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1.
Nat Commun ; 11(1): 5084, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033253

RESUMO

Identifying factors underlying resistance to immune checkpoint therapy (ICT) is still challenging. Most cancer patients do not respond to ICT and the availability of the predictive biomarkers is limited. Here, we re-analyze a publicly available single-cell RNA sequencing (scRNA-seq) dataset of melanoma samples of patients subjected to ICT and identify a subset of macrophages overexpressing TREM2 and a subset of gammadelta T cells that are both overrepresented in the non-responding tumors. In addition, the percentage of a B cell subset is significantly lower in the non-responders. The presence of these immune cell subtypes is corroborated in other publicly available scRNA-seq datasets. The analyses of bulk RNA-seq datasets of the melanoma samples identify and validate a signature - ImmuneCells.Sig - enriched with the genes characteristic of the above immune cell subsets to predict response to immunotherapy. ImmuneCells.Sig could represent a valuable tool for clinical decision making in patients receiving immunotherapy.


Assuntos
Perfilação da Expressão Gênica , Imunoterapia , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores Imunológicos/metabolismo , Linfócitos T/metabolismo , Área Sob a Curva , Linfócitos B/metabolismo , Biomarcadores Tumorais/metabolismo , Humanos , Macrófagos/patologia , Melanoma/genética , Melanoma/patologia , Reprodutibilidade dos Testes
2.
Chirurgia (Bucur) ; 115(4): 476-485, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32876021

RESUMO

Background: The accuracy of the staging, along with the reproductibility of intraoperative lymph car-tography, and lymph node biopsy in patients with malignant melanoma was unanimously validated in the last decade. This technique allows the discovery of lymph node micrometastses with the help of immunohistochemical methods. The goal of the present study is to present the experience of our clinic in identification and biopsy protocol of the lymph node. Methods: A year-long retrospective analysis was running between March 2019 - December 2019 con-cerning 57 patients with cutaneous melanoma on which detection and excisional biopsy of the lymph node was performed. The procedure was performed by the double method using vital dye and a ra-dio-active tracer. Demographic information was filed, as well as data on location of primary tumors, tumor histology, and radioactivity level. Results: The mean Breslow thickness of primary skin melanomas was 2.7 mm. At least one lymph node was identified in 56 of the 57 patients included in the study. Among those, 15 (26%) had at least one metastatic node. The mean number of excised lymph nodes per patient was 1.6. Conclusions: The cartography and biopsy of lymph nodes need the involvement of a complex multi disciplinary team made of nuclear medicine, surgery, and anatomopathology specialists. This way one provides both a correct staging of the patient with melanoma and access to adjuvant innovative therapies, thus considerably improving the prognosis.


Assuntos
Melanoma/patologia , Linfonodo Sentinela/patologia , Neoplasias Cutâneas/patologia , Humanos , Metástase Linfática , Estadiamento de Neoplasias , Estudos Retrospectivos , Biópsia de Linfonodo Sentinela , Resultado do Tratamento
3.
N Z Med J ; 133(1520): 50-60, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32994593

RESUMO

AIM: Therapeutic lymphadenectomy remains the gold standard for surgical management of clinically evident regional cervical disease for cutaneous malignancy. However, international consensus on adequate lymphadenectomy is lacking. Attempts have been made to establish quality measures; suggested benchmarks for minimum and average nodal yield, as well as recurrence and complication rates have been quoted. We aim to compare our key performance indicators to those benchmarks published in the literature. METHODS: This is a retrospective observational study conducted with prospectively maintained data, over an 11-year period (2007-2018). RESULTS: Of 91 cervical lymphadenectomies included, mean nodal yield for ≤3 and ≥4 dissection levels were 19.7 and 38.7 respectively. We observed a combined locoregional recurrence rate of 25%. Subgroup analysis for melanoma (60) and cSCC (28) revealing regional nodal recurrence of 15% and 11%, respectively. We observed a 38.5% complication rate; however, less than 5.5% was considered grade IIIb/IIIb(d) [Clavein-Dindo]. Median follow-up of 19.3 months, five-year survivial rate of 38% and 32% for melanoma and cSCC, respectively. CONCLUSION: Our data indicates that we are meeting quality measures, set by higher volume centres. We believe that any surgeon with subspecialty training in head and neck surgery can meet quality measures with regards to cervical lymphadenopathy for cutaneous malignancy.


