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Porokeratosis is a clonal keratinization disorder characterized by solitary, linearly arranged, or generally distributed multiple skin lesions. Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS-genes in the mevalonate pathway-cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles. Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway. Skin lesions of the generalized form had germline and lesion-specific somatic variants on opposite alleles in FDFT1, representing FDFT1-associated hereditary porokeratosis identified in this study. Conversely, lesions of the solitary or linearly arranged localized form had somatic bi-allelic promoter hypermethylation or mono-allelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis. FDFT1 localization was uniformly diminished within the lesions, and lesion-derived keratinocytes showed cholesterol dependence for cell growth and altered expression of genes related to cell-cycle and epidermal development, confirming that lesions form by clonal expansion of FDFT1-deficient keratinocytes. In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to the disease. Finally, consistent with its genetic etiology, topical statin treatment ameliorated lesions in FDFT1-deficient porokeratosis. In conclusion, we identified bi-allelic genetic and/or epigenetic alterations of FDFT1 as a cause of porokeratosis and shed light on the pathogenesis of skin mosaicism involving clonal expansion of epigenetically altered cells.
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Metilação de DNA , Epigênese Genética , Queratinócitos , Mosaicismo , Poroceratose , Regiões Promotoras Genéticas , Poroceratose/genética , Poroceratose/patologia , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Regiões Promotoras Genéticas/genética , Masculino , Alelos , FemininoRESUMO
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.
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BACKGROUND: No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget's disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack of solid evidence from prospective trials. However, the immunohistochemical profile of EMPD reportedly resembles that of breast cancer, particularly in terms of human epidermal growth factor receptor 2 (HER2) expression, suggesting that HER2 is a promising therapeutic target for advanced HER2-positive EMPD. METHODS: In this phase II single-arm trial, 13 Japanese patients received intravenous trastuzumab (loading dose of 8 mg/kg and maintenance dose of 6 mg/kg) and docetaxel (75 mg/m2) every 3 weeks for up to 2 years. The docetaxel dose was reduced or discontinued according to its toxicity. The primary trial endpoints were objective response rate (ORR) after 3 cycles of treatment and safety throughout the study period. RESULTS: All 13 patients completed 3 cycles of combination therapy. The median follow-up was 27.9 months. The ORR was 76.9% (n =â 10/13; 90% CI, 50.5-93.4). Frequently observed adverse events were neutropenia (100%), hypoalbuminemia (84.6%), and mucocutaneous infection (84.6%), all of which were well tolerated. CONCLUSION: The combination of docetaxel and trastuzumab demonstrated a favorable clinical effect and acceptable tolerability, which makes it a good treatment option for HER2-positive metastatic EMPD (ClinicalTrials.gov Identifier: UMIN000021311, jRCTs031180073).
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BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated efficacy over previous cytotoxic chemotherapies in clinical trials among various tumors. Despite their favorable outcomes, they are associated with a unique set of toxicities termed as immune-related adverse events (irAEs). Among the toxicities, ICI-related pneumonitis has poor outcomes with little understanding of its risk factors. This retrospective study aimed to investigate whether pre-existing interstitial lung abnormality (ILA) is a potential risk factor for ICI-related pneumonitis. MATERIALS AND METHODS: Patients with non-small cell lung cancer, malignant melanoma, renal cell carcinoma, and gastric cancer, who was administered either nivolumab, pembrolizumab, or atezolizumab between September 2014 and January 2019 were retrospectively reviewed. Information on baseline characteristics, computed tomography findings before administration of ICIs, clinical outcomes, and irAEs were collected from their medical records. Pre-existing ILA was categorized based on previous studies. RESULTS: Two-hundred-nine patients with a median age of 68 years were included and 23 (11.0%) developed ICI-related pneumonitis. While smoking history and ICI agents were associated with ICI-related pneumonitis (P = .005 and .044, respectively), the categories of ILA were not associated with ICI-related pneumonitis (P = .428). None of the features of lung abnormalities were also associated with ICI-related pneumonitis. Multivariate logistic analysis indicated that smoking history was the only significant predictor of ICI-related pneumonitis (P = .028). CONCLUSION: This retrospective study did not demonstrate statistically significant association between pre-existing ILA and ICI-related pneumonitis, nor an association between radiologic features of ILA and ICI-related pneumonitis. Smoking history was independently associated with ICI-related pneumonitis. Further research is warranted for further understanding of the risk factors of ICI-related pneumonitis.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Renais , Neoplasias Pulmonares , Pneumonia , Humanos , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos Retrospectivos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/patologia , Pneumonia/induzido quimicamente , Pneumonia/diagnóstico por imagem , Neoplasias Renais/tratamento farmacológico , Pulmão/patologiaRESUMO
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.
