RESUMEN
Extramammary Paget disease (EMPD) is a rare skin cancer mainly found in areas rich in apocrine sweat glands. Since the effective treatments for advanced and/or metastasized EMPD are limited, there is an urgent need to develop novel therapeutic approaches. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in cancers and considered to be a promising therapeutic target. NECTIN4 is also expressed in EMPD, but its role and the efficacy of NECTIN4-targeted therapy in EMPD remain unclear. This study investigated the potential of NECTIN4 as a novel therapeutic target for EMPD. NECTIN4 expression was immunohistochemically analysed in EMPD patients' primary (118 samples) and metastatic (21 samples) lesions. Using an EMPD cell line, KS-EMPD-1, the effects of NECTIN4 inhibition on cell proliferation and migration were investigated. NECTIN4 was expressed in primary and metastatic EMPD lesions, and the H-score of NECTIN4 staining was significantly higher in metastatic lesions than in primary ones. Knockdown of NECTIN4 significantly inhibited cell proliferation and affected cell migration. The cytotoxic effects of NECTIN4-targeted antibody-drug conjugate (ADC) were further evaluated, revealing a significant decrease in EMPD cell viability. In conclusion, NECTIN4 is a potential therapeutic target and NECTIN4-targeted ADC is promising as a therapeutic option for EMPD.
Asunto(s)
Neoplasias , Enfermedad de Paget Extramamaria , Humanos , Enfermedad de Paget Extramamaria/tratamiento farmacológico , Enfermedad de Paget Extramamaria/patología , Epidermis/metabolismo , Moléculas de Adhesión CelularRESUMEN
PURPOSE: Oral mucositis (OM) is a side effect associated with cancer treatment. Hangeshashinto (HST), a Kampo medicine, was originally prescribed to treat diarrhea, gastritis, and stomatitis. Several reports have described the effects of HST for OM induced by chemotherapy in patients with gastric or colorectal cancer. In this study, the effects of HST for prevention of OM were investigated in patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Thirty patients scheduled to receive allogeneic grafts were enrolled from July 2020 to December 2021. They were randomly assigned to two groups and instructed to wash their mouth using HST dissolved in saline solution or using only saline solution three times a day. The observation period was from the initiation date of the conditioning regimen to the date of engraftment, and the end point was the incidence of OM. RESULTS: Eighteen patients developed OM, the most severe of which was Grade (G)3. There was no significant difference in the incidence of OM between the HST group and the control group. However, a negative correlation tended to be observed between the duration using HST use and the duration of OM (G2-3: P = 0.027, G3: P = 0.047). CONCLUSIONS: The present study demonstrated that HST use did not clearly inhibit onset of OM but showed a tendency to inhibit OM exacerbation. However, further studies are necessary to fully understand the effects of HST on OM in patients undergoing HSCT. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials on 7 May 2020 (jRCTs071200012).
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Estomatitis , Humanos , Solución Salina/efectos adversos , Estomatitis/inducido químicamente , Estomatitis/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Incidencia , Acondicionamiento Pretrasplante/efectos adversosRESUMEN
OPINION STATEMENT: Nectin-4 is a tumor-associated antigen that is highly expressed on various cancer cells, and it has been further proposed to have roles in tumor development and propagation ranging from cellular proliferation to motility and invasion. Nectin-4 blockade reduces tumor proliferation and induces apoptosis in several malignancies. Nectin-4 has been used as a potential target in antibody-drug conjugate (ADC) development. Enfortumab vedotin, an ADC against Nectin-4, has demonstrated efficacy against solid tumor malignancies. Enfortumab vedotin has received US Food and Drug Administration approval for treating urothelial cancer. Furthermore, the efficacy of ADCs against Nectin-4 against solid tumors other than urothelial cancer has been demonstrated in preclinical studies, and clinical trials examining the effects of enfortumab vedotin are ongoing. Recently, Nectin-4 was reported to be highly expressed in several skin cancers, including malignant melanoma, cutaneous squamous cell carcinoma, and extramammary Paget's disease, and involved in tumor progression and survival in retrospective studies. Nectin-4-targeted therapies and ADCs against Nectin-4 could therefore be novel therapeutic options for skin cancers. This review highlights current knowledge on Nectin-4 in malignant tumors, the efficacy of enfortumab vedotin in clinical trials, and the prospects of Nectin-4-targeted agents against skin cancers.