Assuntos
Excisão de Linfonodo/métodos , Linfonodos/cirurgia , Pescoço/patologia , Neoplasias Cutâneas/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Metástase Linfática/patologia , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Nova Zelândia/epidemiologia , Guias de Prática Clínica como Assunto , Indicadores de Qualidade em Assistência à Saúde , Estudos Retrospectivos , Neoplasias Cutâneas/secundário , Cirurgiões/educação , Taxa de Sobrevida
4.
Cancer Treat Rev ; 89: 102083, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32736188

RESUMO

Melanoma brain metastases (MBM) are common and associated with a particularly poor prognosis; they directly cause death in 60-70% of melanoma patients. In the past, systemic treatments have shown response rates around 5%, whole brain radiation as standard of care has achieved a median overall survival of approximately three months. Recently, the combination of immune checkpoint inhibitors and combinations of MAP-kinase inhibitors both have shown very promising response rates of up to 55% and 58%, respectively, and improved survival. However, current clinical evidence is based on multi-cohort studies only, as prospectively randomized trials have been carried out rarely in MBM, independently whether investigating systemic therapy, radiotherapy or surgical techniques. Here, an interdisciplinary expert team reviewed the outcome of prospectively conducted clinical studies in MBM, identified evidence gaps and provided recommendations for the diagnosis, treatment, outcome evaluation and monitoring of MBM patients. The recommendations refer to four distinct scenarios: patients (i) with 'brain-only' disease, (ii) with oligometastatic asymptomatic intra- and extracranial disease, (iii) with multiple asymptomatic metastases, and (iv) with multiple symptomatic MBM or leptomeningeal disease. Changes in current management recommendations comprise the use of immunotherapy - preferably combined anti-CTLA-4/PD-1-immunotherapy - in asymptomatic MBM minus/plus stereotactic radiosurgery which remains the mainstay of local brain therapy being safe and effective. Adjuvant whole-brain radiotherapy provides no clinical benefit in oligometastatic MBM. Among the systemic therapies, combined MAPK-kinase inhibition provides, in BRAFV600-mutated patients with rapidly progressing or/and symptomatic MBM, an alternative to combined immunotherapy.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Melanoma/patologia , Melanoma/terapia , Animais , Neoplasias Encefálicas/diagnóstico , Ensaios Clínicos como Assunto , Estudos de Coortes , Terapia Combinada , Humanos , Melanoma/diagnóstico , Equipe de Assistência ao Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
5.
Zhonghua Fu Chan Ke Za Zhi ; 55(6): 395-401, 2020 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-32842246

