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.

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.

Current understanding of comparative pathology and prospective research approaches for canine hemangiosarcoma.

Hemangiosarcoma (HSA) is a malignant tumor originating from endothelial cells. HSA typically develops in dogs, but is rare in other animals, including humans. Although surgery and chemotherapy are conventional treatments for HSA, neither treatment can significantly improve patient prognosis. To develop novel and effective therapeutics, a deeper understanding of HSA pathogenesis must be acquired. However, the limited research tools for HSA have been unable to make a breakthrough; therefore, it is crucial to widely utilize or establish novel research tools such as patient-derived xenograft models, organoids, and chicken embryo xenograft models. The pathogenesis of the human counterpart of HSA, angiosarcoma (AS), also remains incompletely understood, preventing the extrapolation of findings from humans to dogs, unlike other diseases. In this review, we summarize the clinicopathological and morphological features of HSA, and then we discuss the current understanding of the molecular pathology of HSA. Finally, we highlight promising research tools that may accelerate HSA basic research toward developing novel therapeutics. We also briefly summarize AS to help researchers comprehend HSA from the perspective of comparative pathology.

Prognostic Analysis of Patients With Extramammary Paget Disease Treated With Conservative Excision.

BACKGROUND: Extramammary Paget disease (EMPD) is a malignant skin tumor with a relatively good prognosis. The standard treatment is wide local resection or Mohs micrographic surgery. However, conservative excision may be a better option when radical wide local excision is difficult to perform due to the patients' mental or physical condition. There have been no studies on the prognosis of patients with EMPD who underwent conservative excision. OBJECTIVE: To compare the prognosis of conservative excision cases to wide excision cases of EMPD. MATERIALS AND METHODS: The authors retrospectively analyzed the clinical data of 69 cases of EMPD without metastases to lymph nodes or organs (11 cases treated with conservative excision, 58 cases treated with wide local excision) who underwent resection of the primary tumor from 2002 to 2022 in the Department of Dermatology at Hokkaido University Hospital. RESULTS: The log-rank test showed no significant differences in overall survival or metastasis-free survival between the wide excision group and the conservative excision group, although conservative surgery was often chosen in elderly patients or patients with lower performance status. CONCLUSION: This study suggests that conservative surgery should be considered as a treatment option for EMPD.

Eribulin inhibits growth of cutaneous squamous cell carcinoma cell lines and a novel patient-derived xenograft.

Advanced cutaneous squamous cell carcinoma (cSCC) is treated with chemotherapy and/or radiotherapy, but these typically fail to achieve satisfactory clinical outcomes. There have been no preclinical studies to evaluate the effectiveness of eribulin against cSCC. Here, we examine the effects of eribulin using cSCC cell lines and a novel cSCC patient-derived xenograft (PDX) model. In the cSCC cell lines (A431 and DJM-1 cells), eribulin was found to inhibit tumor cell proliferation in vitro as assessed by cell ATP levels. DNA content analysis by fluorescence-activated cell sorting (FACS) showed that eribulin induced G2/M cell cycle arrest and apoptosis. In xenograft models of cSCC cell lines, the administration of eribulin suppressed tumor growth in vivo. We also developed a cSCC patient-derived xenograft (PDX) which reproduces the histological and genetic characteristics of a primary tumor. Pathogenic mutations in TP53 and ARID2 were detected in the patient's metastatic tumor and in the PDX tumor. The cSCC-PDX responded well to the administration of eribulin and cisplatin. In conclusion, the present study shows the promising antineoplastic effects of eribulin in cSCC. Also, we established a novel cSCC-PDX model that preserves the patient's tumor. This PDX could assist researchers who are exploring innovative therapies for cSCC.

Systemic Retinoids for Generalized Verrucosis Due to Congenital Immunodeficiency: Case Reports and Review of the Literature.

Generalized verrucosis (GV) is a group of immunodeficiency disorders accompanied by widespread human papillomavirus infection. We revisit two cases of GV due to congenital interleukin-7 deficiency successfully treated with systemic retinoids. We also present a review of the literature on the use of systemic retinoids to treat GV. Our review suggests that systemic retinoids are a safe and effective option for managing recalcitrant wart lesions in cases of GV.

Skin biopsies for diagnosing neuronal intranuclear inclusion disease: A retrospective study of 12 cases.