Asunto(s)
Anticuerpos Monoclonales , Carcinoma de Células Escamosas , Moléculas de Adhesión Celular , Inmunoconjugados , Terapia Molecular Dirigida , Neoplasias Cutáneas , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Moléculas de Adhesión Celular/antagonistas & inhibidores , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias Urológicas/tratamiento farmacológicoRESUMEN
PURPOSE: To retrospectively investigate whether apical lesion, alveolar bone loss, probing pocket depth, or local infectious symptoms were associated with the onset of medication-related osteonecrosis of the jaw (MRONJ) in patients treated with high-dose antiresorptive agents who did not undergo tooth extraction. METHODS: The study included 92 patients receiving high-dose antiresorptive agent therapy who had teeth with apical lesion ⧠3 mm, alveolar bone loss ⧠1/2, probing pocket depth ⧠4 mm, or local infection symptoms such as swelling, pain, and pus discharge, but did not undergo tooth extraction. Univariate and multivariate Cox regression analyses were performed to determine the relationship between each variable and MRONJ onset. RESULTS: MRONJ developed in 15 of 92 patients (35 of 404 teeth) from 74 to 1883 days (median, 383 days) after the first visit. Multiple Cox regression analysis revealed that a lower number of teeth, diabetes, increased leukocyte count, administration of antiresorptive agents for 180 days or more, local infection symptoms, apical lesion ⧠3 mm, and probing pocket depth ⧠4 mm were significantly correlated with the development of MRONJ. CONCLUSION: It is recommended that teeth with apical lesion ⧠3 mm, probing pocket depth ⧠4 mm, or local infection symptoms are extracted before or as early as possible after beginning of medication in cancer patients receiving high-dose antiresorptive agent therapy to prevent the development of MRONJ.
Asunto(s)
Pérdida de Hueso Alveolar , Osteonecrosis de los Maxilares Asociada a Difosfonatos , Conservadores de la Densidad Ósea , Neoplasias , Pérdida de Hueso Alveolar/inducido químicamente , Osteonecrosis de los Maxilares Asociada a Difosfonatos/tratamiento farmacológico , Osteonecrosis de los Maxilares Asociada a Difosfonatos/epidemiología , Osteonecrosis de los Maxilares Asociada a Difosfonatos/etiología , Conservadores de la Densidad Ósea/efectos adversos , Difosfonatos/uso terapéutico , Humanos , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: The Act Regarding the Promotion of the Appropriate Supply of Hematopoietic Stem Cells for Transplant regulates only how public banks store and provide umbilical cord blood (UCB) for research or transplantation. Japan had no laws to regulate how the private banks manage the procedures, harvesting, preparation, and storage of such blood. As a result, the status of UCB distribution remains unknown. We conducted a survey to investigate the current status of UCB storage and provision to private biobanks by Japanese institutions that handle childbirth. METHODS: Questionnaire forms were mailed to 3,277 facilities handling childbirth that were registered in the Japan Council for Quality Health Care website. RESULTS: Of the 1,192 institutions handling childbirth that participated in the survey (response rate: 36.7%), 34.4% responded that they currently provide UCB to private biobanks, while 16.1% of facilities did so in the past. Moreover, some institutions currently provide or formerly provided UCB to medical treatment facilities (2.6%), research institutions (5.9%), companies (2.2%), or overseas treatment facilities, research institutions, or companies (0.3%). A certain number of institutions handling childbirth did not even provide explanations or obtain consent when the UCB was harvested from private bank users. CONCLUSIONS: This is the first study to determine the status of UCB provision to private banks by Japanese institutions handling childbirth. Future studies will need to examine in detail how institutions handling childbirth provide explanations to private bank users and UCB providers as well as how these institutions obtain consent.