RESUMO

Objective: To assess the treatment and prognosis of vulvar melanoma. Methods: A total of 59 cases of primary vulvar melanoma admitted to Cancer Hospital of Peking Union Medical College, Chinese Academy of Medical Sciences from January 1st, 1981 to November 30th, 2019 were collected. The clinical characteristics, treatment, survival and prognostic factors of vulvar melanoma were analyzed retrospectively. The end date of follow-up was January 15th, 2020.The median follow-up time was 26.0 months (range:2-198 months). Results: (1) Clinical characteristics: the median age of 59 patients with vulvar melanoma was 56 years old (range:18-83 years old). According to the American Joint Committee on Cancer stage manual, there were 18, 7, 26 and 8 cases of stage Ⅰ, Ⅱ, Ⅲ and Ⅳ respectively. The lesion of 38 cases was single and the other 21 cases were multiple. The largest diameter of the tumor ranged from 0.3 to 17.0 cm.The surface of the lesion was ulcerated in 17 cases. (2) Treatment: a total of 59 cases with vulvar melanoma, 56 patients received surgery, 36 cases of them received radical resection of vulva and 20 received local extended resection of vulvar tumor due to unilateral vulva lesion. Three patients did not receive surgery,one received chemotherapy combined with interferon, one received interferon, and one received radiotherapy. Lymph node management: among the 56 patients treated by surgery, 37 patients received inguinal lymphadenectomy, 24 (65%, 24/37) of whom were confirmed with inguinal lymph node metastasis by postoperative pathological examination. Inguinal lymph nodes enlargement were not found in 19 cases by preoperative imaging and clinical examination. In these 19 patients, three patients received inguinal lymph node biopsy, among them, one (1/3) patient was confirmed with inguinal lymph node metastasis by postoperative pathological examination, and the remaining 16 patients did not receive inguinal lymph node surgery. Postoperative adjuvant treatment: among the 56 patients who received surgery, 31 received adjuvant chemotherapy,one received adjuvant radiotherapy, four received interferon therapy, 17 received combination therapy including chemotherapy, and three did not receive postoperative adjuvant therapy. (3) Survival:during the follow-up period, the median survival time of 59 patients with vulvar melanoma was 30.0 months (range:2.0-198.0 months). The 3-year survival rate was 42.5%, and the 5-year survival rate was 23.8%. The median survival time of stage Ⅰ, Ⅱ, Ⅲ and Ⅳ were 72.0, 45.0, 24.0 and 23.0 months, respectively. The difference among stage Ⅰ, Ⅱ and stage Ⅲ, Ⅳ were statistically significant (P<0.01). The median survival time of patients undergoing radical resection of the vulva (35.0 months) and local enlarged tumor resection (29.0 months) were significantly longer than that of patients without surgery (9.0 months, P<0.01). The median survival time of the patients who underwent inguinal lymphadenectomy, lymph node biopsy and those who did not undergo surgery were 35.0, 32.0 and 30.0 months, respectively. There were no significant differences among the 3 groups (P>0.05). The median survival time of postoperative adjuvant chemotherapy patients (49.0 months) were significantly longer than that of postoperative adjuvant radiotherapy, interferon,and combination therapy including chemotherapy (9.0, 14.0 and 26.0 months, respectively, all P<0.01). (4) Prognostic factors: the univariate analysis showed that stage, vulvar operation and postoperative adjuvant treatment were the risk factors affecting the prognosis of patients with vulvar melanoma (P<0.01). Multivariate analysis revealed that stage alone was an independent risk factor affecting the prognosis of patients with vulvar melanoma (P<0.01). Conclusions: The prognosis of patients with vulvar melanoma is poor, and stage is an independent prognostic factor.Surgery combined with postoperative adjuvant chemotherapy may achieve relatively good results.


Assuntos
Excisão de Linfonodo , Melanoma/cirurgia , Neoplasias Vulvares/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias Vulvares/mortalidade , Neoplasias Vulvares/patologia , Adulto Jovem
6.
Nat Commun ; 11(1): 3946, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770055

RESUMO

Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFRhi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFRhi cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFRhi tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFRhi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Melanoma/tratamento farmacológico , Proteínas do Tecido Nervoso/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fator de Crescimento Neural/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Linfócitos T Citotóxicos/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , RNA-Seq , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T Citotóxicos/metabolismo , Evasão Tumoral/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Nature ; 585(7823): 113-118, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32814895

RESUMO

Cancer cells, including melanoma cells, often metastasize regionally through the lymphatic system before metastasizing systemically through the blood1-4; however, the reason for this is unclear. Here we show that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in blood. Immunocompromised mice with melanomas derived from patients, and immunocompetent mice with mouse melanomas, had more melanoma cells per microlitre in tumour-draining lymph than in tumour-draining blood. Cells that metastasized through blood, but not those that metastasized through lymph, became dependent on the ferroptosis inhibitor GPX4. Cells that were pretreated with chemical ferroptosis inhibitors formed more metastases than untreated cells after intravenous, but not intralymphatic, injection. We observed multiple differences between lymph fluid and blood plasma that may contribute to decreased oxidative stress and ferroptosis in lymph, including higher levels of glutathione and oleic acid and less free iron in lymph. Oleic acid protected melanoma cells from ferroptosis in an Acsl3-dependent manner and increased their capacity to form metastatic tumours. Melanoma cells from lymph nodes were more resistant to ferroptosis and formed more metastases after intravenous injection than did melanoma cells from subcutaneous tumours. Exposure to the lymphatic environment thus protects melanoma cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood.


