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1.
Acta Dermatovenerol Croat ; 291(1): 58, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34477068

RESUMO

The year 2020 has been marked by the coronavirus disease 2019 (COVID-19) pandemic, caused by an RNA virus called SARS-COV2 (severe acute respiratory syndrome coronavirus). The fight against this epidemic has become the center of our daily clinical practice as well as of our private lives, in which avoiding infection has become one of our most important goals. Even though COVID-19 is a potentially lethal disease, especially for the elderly and people with chronic diseases, it did not cause all the other life-threatening diseases to vanish. On the contrary, many scheduled medical activities and procedures, especially preventive and non-urgent internal and surgical activities, had to be postponed due to COVID-19 crisis. This interruption in the health care system can negatively affect the diagnosis and management of our patients with other health issues, namely malignant skin tumors, of which melanoma is the most aggressive. In this letter, we as dermatovenereologists from the Croatian Referral Centre of The Ministry of Health for Melanoma needed to express our concern regarding the increasing number of patients with delayed diagnosis of skin cancer, with special emphasis on melanoma detection and treatment. In the last few months, a large number of our newly-diagnosed patients with melanoma, as well as those with non-melanoma skin cancers, reported that they had noticed a suspicious skin lesion a few months ago but decided not to seek help from dermatologist due to the worrisome epidemiologic situation. In the current environment, clinical skin examination may be viewed as less important and thus postponed, but neglecting melanoma throughout the virus outbreak may lead to increased rates of morbidity, mortality, and consequently a greater financial burden for the health system (1). There are several reasons for such a relaxed attitude towards skin health in our patients. Unlike cardiac, pulmonary, or digestive difficulties, which patients consider life-threatening and for which they seek emergency care despite the coronavirus pandemic, skin tumors do not cause great subjective or significantly noticeable objective symptoms. Moreover, all of the skin tumors and especially melanoma , mostly present as small changes of just a few millimeters in diameter in the early stage at which they are prognostically most favorable. For the average person with no medical education, such small lesions usually do not cause any concern as they have no awareness of the fact that small and inconspicuous skin lesions may be dangerous and potentially even lethal. According to the recommendations concerning patient management during COVID-19 pandemic, oncological examinations should still be performed regularly (2). In spite of that, the cancelation of appointments, especially by patients who are being monitored for high-risk lesions, is inevitable when COVID-19 is disrupting everyone's lives. With the pandemic evolving and no clear solutions in sight, now is the time to emphasize the importance of self-examination and teledermatology in early melanoma diagnosis. Even though diagnosing and managing pigmented skin lesions usually requires face-to-face examinations and dermoscopy as a crucial tool in early melanoma detection, in these times, and especially for people with a higher risk of SARS-COV2 infection, remote communication could prevent delays resulting in worse prognosis and could also eliminate the risk of infecting healthcare workers. Moreover, teledermatology can also be initiated by doctors asking patients to monitor lesions between clinical visits (3). However, we should not rely solely on this technology but should instead assess every patient individually and insist on a face-to-face examination for those at greater risk, with the aim that, if necessary, surgery be performed in timely manner. The collaboration between general practitioners and dermatologists represents an important aspect of achieving the most rational and effective health care in terms of performing triage of patients who can be assessed by teledermatology as well as referring to hospital centers those who need face-to-face examination and further treatment. During the first breakout of the epidemic in March 2020, the multidisciplinary team for melanoma from the Croatian National Referral Melanoma Centre provided recommendations for the management of patients with melanoma during COVID epidemic, designed according to the guidelines of the National Comprehensive Cancer Network (NCCN) (4) and considering the specifics of health care and clinical practice in the Republic of Croatia. Due to epidemic circumstances, preventive actions such as Euromelanoma and many other campaigns that included massive preventive skin examinations of the population and which were conducted for years by Croatian dermatologists throughout the country, could not be organized this year. This is particularly worrisome because on average about 800 patients are diagnosed with melanoma annually in Croatia, of which 60 during public health preventive actions. Despite these circumstances, we were able to maintain public awareness of the importance of early skin cancer recognition by sending the message through different media such as newspapers, television, and social media (Facebook and Instagram). We find that now more than ever it is essential to remind and teach the population about the importance of regular monthly skin self-examinations and recognition of atypical lesions. Clearly, a thorough dermatological examination includes full skin examination from head to toe. Herein we would also like to remind our readers that most skin cancers develop in the head and neck area, which is the most UV-exposed part of the body. Therefore, despite the epidemic conditions, the removal of patients' masks and thorough inspection of the face is mandatory. We find it most practical and efficient to perform the body and scalp examination first, followed by the face examination after the patient gets dressed. Prior to removal of the mask, we ask the patient not to talk during close examination. Even though this could make dermoscopic examination harder to perform, we strongly suggest wearing a protective shield and mask during close examination whenever possible. Between patients, the examining room should be disinfected and ventilated. As doctors, we live in uncertain times when we are heavily burdened by the currently unstoppable COVID epidemic, always awaiting new instructions from the state administration every day and wondering whether perhaps tomorrow we dermatologists will be assigned solely to the service of patients with COVID-19. In the end, we would like to once again remind you that despite the ravaging COVID pandemic and all the epidemiological measures that come with it, other diseases still exist. It is expected of us to draw attention to the still growing incidence of skin cancers and the serious consequences that can occur as a result of a delayed diagnosis.