Asunto(s)
Bancos de Sangre , Sangre Fetal , Bancos de Muestras Biológicas , Parto Obstétrico , Femenino , Humanos , Japón , EmbarazoRESUMEN
OPINION STATEMENT: In the era of molecular targeted therapy, the accurate detection of BRAF mutation in melanoma has become increasingly important. With the advances of molecular analyses and immunohistochemistry, the presence of BRAF mutational heterogeneity in melanoma has been widely recognized. Although most patients with melanoma have a homogeneous BRAF mutation status because the BRAF mutation occurs at an early stage of melanoma development and acts as a driver gene mutation, BRAF mutational heterogeneity does exist, among different tumor sites of a single patient (intertumor heterogeneity) and/or even within a single tumor (intratumor heterogeneity). To summarize the published reports, about 10% of melanoma patients may show intertumorally discordant BRAF status and about 15% of BRAF-mutated melanomas may have intratumor BRAF heterogeneity, although the reported results vary strikingly among the studies and methods used. Considering the BRAF heterogeneity of melanoma, a single biopsy from a single tumor may not be sufficient to uncover the entire BRAF status of a patient. Multiple samples from different sites may be preferable to assess the indication of BRAF/MEK inhibitors, as recommended by the current clinical guidelines. The impact of BRAF heterogeneity on patient survival or the response to treatment with BRAF/MEK inhibitors is an interesting issue, but requires further investigation.
Asunto(s)
Biomarcadores de Tumor , Heterogeneidad Genética , Melanoma/etiología , Melanoma/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Animales , Análisis Mutacional de ADN , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Regulación Neoplásica de la Expresión Génica , Humanos , Melanoma/diagnóstico , Melanoma/terapia , Técnicas de Diagnóstico Molecular , Mutación , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Proteínas Proto-Oncogénicas B-raf/metabolismoRESUMEN
Malignant melanoma is the most common lethal skin cancer and causes death in a short time when metastasized. Although BRAF inhibitors (BRAFi) have greatly improved the prognosis of BRAF-mutated melanoma, drug resistance is a major concern even when they are combined with MEK inhibitors. Alternative treatments for BRAFi-resistant melanoma are highly anticipated. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed and associated with progression in tumors. We aimed to investigate the role of NECTIN4 in melanoma and its potency as a therapeutic target using 126 melanoma samples and BRAFi-resistant cells. Immunohistochemically, most of the clinical samples expressed NECTIN4, at least in part. NECTIN4 was highly expressed in BRAF-mutated melanoma and its high expression was associated with disease-free survival. In BRAFi-resistant melanoma cells, NECTIN4 and the PI3K/Akt pathway were upregulated, along with the acquisition of BRAFi resistance. Monomethyl auristatin E, a cytotoxic part of NECTIN4-targeted antibody-drug conjugate, was effective for BRAF-mutated or BRAFi-resistant melanoma cells. NECTIN4 inhibition increased the sensitivity of BRAFi-resistant cells to BRAFi and induced apoptosis. In conclusion, we revealed the expression and roles of NECTIN4 in melanoma. Targeted therapies against NECTIN4 can be a novel treatment strategy for melanoma, even after the acquisition of BRAFi resistance.
Asunto(s)
Moléculas de Adhesión Celular/antagonistas & inhibidores , Melanoma/tratamiento farmacológico , ARN Interferente Pequeño/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/genética , Melanoma/metabolismo , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/farmacología , Estudios Retrospectivos , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Adulto Joven , Melanoma Cutáneo MalignoRESUMEN
Extramammary Paget's disease (EMPD) is a rare skin cancer arising in the apocrine gland-rich areas. Most EMPD tumors are dormant, but metastatic lesions are associated with poor outcomes owing to the lack of effective systemic therapies. Trophoblast cell surface antigen 2 (Trop2), a surface glycoprotein, has drawn attention as a potential therapeutic target for solid tumors. Sacituzumab govitecan, an antibody-drug conjugate of Trop2, has recently entered clinical use for the treatment of various solid cancers. However, little is known about the role of Trop2 in EMPD. In this study, we immunohistochemically examined Trop2 expression in 116 EMPD tissue samples and 10 normal skin tissues. In normal skin, Trop2 was expressed in the epidermal keratinocytes, inner root sheaths, and infundibulum/isthmus epithelium of hair follicles, eccrine/apocrine glands, and sebaceous glands. Most EMPD tissues exhibited homogeneous and strong Trop2 expression, and high Trop2 expression was significantly associated with worse disease-free survival (p = 0.0343). These results suggest the potential use of Trop2-targeted therapy for EMPD and improve our understanding of the skin-related adverse effects of current Trop2-targeted therapies such as sacituzumab govitecan.