Assuntos
Furanos , Doença de Paget Extramamária , Policetídeos de Poliéter , Adulto , Humanos , Ensaios Clínicos Fase II como Assunto , Cetonas/uso terapêutico , Doença de Paget Extramamária/tratamento farmacológico , Doença de Paget Extramamária/patologia , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Extramammary Paget disease (EMPD) is an intraepithelial adenocarcinoma that primarily affects the genital and axillary areas in older individuals. A limited number of paired patients with familial EMPD (i.e. parent-offspring, siblings) have been reported but the genetics have not yet been adequately studied. We report, to the best of our knowledge, the first familial cases of patients with EMPD involving three affected siblings. The tumour-only multigene panel testing using surgical specimens revealed a heterozygous c.2997A>C (p.Glu999Asp) nonsynonymous variant in the proto-oncogene MET (NM_000245.4) in the three affected siblings. The germline multigene panel testing using peripheral blood lymphocytes revealed the same missense MET variant in all five family members who were tested, including two asymptomatic offspring (51 and 37â years of age). The MET variant we identified could be involved in EMPD carcinogenesis. Further genomic analyses of patients with familial EMPD are warranted to validate the pathogenic relevance of MET variants in EMPD development.
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Doença de Paget Extramamária , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-met , Irmãos , Humanos , Masculino , Doença de Paget Extramamária/genética , Doença de Paget Extramamária/patologia , Pessoa de Meia-Idade , Feminino , Proteínas Proto-Oncogênicas c-met/genética , Adulto , Mutação de Sentido Incorreto , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Idoso , LinhagemRESUMO
Central hypothyroidism and dyslipidemia are well-known adverse events (AEs) of bexarotene therapy. Although hypothyroidism is known to cause dyslipidemia, no study has examined the association between hypothyroidism and dyslipidemia in patients undergoing bexarotene therapy. The aim of this study is to examine this association. A retrospective observational study was performed among 294 patients who initiated bexarotene therapy in Japan (nation-wide postmarketing complete surveillance). Jonckheere-Terpstra (one sided) test was performed to evaluate the effect of the bexarotene dose on lipid metabolisms, and regression analyses were performed to evaluate associations of bexarotene dose, free thyroxine (FT4), body mass index (BMI), and lipid metabolisms. Most patients developed hypothyroidism. Two-third of patients showed FT4 values below the lower limit at 1 week. Triglycerides (TG) increased in a bexarotene dose-dependent manner, and grade ≥3 AEs on hypertriglyceridemia was observed in 39% of the patients. Additionally, one-third of grade ≥3 AEs on hypertriglyceridemia occurred within 1 week. The delta_FT4 (difference in FT4 from baseline) negatively correlated with TG increase at 1 week (p = 0.012) but not with low density lipoprotein cholesterol (LDL-C) increase at any week. Bexarotene-induced hypothyroidism is almost inevitable and occurred quickly. Bexarotene-induced hypertriglyceridemia showed positive bexarotene dose dependency and negative delta_FT4 dependency. Prophylactic and appropriate thyroid hormone compensation therapy and starting bexarotene at low doses with subsequent titration while managing dyslipidemia may have a beneficial effect for the successful continuation of bexarotene therapy without severe endocrine and metabolic AEs.
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Bexaroteno , Dislipidemias , Hipotireoidismo , Humanos , Bexaroteno/efeitos adversos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Dislipidemias/induzido quimicamente , Japão/epidemiologia , Tiroxina/sangue , Triglicerídeos/sangue , Adulto , Tetra-Hidronaftalenos/efeitos adversos , Tetra-Hidronaftalenos/uso terapêutico , Idoso de 80 Anos ou mais , Anticarcinógenos/uso terapêutico , Anticarcinógenos/efeitos adversos , Hipertrigliceridemia/induzido quimicamenteRESUMO
Here we present a patient with cutaneous eyelid melanoma patient with lacrimal sac metastasis. Clinicopathological findings in this case support the theory that lacrimal fluid can be a metastatic pathway for tumour cells. Dermatologists should be aware of the possibility that cutaneous eyelid melanoma may involve the nasolacrimal system and should examine it during the perioperative period and in postoperative follow-up.
