cells. In the trastuzumab-sensitive EMPD-PDX mouse model, PTEN inhibitors partially restored trastuzumab-mediated tumour regression. The TR EMPD-PDX responded favourably to targeted therapy (lapatinib, abemaciclib, palbociclib) and chemotherapy (eribulin, docetaxel, trastuzumab deruxtecan). CONCLUSIONS: This study demonstrates an innovative TR EMPD-PDX model and introduces promising antineoplastic effects with various treatments for TR EMPD tumours.

Study Design of a Phase 2/3 Randomized Controlled Trial of Dupilumab in Adults with Bullous Pemphigoid: LIBERTY-BP ADEPT.

BACKGROUND: Bullous pemphigoid (BP) is a rare, autoimmune, blistering skin disease associated with high disease burden, profoundly decreased quality of life and increased morbidity. Emerging evidence supports an important role for type 2 inflammation in disease pathogenesis. Current management relies on topical and/or systemic corticosteroids, non-selective immunosuppressants and antibiotics with anti-inflammatory properties, which are all limited by side effects and toxicities. Therefore, targeted, efficacious and safe therapies are needed. Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13, key and central drivers of type 2 inflammation. Several reports of patients successfully treated with dupilumab have been published; however, dupilumab has not been formally assessed in a double-blind, placebo-controlled trial. OBJECTIVES: We report the design of LIBERTY-BP ADEPT, a multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of dupilumab in adults with BP. METHODS: LIBERTY-BP ADEPT comprises a 35-day screening, 52-week treatment and 12-week follow-up period. Approximately 98 adults aged 18-90 years with moderate-to-severe BP are being enrolled at 51 sites on 4 continents and randomized 1:1 to subcutaneous dupilumab or placebo every 2 weeks. All participants will receive concomitant oral corticosteroids (OCS). PLANNED OUTCOMES: The primary endpoint is the proportion of patients achieving complete remission off steroid therapy at week 36. Key secondary endpoints include total cumulative OCS dose to week 36, percent change and proportion of patients with ≥ 4-point reduction in the weekly average of daily Peak Pruritus Numerical Rating Scale from baseline to week 36 and percent change in Bullous Pemphigoid Area Index score from baseline to week 36. CONCLUSION: The trial results will provide evidence on whether the efficacy and safety of dupilumab support its use as a potential novel treatment approach for BP and will provide new insights into the role of type 2 inflammation in BP pathogenesis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04206553.

Dermoscopic Features of Heterotopic Salivary Gland Tissue in the Neck: Report of a Case.

Introduction: Heterotopic salivary gland tissue (HSGT) is diagnosed when salivary gland tissue is found in areas other than the major or minor salivary glands. No dermoscopic findings of HSGT have been reported. Case Presentation: This case report gives the dermoscopic findings of a 45-year-old woman with HSGT who presented with a longstanding pale red macule on her neck, characterized by repeated clear fluid discharge. Dermoscopic examination showed a red dot with a pale pink halo and telangiectasia throughout the lesion. An excisional biopsy confirmed the diagnosis of HSGT, revealing the presence of mucous and serous salivary glandular structures within subcutaneous fat tissue. It has been reported that HSGT is associated with periductal lymphocytic infiltration, which was also observed in this case. Conclusion: We think that the "red dot with a pale pink halo" is a unique dermoscopic finding of HSGT, which is rarely observed in branchial anomalies.

Eribulin for patients with metastatic extramammary Paget disease: Study protocol for a single-arm phase II trial.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy that predominantly affects the anogenital areas of the elderly. Although the efficacy of docetaxel and other cytotoxic agents for advanced EMPD has been reported in small retrospective case studies, no treatment has been proven effective in prospective clinical trials. We established the world's first in vivo EMPD experimental model (a patient-derived xenograft model). In our treatment experiment, xenograft tumours showed a remarkable response to eribulin. This study evaluates the efficacy of eribulin for patients with advanced EMPD. In October 2022, we started a single-arm phase II trial to evaluate the efficacy of eribulin as a treatment for adult patients with unresectable EMPD with measurable lesions. Enrolment in this clinical trial is open to patients with any prior treatment for EMPD. The primary endpoint is overall response rate; the secondary endpoints include disease control rate, overall survival, progression-free survival and adverse events. The study protocol was approved by the Ethics Committee of Hokkaido University and the other collaborating institutions. If the primary endpoint is met, it is our hope that eribulin will be regarded as a standard medication for patients with advanced EMPD.

Multiple courses of steroid pulse therapy are required in treating acquired idiopathic generalized anhidrosis patients with a large anhidrotic area: A retrospective study of 28 cases.

Patients with acquired idiopathic generalized anhidrosis (AIGA) demonstrate a sudden loss of sweating function without neurological or endocrine abnormalities. The main treatment is steroid pulse therapy. However, the number of courses required for improvement has been unclear. This study aims to clarify the factors associated with AIGA disease severity and with AIGA patients' responses to steroid pulse therapy. We retrospectively analysed the clinical information of 28 patients with AIGA in our department from the last 10 years. Univariate analysis revealed that patients with a large anhidrotic area need multiple courses of steroid pulse therapy.

Association between weight loss and death in patients with malignant melanoma: A retrospective study of 28 cases.