Assuntos
Ferroptose , Linfa/metabolismo , Melanoma/patologia , Metástase Neoplásica/patologia , Animais , Sobrevivência Celular , Coenzima A Ligases/metabolismo , Feminino , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Ferro/metabolismo , Masculino , Melanoma/sangue , Melanoma/metabolismo , Camundongos , Metástase Neoplásica/tratamento farmacológico , Ácido Oleico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Análise de Componente Principal
8.
Anticancer Res ; 40(7): 3723-3732, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620611

RESUMO

BACKGROUND/AIM: Skin melanoma belongs to the most invasive malignancies with no cure for a progressing disease. Personalized therapy would allow for the selection of patients that will benefit from treatment. For this purpose, proper predictive biomarkers must be defined. MATERIALS AND METHODS: Allogeneic whole-cell gene-modified therapeutic melanoma vaccine (AGI-101H) was applied in advanced melanoma patients. Humoral responses were analyzed using SEREX, and in silico gene expression analysis in TCGA melanoma patients was performed. RESULTS: A specific antibody response was raised against an antigen identified as BNIP3L, which correlated with a good prognosis. Moreover, AGI-101H directs an immune response against autophagy, as BNIP3L is a marker of this process. Medium and high expression of BNIP3L was also linked with longer overall survival. CONCLUSION: BNIP3L is a candidate prognostic marker of clinical outcome of melanoma patients treated with AGI-101H, and may be considered as a prediction marker for patient survival.


Assuntos
Autofagia/fisiologia , Biomarcadores Tumorais/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Proteínas Supressoras de Tumor/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Vacinas Anticâncer/imunologia , Feminino , Humanos , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia
9.
J Cancer Res Clin Oncol ; 146(10): 2589-2594, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32700108

RESUMO

BACKGROUND: Primary pineal malignant melanoma (PPMM) is a rare entity of primary central nervous system melanomas, with only 26 cases reported in the literature to date. CASE PRESENTATION: We report the case of a 65-year-old male with a PPMM who has prolonged survival of more than 104 weeks after combined microsurgical and endoscopic total resection. This is the first report: combined microscope and endoscopy total resection; PPMM in China; PPMM with total resection alone. CONCLUSION: Combined microscope and endoscopy total resection is beneficial to prolong the survival of patients. But the best approach to treatment needs verification from more clinical cases in future.


Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Melanoma/patologia , Melanoma/cirurgia , Glândula Pineal/patologia , Glândula Pineal/cirurgia , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Endoscopia/métodos , Humanos , Imagem por Ressonância Magnética , Masculino , Melanoma/diagnóstico por imagem , Glândula Pineal/diagnóstico por imagem
11.
Cancer Treat Rev ; 88: 102060, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32619863

RESUMO

Phenotypic plasticity of malignant melanoma is a well-known phenomenon. Several translational studies and small case series have reported this clinical and biological entity, particularly in metastatic melanoma, showing frequent aberrant expression of non-melanocytic differentiation markers of different lineages, posing remarkable challenges due to several alternative differential diagnoses including undifferentiated carcinoma and sarcomas. When melanoma loses its typical morpho-phenotype by routinely used diagnostic immunohistochemical markers, it is defined as "dedifferentiated melanoma". Historically, this process was closely related to diagnostic interpretative difficulties. In recent years, however, dedifferentiation has been increasingly recognized as an important biological phenomenon that demonstrates the phenotypic and genetic plasticity of melanoma, and specifically the non-irreversibility of the multistep cancerogenesis. Furthermore, dedifferentiation emerged as a general hallmark of cancer evolution and a common denominator of cross-resistance to both targeted and immunotherapy. In this review, we summarize the histopathological features, the genetic and epigenetic bases underlying the dedifferentiated phenotype in melanomas and provide additional support that dedifferentiation is a mechanism of resistance to immunotherapy and targeted therapy.