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Neoplasias Palpebrais , Doenças do Aparelho Lacrimal , Melanoma , Ducto Nasolacrimal , Neoplasias Cutâneas , Humanos , Ducto Nasolacrimal/patologia , Ducto Nasolacrimal/cirurgia , Melanoma/patologia , Neoplasias Cutâneas/patologia , Pálpebras , Neoplasias Palpebrais/patologia , Doenças do Aparelho Lacrimal/patologia , Doenças do Aparelho Lacrimal/cirurgia , Melanoma Maligno CutâneoRESUMO
To evaluate the feasibility of adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) in Japanese patients with melanoma who failed immune-checkpoint inhibitor therapy, an open-label, single-arm, pilot study was conducted. We investigated the immunological and genetic factors of the pretreatment tumor and expanded TILs that may be associated with the clinical response. The treatment protocol comprised preparation of TIL culture, lympho-depleting non-myeloablative preconditioning with cyclophosphamide and fludarabine, TIL infusion, and intravenous administration of low-dose IL-2. Three patients of clinical subtypes mucosal, superficial spreading, and acral melanoma underwent TIL-ACT. Most severe adverse events, including fever and leukopenia, were manageable with the supportive regimen specified in the protocol, suggesting that the TIL-ACT regimen is suitable for Japanese patients with melanoma. One patient showed a short-term partial response, one relatively long-stable disease, and one experienced disease progression. Whole-exome and transcriptional sequencing of isolated tumor cells and immunohistochemical analyses before TIL-ACT revealed various immunostimulatory factors, including a high tumor mutation burden and immune cell-recruiting chemokines, as well as various immunosuppressive factors including TGF-ß, VEGF, Wnt/ß-catenin, and MAPK signaling and epithelial-to-mesenchymal transition, which might influence the efficacy of TIL-ACT. Our results imply mechanisms for the antitumor effect of and resistance to TIL-ACT. Further studies of immune-resistant mechanisms of TIL-ACT are warranted. This study is registered with the UMIN Clinical Trial Registry (UMIN 000011431).
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Ciclofosfamida/administração & dosagem , Interleucina-2/administração & dosagem , Linfócitos do Interstício Tumoral/transplante , Melanoma/terapia , Vidarabina/análogos & derivados , Administração Intravenosa , Técnicas de Cultura de Células , Ciclofosfamida/uso terapêutico , Estudos de Viabilidade , Redes Reguladoras de Genes , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia Adotiva , Linfócitos do Interstício Tumoral/citologia , Masculino , Melanoma/genética , Melanoma/imunologia , Pessoa de Meia-Idade , Projetos Piloto , Condicionamento Pré-Transplante , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/uso terapêuticoRESUMO
BACKGROUND: Completion lymph node dissection (CLND) has long been the standard treatment for stage III melanomas identified as metastasis on the sentinel node (SN-positive). Two major changes occurred in 2017 and 2018, the change in the CLND criteria for SN-positive patients and the approval of several adjuvant therapies could revolutionize such management approach. However, their effects have not been fully investigated on the real-world outcomes of stage III melanoma patients. Therefore, we investigated the impact of these changes on the prognosis of Japanese stage III melanoma patients. METHODS: Totally, 119 stage III, SN-positive melanoma patients were included. They were categorized into those diagnosed as SN-positive between January 2015 and June 2017 (pre-June 2017 group) and between July 2017 and December 2019 (post-July 2017 group). Recurrence-free survival (RFS), overall survival, and prognostic factors were analyzed. RESULTS: The frequency of patients who received CLND was significantly higher in the pre-June 2017 group (p = 0.001), and those who received adjuvant therapy were significantly higher in the post-July 2017 group (p < 0.001). The 2-year RFS was 50.1% and 68.5% in the pre-June and post-July 2017 groups, respectively (p = 0.049). Cox proportional hazards model analysis for RFS showed that adjuvant therapies reduce the risk of recurrence (hazard ratio 0.37; 95% confidence interval 0.14-0.99; p = 0.047). CONCLUSION: Changes in the CLND criteria in SN-positive patients and the approval of adjuvant therapies for stage III melanomas have significantly impacted Japanese melanoma medicine. Adjuvant therapy tended to prolong patient's RFS while omitting immediate CLND had no significant negative influence on it.
