Although the prognosis of advanced extramammary Paget's disease (EMPD) is poor, there have been no preclinical research models for the development of novel therapeutics. This study aims to establish ...a preclinical research model for EMPD. We transplanted EMPD tissue into immunodeficient NOD/Scid mice. Histopathological and genetic analyses using a comprehensive cancer panel were performed. For in vivo preclinical treatments, trastuzumab, lapatinib, docetaxel, or eribulin were administered to patient-derived xenograft (PDX) models. Tissue transplanted from the EMPD patient was enlarged in NOD/Scid mice and was transplanted into further generations. Both the transplantation of PDX into nu/nu mice and the reanimation of the cryopreserved xenografted tumors in NOD/Scid mice were successful. We also established an EMPD-PDX-derived primary cell culture. Histopathologically, the xenografted tumors were positive for CK7, which was consistent with the patient's tumors. Genetically, the pathogenic mutation ERBB2 S310F was detected in the patient's tumors (primary intraepidermal lesion, metastatic lymph node) and was observed in the xenografted tumors even after continued passages. The xenografted tumors responded well to trastuzumab and lapatinib therapy. Also, cytotoxic agents (docetaxel and eribulin) were effective against the xenografted tumors. This PDX model (EMPD-PDX-H1) could be a powerful tool for the research and development of EMPD treatments.
Abstract
The incidence of cutaneous squamous cell carcinoma has been increasing rapidly in recent years, especially among the elderly. The purpose of this review article is to summarize the findings ...of studies on systemic therapy for advanced cutaneous squamous cell carcinoma, to review geriatric screening tools, which can assess frailty and predict treatment outcomes, and discuss the indications of their use in advanced cases. A literature review revealed that studies on systemic therapy for advanced cutaneous squamous cell carcinoma often included relatively older patients. However, there has been little research on the safety and efficacy of systemic therapy for advanced disease that takes older age and frailty into account. Notably, studies on geriatric screening for skin cancer have been conducted in recent years, mainly to detect early-stage resectable cases. The Geriatric 8 screening tool is considered the most useful for predicting post-operative complications in patients with early-stage cancer, as it can evaluate comorbidities, polypharmacy and cognition, has appropriate measurement properties, can be quickly executed and is clinically relevant, easily understandable and interpretable. This geriatric screening tool may also be applicable in advanced-stage cancer. In conclusion, despite the fact that advanced cutaneous squamous cell carcinoma occurs mainly in the elderly, the importance of geriatric screening has not yet been fully appreciated by dermato-oncologists. In the future, geriatric screening tools should be actively used in clinical trials for the appropriate assessment of drug efficacy and toxicity in elderly patients with advanced cutaneous squamous cell carcinoma.
With regard to advanced-stage cutaneous squamous cell carcinoma, which primarily occurs in the elderly, geriatric medicine is still in its infancy. Clinical trials employing geriatric screening tools are required.
Extramammary Paget’s disease (EMPD) is a rare adnexal neoplasm commonly seen in the genital areas among the senior population. The prognosis of advanced EMPD is not favorable; thus, the development ...of potential treatments has long been sought. Cyclin‐dependent kinase (CDK) 4/6 inhibitors such as abemaciclib and palbociclib have been proven effective against metastatic breast cancer; however, no studies have addressed CDK4/6 inhibitors as an EMPD treatment. We herein examine the efficacy of CDK4/6 inhibitors against an EMPD patient‐derived xenograft (PDX) model. Abemaciclib (50 mg/kg/day) or palbociclib (120 mg/kg/day) was given orally to tumor‐bearing NOD/Scid mice over a 3‐week period. We also investigated the protein expression levels of CDK4/6 and cyclin D1 through immunohistochemical staining using EMPD clinical samples. Treatment with abemaciclib or palbociclib as a single agent was found to significantly suppress tumor growth in EMPD‐PDX. The Ki‐67‐positive ratio of the treated EMPD‐PDX tumors was significantly lower than that of the nontreated tumors. Clinically, the expression levels of CDK4 and cyclin D1 were significantly higher in the EMPD tumor cells than in the normal epidermis. Our results suggest that CDK4/6 inhibitors could be novel and potent therapeutics for the treatment of EMPD.