Asunto(s)
Antígenos de Neoplasias/biosíntesis , Moléculas de Adhesión Celular/biosíntesis , Enfermedad de Paget Extramamaria/metabolismo , Neoplasias Cutáneas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Glándulas Apocrinas/metabolismo , Biomarcadores de Tumor , Camptotecina/análogos & derivados , Camptotecina/farmacología , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Femenino , Expresión Génica/genética , Regulación de la Expresión Génica/genética , Folículo Piloso/metabolismo , Humanos , Inmunoconjugados/farmacología , Queratinocitos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , Enfermedad de Paget Extramamaria/tratamiento farmacológico , Enfermedad de Paget Extramamaria/genética , Enfermedad de Paget Extramamaria/patología , Glándulas Sebáceas/metabolismo , Piel/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
Extramammary Paget's disease (EMPD) is a rare skin cancer arising in the anogenital area. Most EMPD tumors remain dormant as in situ lesions, but the outcomes of patients with metastatic EMPD are poor because of the lack of effective systemic therapies. Nectin cell adhesion molecule 4 (NECTIN4) has attracted attention as a potential therapeutic target for some cancers. Urothelial cancer is one such cancer, and clinical trials of enfortumab vedotin, a drug-conjugated anti-NECTIN4 antibody, are ongoing. However, little is known regarding the role of NECTIN4 in EMPD. In this study, we conducted immunohistochemical analysis of NECTIN4 expression in 110 clinical EMPD samples and normal skin tissue. In normal skin, positive signals were observed in epidermal keratinocytes (particularly in the lower part of the epidermis), eccrine and apocrine sweat glands, inner and outer root sheaths, and matrix of the hair follicles. The most EMPD lesions exhibited strong NECTIN4 expression, and high NECTIN4 expression was significantly associated with increased tumor thickness, advanced TNM stage, and worse disease-specific survival. These results support the potential use of NECTIN4-targeted therapy for EMPD. Our report contributes to the better understanding of the pathobiology of NECTIN4 in the skin and the skin-related adverse effects of NECTIN4-targeted therapy.
Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Enfermedad de Paget Extramamaria/metabolismo , Neoplasias Cutáneas/metabolismo , Anciano , Anciano de 80 o más Años , Moléculas de Adhesión Celular/genética , Femenino , Folículo Piloso/metabolismo , Humanos , Queratinocitos/metabolismo , Masculino , Persona de Mediana Edad , Enfermedad de Paget Extramamaria/patología , Neoplasias Cutáneas/patología , Glándulas Sudoríparas/metabolismoRESUMEN
Epidermal keratinocytes represent a rich source of C-C motif chemokine 20 (CCL20) and recruit CCR6+ interleukin (IL)-17A-producing T cells that are known to be pathogenic for psoriasis. A previous study revealed that scratch injury on keratinocytes upregulates CCL20 production, which is implicated in the Koebner phenomenon characteristically seen in psoriasis patients. However, the molecular mechanisms leading to scratch-induced CCL20 production remain elusive. In this study, we demonstrate that scratch injury upregulates the phosphorylation of epidermal growth factor receptor (EGFR) and that the specific EGFR inhibitor PD153035 attenuates scratch-induced CCL20 upregulation in an extracellular signal-related kinase (ERK)-dependent, and to a lesser extent, a c-Jun N-terminal kinase (JNK)-dependent but p38 mitogen-activated protein kinase (MAPK)-independent manner. Immunoreactive CCL20 was visualized in the keratinocytes that lined the scratched wound. IL-17A also induced the phosphorylation of EGFR and further augmented scratch-induced CCL20 upregulation. The EGFR-ERK/JNK-CCL20 pathway in scratched keratinocytes may explain why Koebnerization is frequently seen in psoriasis patients.
Asunto(s)
Quimiocina CCL20/metabolismo , Receptores ErbB/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Queratinocitos/metabolismo , Psoriasis/metabolismo , Transducción de Señal , Línea Celular , Receptores ErbB/antagonistas & inhibidores , Humanos , Interleucina-17/metabolismo , Queratinocitos/patología , Masculino , Fosforilación , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The current development of BRAF inhibitors has revolutionized the treatment of unresectable melanoma. As the potential heterogeneity of BRAF mutations in melanoma has been reported, accurate detection of BRAF mutations are important. However, the genetic heterogeneity of acral melanoma-a distinct type of melanoma with a unique genetic background-has not fully been investigated. We conducted a retrospective review of our acral melanoma patients. Of the 196 patients with acral melanoma, we retrieved 31 pairs of primary and matched metastatic melanomas. We immunostained the 31 pairs with VE1, a BRAFV600E-mutation-specific monoclonal antibody. Immunohistochemistry with VE1 showed a high degree of sensitivity and specificity for detecting BRAFV600E mutations compared with the real-time polymerase chain reaction method. A total of nine primary (29.0%) and eight metastatic (25.8%) acral melanomas were positive for VE1. In three patients (9.7%), we observed a discordance of VE1 staining between the primary and metastatic lesions. Of note, VE1 immunohistochemical staining revealed a remarkable degree of intra-tumor genetic heterogeneity in acral melanoma. Our study reveals that VE1 immunostaining is a useful ancillary method for detecting BRAFV600E mutations in acral melanoma and allows for a clear visualization of intra- and inter-tumor BRAF heterogeneity.