Assuntos
COVID-19/epidemiologia , Diagnóstico Tardio , Melanoma/diagnóstico , Melanoma/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Tempo para o Tratamento , Croácia/epidemiologia , Acesso aos Serviços de Saúde , Humanos , Pandemias , Aceitação pelo Paciente de Cuidados de Saúde , SARS-CoV-2
2.
Clin Plast Surg ; 48(4): 561-576, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34503717

RESUMO

Despite the ability of immune-based interventions to dramatically increase the survival of patients with melanoma, a significant subset fail to benefit from this treatment, underscoring the need for accurate means to identify the patient population likely to respond to immunotherapy. Understanding how melanoma evades natural or manipulated immune responses could provide the information needed to identify such resistant individuals. Efforts to address this challenge are hampered by the vast immune diversity characterizing tumor microenvironments that remain largely understudied. It is thus important to more clearly elucidate the complex interactions that take place between the tumor microenvironment and host immune system.


Assuntos
Melanoma , Humanos , Imunoterapia , Melanoma/terapia , Microambiente Tumoral
3.
Clin Plast Surg ; 48(4): 631-642, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34503723

RESUMO

Malignant melanoma is the 5th most common cancer and stage IV melanoma accounts for approximately 4% of new melanoma diagnoses in the United States. The prognosis for regionally advanced disease is poor, but there have been numerous recent advances in the medical management of melanoma in-transit metastases. The goal of this paper is to review currently accepted treatment options for in-transit metastases and introduce emerging therapies. Therapies to be discussed include limb perfusion and infusion, immunotherapy, checkpoint inhibitors, and radiation therapy.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Imunoterapia , Melanoma/terapia , Neoplasias Cutâneas/terapia , Estados Unidos
4.
Clin Plast Surg ; 48(4): 699-705, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34503730

RESUMO

Rare variants of melanoma include melanoma in pregnancy and pediatric melanoma. Because of their low incidence, treatment recommendations are based on standards of treatment for cutaneous melanoma; however, each of these forms requires specific considerations during diagnosis, staging, and treatment.


Assuntos
Melanoma , Pediatria , Neoplasias Cutâneas , Criança , Feminino , Humanos , Incidência , Melanoma/diagnóstico , Melanoma/epidemiologia , Melanoma/terapia , Estadiamento de Neoplasias , Gravidez , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/cirurgia
5.
Clin Plast Surg ; 48(4): 707-711, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34503731

RESUMO

Mucosal melanoma is a rare but aggressive cancer arising in mucosal surfaces most commonly in the head and neck. The clinical presentation is often nonspecific and differs in relation to the site of origin so often diagnosis is delayed resulting in poor prognosis. Mucosal melanoma has a 5-year survival of only 25%. Surgery with negative margins is the mainstay of treatment but dependent on several variables including anatomic location, involved structures, and size of tumor. Although not well defined given the rarity of mucosal melanoma, there is a role for radiation and systemic therapy in the treatment of this disease.