Assuntos
Melanoma/genética , Melanoma/terapia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Animais , Desdiferenciação Celular/fisiologia , Reprogramação Celular/fisiologia , Epigênese Genética , Humanos , Melanoma/patologia , Neoplasias Cutâneas/patologia
12.
Cancer Invest ; 38(7): 415-423, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32643437

RESUMO

The aim of the study was to investigate if there was an association between intraoperative NSAID use and recurrence or survival. A cohort of patients who underwent sentinel lymph node biopsy for the treatment of cutaneous melanoma was retrospectively recruited. After applying inclusion and exclusion criteria, 516 were included (NSAIDs = 307). The 10-year melanoma-specific survival was 63.2%. Log-rank test showed no statistically significant differences in time to treatment failure, melanoma-specific survival, disease-free survival, and overall survival between the study groups. The current study did not support the use of intraoperative NSAIDs in preventing death or recurrence in patients with melanoma.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Melanoma/patologia , Melanoma/cirurgia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Idoso , Estudos de Coortes , Feminino , Humanos , Isoxazóis/uso terapêutico , Estimativa de Kaplan-Meier , Cetorolaco/uso terapêutico , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Período Perioperatório , Piroxicam/análogos & derivados , Piroxicam/uso terapêutico , Estudos Retrospectivos , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/mortalidade , Resultado do Tratamento
13.
Gene ; 759: 144964, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32717308

RESUMO

BACKGROUND: Mucosal melanoma is a tumor caused by the malignant transformation of pigment-producing cells and can arise from any mucosal tissue where melanocytes are present. Due to its rarity, the mucosal melanoma subtype is poorly described, and its genetic characteristics are infrequently studied. The discovery or confirmation of new mucosal melanoma susceptibility genes will provide important insights for the study of its pathogenesis. MATERIALS AND METHODS: We performed deep targeted sequencing of 100 previously reported melanoma-related genes in 39 mucosal melanoma samples and a gene-level loss-of-function (LOF) variant enrichment analysis for mucosal melanoma from different incidence sites. RESULTS: We detected 7,589 variants in these samples, and 484 were LOF variants (gain or loss of a stop codon, missense, and splice site). Four different gene-level enrichment analyses revealed that FSIP1 (fibrous sheath interacting protein 1) is a susceptibility gene for oral mucosal melanoma (OR = 0.33, PChi = 4.05 × 10-2, Pburden = 3.06 × 10-2, Pskat = 3.01 × 10-2, Pskato = 3.01 × 10-2), whereas the different methods did not detect a significant susceptibility gene for the other subtypes. CONCLUSIONS: In our study, a susceptibility gene for oral mucosal melanoma was confirmed in a Chinese Han population, and these findings contribute to a better genetic understanding of mucosal melanoma of different subtypes.


Assuntos
Proteínas de Transporte/genética , Mutação com Perda de Função , Melanoma/genética , Proteínas de Plasma Seminal/genética , Idoso , Feminino , Humanos , Masculino , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/classificação , Melanoma/patologia , Pessoa de Meia-Idade , Membrana Mucosa/metabolismo , Membrana Mucosa/patologia
14.
Medicine (Baltimore) ; 99(28): e20957, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664098

RESUMO

Primary malignant melanoma of esophagus (PMME) is a rare malignant tumor of esophagus. This study aimed to investigate the clinic pathologic characteristics and analyze the factors that might affect the prognosis of PMME patients.A total of 20 PMME patients who underwent surgical treatment in our hospital from 1975 to 2017 were analyzed. The clinical data, surgical and pathologic features of all patients were collected.For 20 PMME patients, the average age was 57.3 ±â€Š10.7 years, and the male patients account for 75%. Most of the tumors (95%) were located in the middle and lower of the esophagus. There were 7 patients with primary tumor invasion beyond the muscular layer (T3 + T4) and 10 patients with lymph node metastasis (LNM). The median survival time of 20 patients was 12 months, and the 1-year and 5-year survival rates were 50% and 16.9%, respectively. The probability of LNM in tumors confined to submucosa (T1) and myometrium (T2) was lower than that in tumors with deeper invasion (T3, T4) (P = .035). Multivariate analysis showed that tumor node metastasis (TNM) staging was the independent prognostic factor for survival of PMME patients (hazard ratio [95% confidence interval], 4.15 [1.36-12.67]; P = .012).For PMME patients, tumors with deeper invasion were more likely to have LNM, and TNM staging was an independent predictor of prognosis for survival. Early detection of the disease and radical resection of the tumor are critical for better survival of the PMME patients.