Malignant melanoma (MM) is often associated with a poor prognosis due to metastasis and cancer death. The monitoring of prognostic factors is of vital importance, and among these factors, elevated lactate dehydrogenase (LDH) should be closely observed during the disease course. Important factors for predicting the survival of MM patients include tumor thickness, ulceration, the number of lymph node metastases, metastatic lesions, and the sites of metastasis. Weight loss is not generally included in the prognostic factors of MM, but it is monitored in other cancers, such as lung cancer and gastrointestinal cancer. The objective of this study was to investigate the association between weight loss and MM prognosis. Using data from MM patients who had been treated at our institution, we assessed the prognoses of two groups: weight loss of at least 5% body weight or weight loss not exceeding 5% body weight within a 12-month period. As a result, a higher mortality rate was found for the former group. Furthermore, the loss of at least 5% of body weight within a month was found to almost always adversely affect the patient's prognosis. The present study indicates that there may be an association between MM prognosis and weight loss of at least 5% within a year, and body weight could potentially serve as an informative factor for MM survival.

Dermal discoloration due to osmium tetroxide.

INTRODUCTION: Osmium tetroxide is a strong oxidizing agent. After dermal exposure to osmium tetroxide, skin discoloration and red papules can occur. We describe a patient with skin discoloration due to osmium tetroxide. CASE SUMMARY: A 25-year-old postgraduate student unintentionally exposed his hand to osmium tetroxide while working in a laboratory setting. After immediate washing, he sought medical care due to left middle finger discoloration. He reported no discomfort in the affected area. Thorough water rinsing was continued, and corticosteroid ointment was applied. IMAGES: Our patient developed dark brown pigmentation on the ventral side of the left middle finger. The pigmentation disappeared one week later. CONCLUSION: Osmium tetroxide may induce dark brown skin discoloration.

Development of a nutritionally balanced, melt-in-the-mouth chocolate for patients with epidermolysis bullosa.

Epidermolysis bullosa (EB) is a group of inherited blistering disorders that primarily affect the skin and mucous membranes of the digestive tract, which can lead to poor nutritional status. Dietary supplements and nutritional support methods, such as nasogastric tubes and gastrostomy, have been employed to improve the nutritional status of patients with EB; however, few foods are suitable for enjoyable eating with family and friends. Here, we introduce a nutritionally balanced, melt-in-the-mouth chocolate called andew, which was specifically designed for patients with EB. The andew chocolate is nutritionally superior and melts more easily than traditional chocolates, thus it is suitable for patients with EB, who are prone to oral erosions. Patients responded more favorably to the taste and texture of andew than to those of other dietary supplements. Not only does andew provide nutritional benefits, but it also promotes enjoyable eating with family members and friends, which could positively impact patients' mental health.

Detection of a natural antibody targeting the shed ectodomain of BP180 in mice.

BACKGROUND: Pemphigoid diseases are characterized by subepidermal blister formation accompanied by autoantibodies targeting skin component molecules, such as BP180. It is suggested that an epitope-phenotype correlation exists among autoantibodies recognizing BP180. However, it is unclear which regions of BP180 are likely targets for autoantibodies. OBJECTIVE: To elucidate the portions of BP180 where antibodies tend to react under the breakdown of immune tolerance. METHODS: We immunized mice with full-length mouse BP180 (mBP180) to produce anti-mBP180 antibodies. Using the immunized mice, hybridoma cells were established to produce anti-mBP180 antibodies. We analyzed the characteristics of the anti-mBP180 antibodies that were produced in terms of epitopes, immunoglobulin subclasses, and somatic hypermutations. RESULTS: Hybridoma cells derived from immunized mice with full-length mBP180 produced antibodies targeting the intracellular domain (IC) and the shed ectodomain (EC) of mBP180. Using the domain-deleted mBP180 recombinant protein, we revealed that monoclonal anti-mBP180 EC antibodies react to neoepitopes on the 13th collagenous region of cleaved mBP180, which corresponds to the epitopes of linear IgA bullous dermatosis antibodies in human BP180. Furthermore, the subclasses of these antibodies could be distinguished by epitope: The subclass of the anti-mBP180 IC monoclonal antibodies was IgG, whereas that of the anti-mBP180 EC antibodies was IgM. Of note, a clone of these IgM mBP180 EC antibodies was a germline antibody without somatic hypermutation, which is also known as a natural antibody. CONCLUSION: These data suggest that mice potentially have natural antibodies targeting the neoepitopes of cleaved mBP180 EC.

Pseudotumor of the skin due to Mycobacterium genavense.

Mycobacterium genavense is a rare type of nontuberculous Mycobacterium that has been reported to cause disseminated infections in patients who are immunocompromised. Because M. genavense is slow-growing and poorly able to form colonies on Ogawa medium, genetic and molecular analyses are necessary to identify this pathogen. Nontuberculous Mycobacterium infections present with various cutaneous manifestations. Of these, rare cases have been reported to present with mycobacterial pseudotumors. However, there are no reports of M. genavense with cutaneous pseudotumors. In this paper, we report a case of a pseudotumor due to M. genavense infection that was observed only in a cutaneous lesion. The patient was taking 5 mg of prednisolone and was aware of a tumor on the right lower leg. Biopsy samples showed diffuse spindle-shaped histiocytes and various other inflammatory cell infiltrates, and Ziehl-Neelsen staining detected Mycobacterium. Because no colonies formed on the Ogawa medium, genetic testing was performed, and M. genavense was identified by DNA sequence analysis. There were no other disseminated lesions beyond the skin, including in the lungs and liver. Because the patient was immunosuppressed, in accordance with previous literature, a combination therapy of clarithromycin, ethambutol, and rifampicin for 4 months was recommended. When no growth is observed on the Ogawa medium in cases of infection, it is essential to identify the infectious pathogen by genetic analysis.