Asunto(s)
Inmunohistoquímica/métodos , Melanoma/genética , Mutación Missense , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Melanoma/metabolismo , Persona de Mediana Edad , Sensibilidad y Especificidad , Neoplasias Cutáneas/metabolismo , Melanoma Cutáneo MalignoRESUMEN
PURPOSE: The aim of this study was to evaluate the usefulness of covering open wounds with a polyglycolic acid (PGA) sheet and a fibrin glue spray after partial glossectomy. MATERIALS AND METHODS: We clinically evaluated postoperative pain and scar contracture in 44 patients who underwent partial glossectomy followed by covering with a PGA sheet and a fibrin glue spray (PGA sheet group), as compared with 29 patients who were closed primarily (primary closure group). RESULTS: Duration of nonsteroidal anti-inflammatory drugs was almost the same between the PGA sheet group and the primary closure group. The degree of scar contracture was mild in many cases in both groups. In the case in which the excision area was wide and depth was shallow, there was a tendency for the scar contracture to be less in the PGA sheet group. CONCLUSIONS: Our findings showed that the use of a PGA sheet and fibrin glue spray for open wounds resulting from partial glossectomy was useful in terms of rapid relief from postoperative pain and prevention of scar contracture.
Asunto(s)
Materiales Biocompatibles/química , Adhesivo de Tejido de Fibrina/uso terapéutico , Glosectomía/métodos , Ácido Poliglicólico/química , Adhesivos Tisulares/uso terapéutico , Técnicas de Cierre de Heridas/instrumentación , Adulto , Anciano , Anciano de 80 o más Años , Antiinflamatorios no Esteroideos/uso terapéutico , Carcinoma in Situ/cirugía , Carcinoma de Células Escamosas/cirugía , Cicatriz/prevención & control , Contractura/prevención & control , Femenino , Humanos , Leucoplasia Bucal/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Dolor Postoperatorio/prevención & control , Repitelización/fisiología , Mallas Quirúrgicas , Factores de Tiempo , Neoplasias de la Lengua/cirugía , Adulto JovenAsunto(s)
Urticaria/patología , Adulto , Anciano , Antiinflamatorios/uso terapéutico , Enfermedad Crónica , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Insuficiencia del Tratamiento , Urticaria/diagnóstico , Urticaria/tratamiento farmacológicoRESUMEN
Cathepsin D is an aspartic lysosomal endopeptidase present in most mammalian cells. Overexpression of cathepsin D is associated with the progression of several human cancers including melanoma. We examined the expression levels of cathepsin D in 20 primary malignant melanomas, 20 metastatic malignant melanomas, 20 benign nevus pigmentosus and 10 normal skin samples in Japanese. In normal skin, granular or dotted pattern of positive staining was observed along the granular layer of epidermis and hair follicle with apparent moderate to strong staining in sebaceous and eccrine glands. The percent positivity and staining intensity of cathepsin D in primary and metastatic malignant melanomas were significantly higher than that of nevus pigmentosus. Moreover, the expression levels of cathepsin D in metastatic malignant melanomas were significantly higher than those of primary malignant melanomas. Data from our and previous reports strongly supports a notion that the upregulation of cathepsin D may be critically involved in the malignant transformation and progression of melanocytic tumors.