Assuntos
Neoplasias de Cabeça e Pescoço , Melanoma , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Melanoma/diagnóstico , Melanoma/terapia , Membrana Mucosa , Prognóstico
6.
Clin Plast Surg ; 48(4): 713-733, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34503732

RESUMO

Great strides in immunotherapy and targeted therapy have revolutionized the management of previously devastating, advanced melanomas. Although these subfields continue to progress, novel approaches in intratumoral oncolytic therapy, adoptive cell therapy, and vaccine therapies are being developed as adjuncts or alternatives. Cytokines, meanwhile, are seeing a resurgence as a viable option as well. The array of effective agents will, in the next few years, provide options for therapy not only in the adjuvant or unresectable settings but also in the neoadjuvant settings. Perhaps, too, in earlier stage melanomas.


Assuntos
Melanoma , Humanos , Imunoterapia , Melanoma/terapia , Terapia Neoadjuvante
7.
J Transl Med ; 19(1): 381, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496872

RESUMO

BACKGROUND: Tumor-derived exosomes (TEXs) are involved in tumor progression and the immune modulation process and mediate intercellular communication in the tumor microenvironment. Although exosomes are considered promising liquid biomarkers for disease diagnosis, it is difficult to discriminate TEXs and to develop TEX-based predictive biomarkers. METHODS: In this study, the gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) database, IMvigor210 cohorts, and six independent Gene Expression Omnibus datasets. A TEXs-associated signature named TEXscore was established to predict overall survival in multiple cancer types and in patients undergoing immune checkpoint blockade therapies. RESULTS: Based on exosome-associated genes, we first constructed a tumor-derived exosome signature named TEXscore using a principal component analysis algorithm. In single-cell RNA-sequencing data analysis, ascending TEXscore was associated with disease progression and poor clinical outcomes. In the TCGA Pan-Cancer cohort, TEXscore was elevated in tumor samples rather than in normal tissues, thereby serving as a reliable biomarker to distinguish cancer from non-cancer sources. Moreover, high TEXscore was associated with shorter overall survival across 12 cancer types. TEXscore showed great potential in predicting immunotherapy response in melanoma, urothelial cancer, and renal cancer. The immunosuppressive microenvironment characterized by macrophages, cancer-associated fibroblasts, and myeloid-derived suppressor cells was associated with high TEXscore in the TCGA and immunotherapy cohorts. Besides, TEXscore-associated miRNAs and gene mutations were also identified. Further experimental research will facilitate the extending of TEXscore in tumor-associated exosomes. CONCLUSIONS: TEXscore capturing tumor-derived exosome features might be a robust biomarker for prognosis and treatment responses in independent cohorts.


Assuntos
Exossomos , Melanoma , Biomarcadores Tumorais/genética , Humanos , Imunoterapia , Melanoma/genética , Melanoma/terapia , Prognóstico , Análise de Célula Única , Microambiente Tumoral
8.
J Immunol ; 207(5): 1468-1477, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34408009

RESUMO

Immuno-positron emission tomography (PET), a noninvasive imaging modality, can provide a dynamic approach for longitudinal assessment of cell populations of interest. Transformation of mAbs into single-chain variable fragment (scFv)-based PET imaging agents would allow noninvasive tracking in vivo of a wide range of possible targets. We used sortase-mediated enzymatic labeling in combination with PEGylation to develop an anti-mouse CD4 scFv-based PET imaging agent constructed from an anti-mouse CD4 mAb. This anti-CD4 scFv can monitor the in vivo distribution of CD4+ T cells by immuno-PET. We tracked CD4+ and CD8+ T cells in wild-type mice, in immunodeficient recipients reconstituted with monoclonal populations of OT-II and OT-I T cells, and in a B16 melanoma model. Anti-CD4 and -CD8 immuno-PET showed that the persistence of both CD4+ and CD8+ T cells transferred into immunodeficient mice improved when recipients were immunized with OVA in CFA. In tumor-bearing animals, infiltration of both CD4+ and CD8+ T cells increased as the tumor grew. The approach described in this study should be readily applicable to convert clinically useful Abs into the corresponding scFv PET imaging agents.