Assuntos
Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Melanoma/mortalidade , Melanoma/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
15.
Nat Commun ; 11(1): 3326, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620791

RESUMO

Tumour cells adapt to nutrient deprivation in vivo, yet strategies targeting the nutrient poor microenvironment remain unexplored. In melanoma, tumour cells often experience low glutamine levels, which promote cell dedifferentiation. Here, we show that dietary glutamine supplementation significantly inhibits melanoma tumour growth, prolongs survival in a transgenic melanoma mouse model, and increases sensitivity to a BRAF inhibitor. Metabolomic analysis reveals that dietary uptake of glutamine effectively increases the concentration of glutamine in tumours and its downstream metabolite, αKG, without increasing biosynthetic intermediates necessary for cell proliferation. Mechanistically, we find that glutamine supplementation uniformly alters the transcriptome in tumours. Our data further demonstrate that increase in intra-tumoural αKG concentration drives hypomethylation of H3K4me3, thereby suppressing epigenetically-activated oncogenic pathways in melanoma. Therefore, our findings provide evidence that glutamine supplementation can serve as a potential dietary intervention to block melanoma tumour growth and sensitize tumours to targeted therapy via epigenetic reprogramming.


Assuntos
Proliferação de Células/efeitos dos fármacos , Suplementos Nutricionais , Epigênese Genética/efeitos dos fármacos , Glutamina/farmacologia , Melanoma/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Epigênese Genética/genética , Glutamina/administração & dosagem , Histonas/metabolismo , Humanos , Lisina/metabolismo , Masculino , Melanoma/genética , Melanoma/patologia , Metilação/efeitos dos fármacos , Camundongos Nus , Transdução de Sinais/genética , Transcriptoma/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Nature ; 585(7823): 107-112, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32728218

RESUMO

Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with treatment-refractory tumours1,2. We are testing melanoma FixVac (BNT111)-an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent in melanoma-in an ongoing, first-in-human, dose-escalation phase I trial in patients with advanced melanoma (Lipo-MERIT trial, ClinicalTrials.gov identifier NCT02410733). We report here data from an exploratory interim analysis that show that melanoma FixVac, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. Clinical responses are accompanied by the induction of strong CD4+ and CD8+ T cell immunity against the vaccine antigens. The antigen-specific cytotoxic T-cell responses in some responders reach magnitudes typically reported for adoptive T-cell therapy, and are durable. Our findings indicate that RNA-LPX vaccination is a potent immunotherapy in patients with CPI-experienced melanoma, and suggest the general utility of non-mutant shared tumour antigens as targets for cancer vaccination.


Assuntos
Antineoplásicos/uso terapêutico , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Melanoma/imunologia , Melanoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA Neoplásico/genética , Linfócitos T/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos/farmacologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Terapia Combinada , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Estadiamento de Neoplasias , Linfócitos T/citologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Vacinação
17.
BMC Bioinformatics ; 21(1): 329, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703153

RESUMO

BACKGROUND: Melanoma phenotype and the dynamics underlying its progression are determined by a complex interplay between different types of regulatory molecules. In particular, transcription factors (TFs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) interact in layers that coalesce into large molecular interaction networks. Our goal here is to study molecules associated with the cross-talk between various network layers, and their impact on tumor progression. RESULTS: To elucidate their contribution to disease, we developed an integrative computational pipeline to construct and analyze a melanoma network focusing on lncRNAs, their miRNA and protein targets, miRNA target genes, and TFs regulating miRNAs. In the network, we identified three-node regulatory loops each composed of lncRNA, miRNA, and TF. To prioritize these motifs for their role in melanoma progression, we integrated patient-derived RNAseq dataset from TCGA (SKCM) melanoma cohort, using a weighted multi-objective function. We investigated the expression profile of the top-ranked motifs and used them to classify patients into metastatic and non-metastatic phenotypes. CONCLUSIONS: The results of this study showed that network motif UCA1/AKT1/hsa-miR-125b-1 has the highest prediction accuracy (ACC = 0.88) for discriminating metastatic and non-metastatic melanoma phenotypes. The observation is also confirmed by the progression-free survival analysis where the patient group characterized by the metastatic-type expression profile of the motif suffers a significant reduction in survival. The finding suggests a prognostic value of network motifs for the classification and treatment of melanoma.