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative condition. Skin biopsies taken from the lower leg were reported to be a standard diagnostic procedure for NIID; however, no studies have addressed the optimal skin biopsy locations. We retrospectively analyzed 12 cases in which skin biopsies were performed for diagnosing NIID. We collected clinical information including age, sex, skin biopsy site, the presence of nuclear inclusion bodies, the results of p62 immunostaining, the final diagnosis from the department of neurology, and the presence of abnormal GGC repeats in the NOTCH2NLC gene. Four of the 12 cases had a final diagnosis of NIID. One of the four cases was biopsied from the lower leg, whereas the other three cases were biopsied from the abdomen or thigh. Biopsy specimens of the four definite NIID cases revealed the average rates of nuclear inclusion body-positive cells in adipocytes, sweat gland cells, and fibroblasts to be 13.2%, 10.3%, and 6.3%, respectively. GGC repeat abnormalities in the NOTCH2NLC gene were observed in two of the four cases. The present study indicates that sites with ample subcutaneous fat tissue could be promising for diagnostic skin biopsies for NIID.

Diagnosis and Management of Porocarcinoma.

Eccrine porocarcinoma, also known as porocarcinoma (PC) and malignant eccrine poroma, is very rare and is known to arise from the cutaneous intraepidermal ducts of the sweat glands. Its etiology is not well understood; however, some studies suggest that PC tumors originate from benign eccrine poroma. Recently, several gene alterations have been reported in PC that can reveal mechanisms of the oncogenic process. Since the clinical and histopathological findings of PC are variable, PC is difficult to diagnose precisely, especially when the histology resembles that of cutaneous squamous cell carcinoma or poroma. Immunohistochemical staining with carcinoembryonic antigen and epithelial membrane antigen may help to distinguish PC from other tumors. The standard treatment for local PC is wide local excision. The prognosis of patients with metastatic PC is poor, with mortality rates of approximately 60-70%. The efficacy of radiation and chemotherapy for metastatic PC is limited; however, immunotherapy with pembrolizumab, a programmed cell death protein 1 inhibitor, could be a promising treatment. This review focuses on the history, pathogenesis, pathological features, diagnosis, and treatment of eccrine porocarcinoma.

Adjuvant nivolumab therapy may not improve disease-free survival in resected acral lentiginous melanoma patients: A retrospective case series.

Adjuvant nivolumab therapy has been reported to improve the survival of melanoma patients. Acral lentiginous melanoma (ALM) has been reported to be less likely to respond to immune checkpoint inhibitors (ICIs) than other subtypes. However, the efficacy of adjuvant nivolumab therapy for ALM patients remains uncertain due to the low number of cases. In this single-center retrospective case series, we analyzed the clinical data of patients with resected stage III/IV ALM who were referred to our department between April 1, 2004 and March 31, 2022. The analyzed clinical data included age, sex, TNM stage, treatments, adverse events and disease-free survival (DFS). Enrolled patients were divided into a nivolumab group and a non-ICI group according to the adjuvant therapy they received. In total, 27 patients were included. The nivolumab and non-ICI groups had 5 and 22 patients, respectively. There were no significant differences in patient characteristics between the two groups. There were no serious treatment-related adverse events in the non-ICI group, but one patient in the nivolumab group developed type 1 diabetes. In the survival analysis, the DFS for the nivolumab group did not exceed that of the non-ICI group in postoperative adjuvant therapy for ALM patients. Given that adjuvant nivolumab therapy sometimes results in serious adverse effects, the administration of the therapy may need to be carefully considered, especially for ALM patients.

HER2-Targeted Antibody-Drug Conjugates Display Potent Antitumor Activities in Preclinical Extramammary Paget's Disease Models: In Vivo and Immunohistochemical Analyses.

Extramammary Paget's disease (EMPD) is an adenocarcinoma that develops mainly in the genital region of older adults. The prognosis for advanced EMPD is almost always poor; thus, novel therapeutic strategies need to be developed. HER2-targeted antibody-drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven effective against HER2-positive breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD. We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring pathogenic ERBB2 mutations and investigate the expression levels of HER2 using EMPD clinical samples. Trastuzumab emtansine or trastuzumab deruxtecan was administered intravenously to tumor-bearing NOD/Scid mice. Treatment with trastuzumab emtansine or trastuzumab deruxtecan was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed for 10 weeks. EMPD tumors extracted 48 h after drug administration revealed the TUNEL-positive ratio to be significantly higher for the HER2-targeted ADC-treated tumors than for the control tumors. EMPD patients' clinical samples revealed a significant correlation between HER2 positivity and invasion, suggesting that HER2 status is associated with tumor progression. Our results suggest that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD, especially in ERBB2-mutant or ERBB2-overexpressed cases.