Asunto(s)
Catepsina D/genética , Catepsina D/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Melanoma/genética , Melanoma/secundario , Regulación hacia Arriba/genética , Pueblo Asiatico , Transformación Celular Neoplásica/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Melanocitos/patología , Melanoma/patología , Nevo Pigmentado/genética , Piel/metabolismo , Regulación hacia Arriba/fisiologíaRESUMEN
Angiosarcoma is a rare, life-threatening soft tissue sarcoma with malignant endothelial cells that is mainly found in the skin. Multidisciplinary approaches are used to treat patients with unresectable metastasized lesions; considering the cellular origin of angiosarcoma, anti-angiogenic therapy has also been used recently. However, these treatments have limited efficacy, and the survival rate remains low. Thus, more effective treatments need to be developed. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in malignant tumors and promotes tumor progression. Thus, NECTIN4 is expected to be a novel therapeutic target for cancer. However, the significance of NECTIN4 in angiosarcoma remains unknown. Using immunohistochemistry, we investigated NECTIN4 expression in 74 tissue samples from angiosarcoma patients, finding variable NECTIN4 expression. In addition, we investigated NECTIN4 expression and function in human angiosarcoma cell lines. NECTIN4 expression was higher in angiosarcoma cells than normal endothelial cells, and angiosarcoma cells were sensitive to monomethyl auristatin E, the cytotoxic part of a NECTIN4-targetting antibody-drug conjugate. NECTIN4 knockdown inhibited the proliferation and angiogenesis of angiosarcoma cells, and Src kinase signaling was shown to be involved in NECTIN4 function, at least in part. NECTIN4-targeted therapy has the potential to be a novel treatment strategy for angiosarcoma.
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Moléculas de Adhesión Celular , Hemangiosarcoma , Neoplasias Cutáneas , Familia-src Quinasas , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular/metabolismo , Células Endoteliales/metabolismo , Hemangiosarcoma/irrigación sanguínea , Hemangiosarcoma/tratamiento farmacológico , Hemangiosarcoma/metabolismo , Humanos , Inmunoconjugados/farmacología , Nectinas , Neovascularización Patológica/tratamiento farmacológico , Neoplasias Cutáneas/irrigación sanguínea , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
(1) Background: To what extent is information manipulation by doctors acceptable? To answer this question, we conducted an exploratory study aimed at obtaining basic data on descriptive ethics for considering this issue. (2) Methods: A self-administered questionnaire survey was conducted on a large sample (n = 3305) of doctors. The participants were queried on (1) whether they consider that information manipulation is necessary (awareness), (2) whether they have actually manipulated information (actual state), and (3) their ethical tolerance. (3) Result: The response rate was 28.7%. Sixty percent of the doctors responded that information manipulation to avoid harm to patients is necessary (awareness), that they have actually manipulated information (actual state), and that information manipulation is ethically acceptable. (4) Conclusion: While the present survey was conducted among doctors in Japan, previous studies have reported similar findings in the United States and Europe. Based on our analysis, we hypothesize that a relationship of trust between patients and medical personnel is crucial and that information manipulation is not needed when such a relationship has been established.
RESUMEN
Background: Sebaceous carcinoma and sweat gland carcinoma (malignant tumours with apocrine and eccrine differentiation) are rare malignant adnexal tumours that differentiate toward sebaceous glands and eccrine and apocrine glands, respectively. Because of the rarity of these malignancies, standard treatments for advanced disease have yet to be established. The outcomes of patients with systemic metastasis remain poor, highlighting the need for novel treatment strategies. Nectin cell adhesion molecule 4 (NECTIN4) and its antibody-drug conjugate, enfortumab vedotin, have attracted attention as potential treatments for solid tumours. Objectives: To examine the potential use of NECTIN4-target therapy for sebaceous and sweat gland carcinoma. Materials & Methods: We immunohistochemically investigated NECTIN4 expression in 14 sebaceous carcinoma samples and 18 sweat gland carcinoma samples, and examined whether NECTIN4-targeted therapy could be applied to these cancers. Results: We found strong and frequent expression of NECTIN4 in both cancers. All tumours exhibited positive staining at least in a part of the lesion, and the mean H-score, a semiquantitative score ranging from 0 to 300, was 259.4 for sebaceous carcinoma and 253.1 for sweat gland carcinoma. Conclusion: Our results suggest that both sebaceous carcinoma and sweat gland carcinoma could be potentially treated with NECTIN4-targeted antibody-drug conjugates, such as enfortumab vedotin.