Assuntos
Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Melanoma/genética , RNA Longo não Codificante/metabolismo , Biologia Computacional/métodos , Humanos , Melanoma/metabolismo , Melanoma/mortalidade , Melanoma/patologia , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Fenótipo , RNA-Seq , Fatores de Transcrição/metabolismo
18.
Clin Nucl Med ; 45(9): 725-726, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32657865

RESUMO

A 33-year-old man had a diagnosis of a spitzoid melanoma by dorsal skin biopsy. During the oncological follow-up, patient underwent whole-body FDG PET/CT for restaging purpose. FDG PET/CT showed a large necrotic mass of the pituitary gland, subsequently confirming a solitary pituitary metastasis from spitzoid melanoma.


Assuntos
Fluordesoxiglucose F18 , Melanoma/patologia , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/secundário , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias Cutâneas/patologia , Adulto , Humanos , Masculino
19.
Anticancer Res ; 40(6): 3505-3512, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487651

RESUMO

AIM: To assess the prognostic significance of nucleolar morphological parameters in a large cohort of patients with uveal melanoma. PATIENTS AND METHODS: The presence, size and number of nucleoli of cancer cells were assessed in haematoxylin and eosin (HE)-stained slides of 164 formalin-fixed paraffin-embedded primary uveal melanoma tissue specimens. The results were correlated with clinicopathological features and patient survival. RESULTS: The presence of macronucleoli and multiple nucleoli significantly correlated with the epithelioid type of uveal melanoma, high mitotic rate, and marked pleomorphism. There was a positive correlation between the presence of macronucleoli as well as the number of nucleoli and the largest tumour basal diameter. The increased nucleolus count in tumour cells positively correlated with primary tumour (pT) staging. The presence of both prominent and multiple nucleoli was associated with significantly reduced overall and disease-free survival. CONCLUSION: Histological assessment of nucleolar morphology in routine HE staining would be a helpful low-cost method to obtain reliable prognostic information.


Assuntos
Nucléolo Celular/patologia , Melanoma/patologia , Neoplasias Uveais/patologia , Idoso , Nucléolo Celular/ultraestrutura , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Melanoma/mortalidade , Melanoma/ultraestrutura , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Carga Tumoral , Neoplasias Uveais/mortalidade , Neoplasias Uveais/ultraestrutura
20.
Medicine (Baltimore) ; 99(21): e19936, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481257

RESUMO

Rapid growth of cutaneous melanoma is associated with aggressive histopathologic features and poor prognosis. However, the impact of growth rate (GR) in acral melanoma (AM) remains largely unknown.We performed this study to identify the impact of GR on lymph node metastasis and survival in AM.We analyzed cases of invasive AM diagnosed at our institution between 1998 and 2017. We investigated the impact of GR on the prognosis of AM.A total of 126 cases of invasive AM were included. Log (GR) was significant associated with lymph node metastasis in the univariate logistic regression analysis (P = .005). The log-rank test revealed statistically significant differences in disease-free survival (DFS) and disease-specific survival (DSS) among the GR quartiles. In the Cox regression analysis, log (GR) was an independent predictor for DFS (P = .041), but not for DSS in multivariate analysis. In the subgroup analysis, log (GR) was an independent predictor for early-stage (≤2A) AM (DFS, P = .002; DSS, P = .004).The limitations of this study include the retrospective design of the study and possible recall bias.Our results suggest that GR is an important prognostic factor for DFS and DSS in AM patients and an independent predictor for early-stage AM.


Assuntos
Doenças do Pé/mortalidade , Doenças do Pé/patologia , Mãos , Melanoma/mortalidade , Melanoma/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Metástase Linfática , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Prognóstico , República da Coreia , Estudos Retrospectivos , Taxa de Sobrevida
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