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Melanoma , Linfonodo Sentinela , Neoplasias Cutâneas , Humanos , Japão , Excisão de Linfonodo , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Prognóstico , Linfonodo Sentinela/cirurgia , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/cirurgiaRESUMO
Primary malignant melanomas (MM) originating from the gynecological tract are rare. They respond poorly to immunotherapy when compared with cutaneous MM. This study reports two cases. The first is of a 54-year-old woman with a cervical amelanotic polypoid mass who was diagnosed as having stage IB1 cervical melanoma according to the International Federation of Gynecology and Obstetrics system. At 17 months post-surgery, a computed tomography examination revealed recurrence of a 68 mm pelvic tumor. The second case is of a 37-year-old woman with a 7 cm hemorrhagic mass on the vaginal wall. The patient was diagnosed as having stage IV vaginal melanoma according to the American Joint Committee on Cancer definition. Both patients received nivolumab therapy, programmed cell death receptor 1 monoclonal antibodies, and the tumors almost disappeared. These cases may add the possibility of using colposcopy with narrow-band imaging and positron-emission tomography to diagnose and evaluate primary MM.
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Antineoplásicos Imunológicos/uso terapêutico , Melanoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias Vaginais/tratamento farmacológico , Colo do Útero/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Vagina/patologiaRESUMO
Immune checkpoint inhibitors have improved the prognosis of advanced melanoma. Although anti-programmed death ligand-1 (PD-L1) is a well-studied biomarker for response to anti-programmed death-1 PD-1 therapy in melanoma, its clinical relevance remains unclear. It has been established that the high expression of indoleamine 2,3-dioxygenase (IDO) is correlated to a response to anti-CTLA-4 treatment in melanoma. However, it is still unknown whether the IDO expression is associated with response to anti-PD-1 therapy in advanced melanoma. In addition, acral and mucosal melanomas, which comprise a great proportion of all melanomas in Asians, are genetically different subtypes from cutaneous melanomas; however, they have not been independently analyzed due to their low frequency in Western countries. To evaluate the association of IDO and PD-L1 expression with response to anti-PD-1 antibody in acral and mucosal melanoma patients, we analyzed 32 Japanese patients with acral and mucosal melanomas treated with anti-PD-1 antibody from the perspective of IDO and PD-L1 expression levels by immunohistochemistry (IHC). Multivariate Cox regression models showed that the low expression of IDO in tumors was associated with poor progression-free survival (HR = 0.33, 95% CI = 0.13-0.81, P = 0.016), whereas PD-L1 expression on tumors was not associated with progression-free survival. Significantly lower expression of IDO in tumors was found in non-responders compared to responders. Assessment of the IDO expression could be useful for the identification of suitable candidates for anti-PD-1 therapy among acral and mucosal melanomas patients. Further validation study is needed to estimate the clinical utility of our findings.
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Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Melanoma/enzimologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/enzimologia , Idoso , Povo Asiático , Feminino , Humanos , Japão , Estimativa de Kaplan-Meier , Masculino , Melanoma/mortalidade , Melanoma/patologia , Melanoma/terapia , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapiaRESUMO
Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma that clinicopathologically resembles breast cancer. The prognosis of metastatic EMPD is poor. Although several chemotherapies have been tried, the effects are temporary; better drugs and combinations are required.In the present study, we retrospectively analyze the efficacy and safety of combination of cisplatin, epirubicin, and paclitaxel in five metastatic EMPD cases. The efficacy was better than that for previously reported regimens: 80% partial responses, including two patients who were refractory to taxane- and/or platinum-based regimens. In terms of safety, four patients who were able to continue treatment exhibited acceptable tolerability.This is the first regimen to combine taxane and anthracycline. When treating breast cancer, anthracycline is regarded as the key cytotoxic agent, and anthracycline in combination with taxane constitutes a key chemotherapeutic regimen. Given our results, we speculate both drugs are critical chemotherapeutic agents for the treatment of metastatic EMPD.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Epirubicina/administração & dosagem , Neoplasias dos Genitais Masculinos/tratamento farmacológico , Doença de Paget Extramamária/tratamento farmacológico , Neoplasias Vulvares/tratamento farmacológico , Idoso , Anemia/induzido quimicamente , Anemia/diagnóstico , Anemia/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Epirubicina/efeitos adversos , Feminino , Neoplasias dos Genitais Masculinos/mortalidade , Neoplasias dos Genitais Masculinos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/diagnóstico , Neutropenia/epidemiologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Doença de Paget Extramamária/mortalidade , Doença de Paget Extramamária/patologia , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Escroto/patologia , Índice de Gravidade de Doença , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Trombocitopenia/epidemiologia , Neoplasias Vulvares/mortalidade , Neoplasias Vulvares/patologiaRESUMO