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Carcinoma de Apéndice Cutáneo , Moléculas de Adhesión Celular/metabolismo , Neoplasias Cutáneas , Neoplasias de las Glándulas Sudoríparas , Glándulas Apocrinas/patología , Carcinoma de Apéndice Cutáneo/patología , Humanos , Neoplasias Cutáneas/patología , Neoplasias de las Glándulas Sudoríparas/patologíaRESUMEN
Sebaceous carcinoma and sweat gland carcinoma (malignant tumors with apocrine and eccrine differentiation) are rare malignant skin adnexal tumors that differentiate toward sebaceous gland and eccrine and apocrine glands, respectively. Owing to the rarity of these carcinomas, standard treatments for advanced disease have not been established. Because the prognosis of patients with systemic metastasis is poor, a new treatment for these diseases is eagerly desired. Trophoblast cell surface antigen 2 (TROP2) and sacituzumab govitecan, an antibody-drug conjugate of TROP2, have attracted attention in the treatment of various solid tumors. In the current study, we immunohistochemically investigated TROP2 expression in 14 sebaceous carcinoma and 18 sweat gland carcinoma samples and found strong and relatively homogeneous TROP2 staining in both cancer types. The mean Histoscore, a semi-quantitative scoring ranging from 0 (negative) to 300, was 265.5 in sebaceous carcinoma and 260.0 in sweat gland carcinoma. These observations directly suggest that both sebaceous carcinoma and sweat gland carcinoma could be potentially treated with TROP2-targeted antibody-drug conjugates such as sacituzumab govitecan.
RESUMEN
Although maxillary sinusitis often occurs in patients with medication-related osteonecrosis of the jaw (MRONJ) of the upper jaw, there have been few reports on the treatment and outcomes for maxillary sinusitis associated with maxillary MRONJ. This study aimed to retrospectively investigate the treatment outcomes of maxillary sinusitis in patients with MRONJ of the upper jaw. There were 34 patients diagnosed with maxillary MRONJ and sinusitis by preoperative computed tomography who underwent surgery in our institution between January 2011 and December 2019. Age, sex, primary disease, stage of MRONJ, class and administration period of an antiresorptive agent, corticosteroid administration, preoperative leukocyte count and serum albumin level, periosteal reaction, sinusitis grade, maxillary sinus surgical procedure, and treatment outcomes of MRONJ and sinusitis were examined. There were 7 male and 27 female patients (average age, 74.7 years). Complete healing of MRONJ was obtained in 29 of 34 patients (85.3%). Maxillary sinusitis resolved or improved in 21 patients (61.8%) but did not change or worsen in 13 patients (38.2%). We found that complete resection of necrotic bone with intraoperative irrigation of the maxillary sinus may provide good treatment outcomes for maxillary sinusitis associated with MRONJ, although our findings were not statistically significant owing to the small number of patients.
Asunto(s)
Osteonecrosis de los Maxilares Asociada a Difosfonatos , Conservadores de la Densidad Ósea , Sinusitis Maxilar , Anciano , Osteonecrosis de los Maxilares Asociada a Difosfonatos/diagnóstico por imagen , Osteonecrosis de los Maxilares Asociada a Difosfonatos/cirugía , Femenino , Humanos , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
A drug holiday of 3 months does not promote separation of sequestra and is not correlated with treatment outcomes after surgical therapy in osteoporosis patients who receive antiresorptive agents and who have medication-related osteonecrosis of the jaw. Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of antiresorptive agents alone or in combination with immune modulators or antiangiogenic medications, in the absence of radiation exposure to the head and neck region. The effectiveness of surgical treatment for MRONJ has been reported, but the timing of the operation remains controversial. The purpose of this study was to clarify whether preoperative drug holidays of antiresorptive agents promote sequestrum separation and improve treatment outcomes in patients who receive low doses of antiresorptive agents. This retrospective study included 173 patients who received low-dose antiresorptive agents and underwent surgical therapy. The effects of a drug holiday on the separation of sequestra and treatment outcomes were analyzed using logistic and Cox regression analyses. Multivariate analysis revealed that administration of an antiresorptive agent for more than 4 years, a high number of lymphocytes, and an extensive osteolytic area were significantly correlated with separation of sequestra, but drug holiday did not promote sequestrum separation. Furthermore, a drug holiday of 90, 120 or 180 days did not show any improvement in treatment outcomes. The drug holiday of the antiresorptive agents for the treatment of MRONJ is unnecessary, and surgical therapy should be performed early.