The therapeutic efficacy of cyclin‐dependent kinase 4/6 inhibitors was assessed using extramammary Paget’s disease patient‐derived xenografts (EMPD‐PDX).Treatment with abemaciclib or palbociclib as a single agent was found to significantly suppress tumor growth in EMPD‐PDX.
•RT-LAMP test kits have good utility.•Detection sensitivity of 1.0 × 101 copies/μL can be obtained within 35 min.•RT-LAMP can be used as a point-of-care test because it is judged by turbidity under ...natural light.
With the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is an urgent need for more rapid and simple detection technologies at the forefront of medical care worldwide.
In this study, we evaluated the effectiveness of the Loopamp® 2019-SARSCoV-2 Detection Reagent Kit, which uses loop-mediated isothermal amplification (LAMP) technology. In this protocol, cDNA is synthesized from SARS-CoV-2 RNA using reverse transcriptase, followed by DNA amplification under isothermal conditions in one step. The RT-LAMP test kit amplified the targeted RNA of a SARS-CoV-2 isolate with a detection limit of 1.0 × 101 copies/μL, which was comparable to the detection sensitivity of quantitative reverse transcription PCR (RT-qPCR).
Comparison with the results of RT-qPCR for 76 nasopharyngeal swab samples from patients with suspected COVID-19 showed a sensitivity of 100 % and a specificity of 97.6 %. In the 24 RNA specimens derived from febrile Japanese patients with or without influenza A, no amplification was observed using RT-LAMP. RT-LAMP could be a simple and easy-to-use diagnostic tool for the detection of SARS-CoV-2.
Advanced cutaneous squamous cell carcinoma (SCC) responds poorly to chemotherapy, leading to significant morbidity or death. Overexpression of epidermal growth factor receptor (EGFR) is frequently ...observed in advanced cutaneous SCC. Vandetanib is a multiple tyrosine kinase targeting vascular endothelial growth factor receptor-2 (VEGFR2), EGFR, and the rearranged during transfection (RET) proto-oncogene. Vandetanib has been reported to inhibit tumor growth in head and neck SCC. However, the efficacy of vandetanib against cutaneous SCC has not been thoroughly investigated. The aim of this study is to evaluate the efficacy of vandetanib against cutaneous SCC in vitro and in vivo. Vandetanib is found to inhibit the proliferation of cutaneous SCC cells as assessed by cell viability and clonogenic assay. Cell death analysis indicates that vandetanib induces cell death in SCC cells but not in normal human keratinocytes or fibroblasts. The in vivo anti-tumor effect of vandetanib is shown in xenograft tumor models using A431 SCC cells. Mechanistically, vandetanib suppresses the phosphorylation of EGFR in SCC cells. Clinically, EGFR expression levels are elevated in cutaneous SCC specimens, relative to normal epidermis. In conclusion, we identified vandetanib as a novel therapeutic option for cutaneous SCC, especially in tumors with high EGFR expression.
Vandetanib inhibits cell growth in EGFR-expressing cutaneous SCC. In the cutaneous SCC cells, the EGFR expression levels are high, and these constantly activate EGFR-MAPK cascades, leading to tumor cell growth. Vandetanib can suppress the activation of EGFR and exerts an anti-tumor effect on cutaneous SCC tumors. Display omitted
•Vandetanib inhibits the proliferation of cutaneous squamous carcinoma (SCC) cells.•Vandetanib induces SCC cell death and inhibits the phosphorylation of EGFR in SCC cells.•Administration of vandetanib inhibits SCC tumor growth in vivo.•Expression levels of EGFR are elevated in cutaneous SCCs.•Vandetanib could be as a novel therapeutic option for EGFR overexpressed-cutaneous SCC.
The prognosis of patients with severe cases of COVID-19 is poor; thus, biomarkers for earlier prediction of COVID-19 progression are vital. We measured levels of five lung injury-related biomarkers, ...SP-D, KL-6, presepsin, kallistatin and stratifin, in serum samples collected serially during hospitalization from 31 patients with mild/moderate or severe/critical COVID-19 pneumonia, and their predictive performances were compared. Like the previously reported presepsin, a new biomarker candidate, stratifin, was significantly elevated with the onset of severe or critical symptoms in COVID-19 patients and decreased with symptom improvement. Notably, changes in stratifin and presepsin levels were distinctly earlier than those in SP-D, KL-6 and even SpO2/FiO2 values. Furthermore, serum levels of these biomarkers were significantly higher at the pre-severe stage (before the start of oxygen support) of patients who eventually advanced to severe/critical stages than in the patients who remained at the mild/moderate stage. These results were confirmed in an independent cohort, including 71 mild/moderate and 14 severe/critical patients, for whom the performance of stratifin and presepsin in discriminating between mild/moderate and pre-severe conditions of COVID-19 patients was superior to that of the SpO2/FiO2 ratio. Therefore, we concluded that stratifin and presepsin could be used as prognostic biomarkers for severe COVID-19 progression.