Objectives: A carbapenem-resistant Enterobacter cloacae complex isolated in Tokyo, Japan, produced a carbapenemase that was detected by a Carba NP test and a modified carbapenem inactivation method, but none of the 'Big Five' carbapenemase genes was detected by PCR. This study aimed to identify the carbapenemase. Methods: Carbapenemase genes were screened by WGS. Next, we generated a recombinant plasmid in which the carbapenemase gene was inserted. We also extracted the carbapenemase gene-carrying plasmid from the E. cloacae complex. The effects of both plasmids on the antibiotic susceptibility of Escherichia coli were then tested. The carbapenemase gene-carrying plasmid in the E. cloacae complex was completely sequenced. Results: A novel carbapenemase gene, blaFRI-4, encoded an amino acid sequence that was 93.2% identical to French imipenemase (FRI-1). E. coli transformed with blaFRI-4 showed reduced carbapenem susceptibility. A complete sequence of the blaFRI-4-carrying 98â508 bp IncFII/IncR plasmid (pTMTA61661) showed that blaFRI-4 and the surrounding region (18.7 kb) were duplicated. Conclusions: The FRI-4-producing E. cloacae complex was isolated in Japan, whereas all other FRI variants have been found in Europe, suggesting that the spread of FRI carbapenemases is global.
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Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Carbapenêmicos/farmacologia , Enterobacter cloacae/genética , beta-Lactamases/genética , Proteínas de Bactérias/isolamento & purificação , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Enterobacter cloacae/efeitos dos fármacos , Enterobacter cloacae/enzimologia , Infecções por Enterobacteriaceae/microbiologia , Escherichia coli/genética , Humanos , Testes de Sensibilidade Microbiana , Plasmídeos/genética , Tóquio , Sequenciamento Completo do Genoma , beta-Lactamases/isolamento & purificaçãoAssuntos
Neoplasias Encefálicas/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Doença de Paget Extramamária/mortalidade , Neoplasias Cutâneas/mortalidade , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Doença de Paget Extramamária/secundário , Doença de Paget Extramamária/terapia , Prognóstico , Radiocirurgia , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Malignant melanoma is one of the lethal malignant tumors worldwide. Previously we reported that adenylate cyclase-associated protein 2 (CAP2), which is a well-conserved actin regulator, was overexpressed in hepatocellular carcinoma; however, CAP2 expression in other clinical cancers remains unclear. The aim of the current study was to clarify the clinicopathological significance of CAP2 overexpression in malignant melanoma. Immunohistochemical analyses revealed that many melanoma cells exhibited diffuse cytoplasmic expression of CAP2, whereas no normal melanocytes showed detectable immunostaining for CAP2. A high level of CAP2 expression was seen in 14 of 50 melanomas and was significantly correlated with greater tumor thickness and nodular melanoma subtypes. In addition, a high level of CAP2 expression was associated with poor overall survival in univariate and multivariate analyses. For 13 patients, samples of primary and metastatic melanoma tissue were available: four patients exhibited higher levels of CAP2 expression in metastatic tumor compared to the primary site, whereas no patient showed lower levels of CAP2 expression in metastatic melanomas. Our findings show that CAP2 overexpression is a novel prognostic marker in malignant melanoma and that CAP2 expression seems to increase stepwise during tumor progression, suggesting the involvement of CAP2 in the aggressive behavior of malignant melanoma.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Melanoma/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Citoplasma/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Melanócitos/patologia , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/patologiaAssuntos
Melanoma , Neoplasias Cutâneas , Humanos , Ipilimumab , Melanoma/terapia , Neoplasias Cutâneas/terapiaRESUMO
We report a 78-year-old woman with rheumatoid neutrophilic dermatosis (RND) presenting with tense blisters; an extremely rare manifestation of this condition. Systemic corticosteroid was of limited efficacy, while dapsone was effective. A literature review of four similar cases showed that tense blisters in this type of RND tended to appear on the lower extremities of aged, female rheumatoid arthritis patients. Of note, half of the cases were resistant to corticosteroids, as anti-neutrophil agents are reported to be effective. Accordingly, it is important to recognise this unusual manifestation for the timely initiation of appropriate therapy.