Assuntos
Antígenos CD4/imunologia , Linfócitos T CD4-Positivos/imunologia , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Melanoma/terapia , Monitorização Imunológica/métodos , Neoplasias Cutâneas/terapia , Animais , Anticorpos Monoclonais/metabolismo , Diagnóstico por Imagem , Feminino , Memória Imunológica , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tomografia por Emissão de Pósitrons , Anticorpos de Cadeia Única/metabolismo
9.
Klin Monbl Augenheilkd ; 238(7): 761-772, 2021 Jul.
Artigo em Inglês, Alemão | MEDLINE | ID: mdl-34376006

RESUMO

BACKGROUND: Uveal melanoma is a rare intraocular tumour, for which there is currently no national evidence-based guideline in Germany. The aim of this project was to provide a common standard operating procedure (SOP) for the diagnosis, treatment and follow-up care of uveal melanoma, within the network of German leading oncology centres funded by German Cancer Aid. The SOP was created as part of a moderated consensus process. RESULTS AND CONCLUSION: In a multistage process, a common SOP was developed for the diagnosis, therapy and follow-up of uveal melanoma, as based on current knowledge of the subject.


Assuntos
Melanoma , Neoplasias Uveais , Assistência ao Convalescente , Alemanha , Humanos , Melanoma/diagnóstico , Melanoma/terapia , Neoplasias Uveais/diagnóstico , Neoplasias Uveais/epidemiologia , Neoplasias Uveais/terapia
10.
Nutrients ; 13(7)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34371857

RESUMO

The conjugated linoleic acid (CLA) diene is a biologically active compound with proven health-promoting effects. In terms of anticancer properties, it has been shown that CLA reduces the proliferation of cancer cells. In this study, it has been demonstrated that a mixture of fatty acids, isolated from chicken egg yolk enriched in CLA isomers by biofortification, reduces (by 30.5%) the proliferation of human melanoma cancer cells line WM793 to a greater extent than a mixture of fatty acids not containing these isomers. At the same time, the tested fatty acid mixtures show no effect on human normal BJ fibroblast cells. For the first time, the genes with increased expression have been identified and the proteins have been activated by the fatty acid mixture of CLA-enriched egg yolk, mainly responsible for mitochondrial pathway-dependent apoptosis.


Assuntos
Antineoplásicos/farmacologia , Gema de Ovo/química , Ácidos Graxos/farmacologia , Alimentos Fortificados , Ácidos Linoleicos Conjugados/farmacologia , Melanoma/terapia , Animais , Apoptose/efeitos dos fármacos , Biofortificação , Linhagem Celular Tumoral , Galinhas , Misturas Complexas , Feminino , Fibroblastos , Humanos , Transdução de Sinais/efeitos dos fármacos
11.
R I Med J (2013) ; 104(7): 42-45, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34437665

RESUMO

We report a 73-year-old male with recurrent amelanotic malignant melanoma of the left foot with in-transit metastases to the left thigh. In-transit metastatic melanoma can often represent a diagnostic and therapeutic challenge for physicians. This patient was treated with talimogene laherparepvec injections (T-VEC; Imlygic) in the left inguinal and the left plantar region every two weeks for one year as oncolytic viral therapy for advanced non- operable malignant melanoma. He then received consistent follow-up including blood work and PET scans every four months, and he also required further lymph node surgical dissection. To date, our patient has survived 3 years and 11 months, which is 27 months longer than the esti- mated median survival of 1 year 8 months for patients diagnosed with in-transit metastatic melanoma.