An n-type α-Ga2O3 layer was grown by mist chemical vapor deposition on a sapphire substrate, and a Ti/α-Ga2O3 Schottky barrier diode was fabricated. Although the α-Ga2O3 layer has a high threading ...dislocation density (larger than 109 cm−2), the ideality factor of 1.03 was obtained from the forward current–voltage characteristic in the range of 298 K–423 K, indicating the clear thermionic emission transport. The reverse current–voltage characteristic was also investigated, and the leakage current showed good agreement with the theoretical calculation based on the thermionic field emission model without any fitting parameter in the temperature range of 298 K–423 K.
•We evaluated the immunochromatographic (IC) assay and chest CT scan for COVID-19.•IC assay had 29.7 % sensitivity in symptomatic cases.•The combination of CT scan and IC assay had 82.4 % sensitivity ...in symptomatic cases.•IC assay alone is not recommended for initial test of COVID-19 because of low sensitivity.•If RT-qPCR is not available, the combination of chest CT and IC assay may be useful.
We evaluated the clinical performance of an immunochromatographic (IC) IgM/IgG antibody assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) and chest computed tomography (CT) for the diagnosis of Coronavirus disease 2019 (COVID-19).
We examined 139 serum specimens collected from 112 patients with COVID-19 and 48 serum specimens collected from 48 non-COVID-19 patients. The presence of IgM/IgG antibody for SARS-COV2 was determined using the One Step Novel Coronavirus (COVID-19) IgM/IgG Antibody Test. Chest CT was performed in COVID-19 patients on admission.
Of the139 COVID-19 serum specimens, IgM was detected in 27.8 %, 48.0 %, and 95.8 % of the specimens collected within 1 week, 1–2 weeks, and >2 weeks after symptom onset and IgG was detected in 3.3 %, 8.0 %, and 62.5 %, respectively. Among the 48 non-COVID-19 serum specimens, 1 generated a false-positive result for IgM. Thirty-eight of the 112 COVID-19 patients were asymptomatic, of whom 15 were positive for IgM, and 74 were symptomatic, of whom 22 were positive for IgM and 7 were positive for IgG. The diagnostic sensitivity of CT scan alone and in combination with the IC assay was 57.9 % (22/38) and 68.4 % (26/38) for the asymptomatic patients and 74.3 % (55/74) and 82.4 % (61/74) for the symptomatic patients, respectively.
The IC assay had low sensitivity during the early phase of infection, and thus IC assay alone is not recommended for initial diagnostic testing for COVID-19. If RT-qPCR is not available, the combination of chest CT and IC assay may be useful for diagnosing COVID-19.
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.
Atomic scale characterization of fine precipitates in an under-aged Cu added Al-Mg-Si alloy was carried out by combination of atomically-resolved annular dark-field scanning transmission electron ...microscopy and energy dispersive X-ray spectroscopy. Two types of precipitates were observed in the alloy. In the case of ordered β" precipitates, β" was proposed as Mg
Al
Si
(x ≈ 1) with solute Cu atoms replacing Al site of β" precipitate. In the case of disordered precipitates, the precipitates were found to consist of β" sub-unit cells, three-fold symmetric structure without Cu atoms, Cu containing structures termed as "Cu sub-unit cluster", and Q' sub-unit cells. Among these structures, the morphologies of three-fold symmetric structure without Cu atoms, Cu sub-unit cluster, and Q' sub-unit cell were almost the same, so that these structures should be the clusters of Q' phase. Since the areal density, length and diameter of precipitates were almost equal between Cu free Al-Mg-Si alloy and Cu added Al-Mg-Si alloy, the increase of hardness by Cu addition should be due to the precipitation of Cu related precipitates, such as Cu sub-unit clusters and Q' sub-unit cells.
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