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.

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.

Atypical clinical and radiological presentations of lumbar spinal tuberculosis mimicking a spinal tumor: A case report.

INTRODUCTION: Tuberculosis (TB) is an important infectious disease worldwide. Classical spinal TB has specific radiological findings involving adjacent vertebral bodies with destruction of the intervertebral disc and involvement of paravertebral soft tissues with cold abscess formation. However, a few cases not exhibiting the radiological characteristics of TB spondylitis have been reported. We report a rare case of lumbar spinal TB with atypical clinical and radiological presentations that was difficult to differentiate from a malignant spinal tumor. PATIENT CONCERNS: A 21-year-old man, who had immigrated to Japan from the Philippines 5 years ago, without a significant medical history, presented with back pain lasting 1 month and progression of gait disturbance 2 weeks prior to presentation. DIAGNOSIS: Laboratory tests showed normal blood cell counts and normal value of C-reactive protein levels. Preoperative imaging studies indicated a possible spinal tumor. However, histopathologic findings of the epidural soft tissues at the first surgery led to the diagnosis of spinal mycobacterial infection. The diagnosis of spinal TB was confirmed by a positive culture of Mycobacterium tuberculosis obtained at the second surgery. INTERVENTIONS: Given the progressive nature of neurologic deterioration, instead of needle biopsy, we proceeded with surgical intervention 8 days after admission; simultaneous neural decompression and open biopsy. Histological findings of the excised epidural soft tissues led to the diagnosis of spinal mycobacterial infection. We performed the second surgery involving additional resection of epidural soft tissues for further dural decompression and to obtain specimens for mycobacterial culture. Immediately after the second surgery, the patient commenced combination therapy with anti-tuberculous drugs. OUTCOMES: The patient demonstrated significant recovery of motor function in the lower extremities, and was able to run at 2 months after the second surgery. The epidural granulomas completely disappeared on magnetic resonance imaging 3 months postoperatively. CONCLUSION: Atypical clinical and radiological presentations of spinal TB present a challenge for appropriate diagnosis and early treatment. Even in developed countries where there are very few spinal TB patients, clinicians should be aware that spinal TB is an important differential diagnosis, especially in elderly patients or patients coming from countries with a middle-high prevalence of TB.

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.

Atypical Neurofibromatous Neoplasm with Uncertain Biologic Potential in the Posterior Mediastinum of a Young Patient with Neurofibromatosis Type 1: A Case Report.

Atypical neurofibromatous neoplasm with unknown biological potential (ANNUBP), proposed in a recent NIH consensus overview, is a rare precursor entity of malignant peripheral nerve sheath tumor (MPNST) in neurofibromatosis type 1 (NF1) patients. Only one report on imaging findings of ANNUBP is available. Herein, we present the case of a 19-year-old female, diagnosed with a mediastinal tumor by chance, who visited to our hospital. She had café-au-lait spots on her trunk and a past history of resected neurofibroma. Her family also had café-au-lait spots; therefore, an NF1-induced tumor was strongly suspected. MRI revealed a paravertebral mass of 7.5 cm in size consisting of an inner rim with low T2 signal intensity and an outer rim with high T2 intensity, which was similar to a target sign, adjacent to the pulmonary veins; the center of the tumor was well enhanced by gadolinium, and the peripheral region was myxoid and slightly enhanced. FDG-PET showed high FDG uptake, SUVmax of 8.5, although the peripheral region represented low FDG accumulation. CT-guided needle biopsy was repeated because of the suspicion of an MPNST, which resulted in the histopathological diagnosis of ANNUBP. Marginal tumor resection was performed, and the final post-resection histopathological diagnosis was ANNUBP transformed from neurofibroma; the region of ANNUBP lost p16 immunostaining, although it was retained in the peripheral region of the neurofibroma. There has been no recurrence or metastasis 1 year after treatment. In conclusion, ANNUBP could be represented as a well-enhanced homogeneous mass on MRI and a high FDG accumulated region on FDG PET/CT, as seen in MPNST, in NF1 patients.