Assuntos
Melanoma , Terapia Viral Oncolítica , Neoplasias Cutâneas , Idoso , Humanos , Masculino , Melanoma/terapia , Neoplasias Cutâneas/terapia
12.
Int J Mol Sci ; 22(13)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34281259

RESUMO

Therapy targeting immune checkpoints represents an integral part of the treatment for patients suffering from advanced melanoma. However, the mechanisms of resistance are responsible for a lower therapeutic outcome than expected. Concerning melanoma, insufficient stimulation of the immune system by tumour neoantigens is a likely explanation. As shown previously, radiotherapy is a known option for increasing the production of tumour neoantigens and their release into the microenvironment. Consequently, neoantigens could be recognized by antigen presenting cells (APCs) and subjected to effector T lymphocytes. Enhancing the immune reaction can trigger the therapeutic response also at distant metastases, a phenomenon known as an abscopal effect (from "ab scopus", that is, away from the target). To illustrate this, we present the case of a 78-year old male treated by anti-CTLA-4/ipilimumab for metastatic melanoma. The patient received the standard four doses of ipilimumab administered every three weeks. However, the control CT scans detected disease progression in the form of axillary lymph nodes metastasis and liver metastasis two months after ipilimumab. At this stage, palliative cryotherapy of the skin metastases was initiated to alleviate the tumour burden. Surprisingly, the effect of cryotherapy was also observed in untreated metastases and deep subcutaneous metastases on the back. Moreover, we observed the disease remission of axillary lymph nodes and liver metastasis two months after the cryotherapy. The rarity of the abscopal effect suggests that even primed anti-tumour CD8+ T cells cannot overcome the tumour microenvironment's suppressive effect and execute immune clearance. However, the biological mechanism underlying this phenomenon is yet to be elucidated. The elicitation of a systemic response by cryotherapy with documented abscopal effect was rarely reported, although the immune response induction is presumably similar to a radiotherapy-induced one. The report is a combination case study and review of the abscopal effect in melanoma treated with checkpoint inhibitors.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Ipilimumab/uso terapêutico , Melanoma/secundário , Melanoma/terapia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Idoso , Células Apresentadoras de Antígenos/imunologia , Antígenos de Neoplasias/metabolismo , Crioterapia , Humanos , Masculino , Melanoma/imunologia , Modelos Imunológicos , Cuidados Paliativos , Neoplasias Cutâneas/imunologia , Resultado do Tratamento , Microambiente Tumoral/imunologia
13.
Ann Acad Med Singap ; 50(6): 456-466, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34195752

RESUMO

INTRODUCTION: Melanomas in Asians have different clinicopathological characteristics and prognosis from melanomas in Caucasians. This study reviewed the epidemiology and treatment outcomes of cutaneous melanoma diagnosed at a tertiary referral dermatology centre in Singapore, which has a multiracial population. The study also determined whether Asians had comparable relapse-free and overall survival periods to Caucasians in Singapore. METHOD: This is a retrospective review of cutaneous melanoma cases in our centre between 1996 and 2015. RESULTS: Sixty-two cases of melanoma were diagnosed in 61 patients: 72.6% occurred in Chinese, 19.4% in Caucasians and 3.2% in Indians, with an over-representation of Caucasians. Superficial spreading melanoma, acral lentiginous melanoma and nodular melanoma comprised 37.1%, 35.5% and 22.6% of the cases, respectively. The median time interval to diagnosis was longer in Asians than Caucasians; median Breslow's thickness in Asians were significantly thicker than in Caucasians (2.6mm versus 0.9mm, P=0.018) and Asians tend to present at a later stage. The mortality rates for Asians and Caucasians were 52% and 0%, respectively. CONCLUSION: More physician and patient education on skin cancer awareness is needed in our Asian-predominant population for better outcomes.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/epidemiologia , Melanoma/terapia , Prognóstico , Estudos Retrospectivos , Singapura/epidemiologia , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/terapia , Resultado do Tratamento
14.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299373

RESUMO

Melanoma is the deadliest type of skin cancer, due to its invasiveness and limited treatment efficacy. The main therapy for primary melanoma and solitary organ metastases is wide excision. Adjuvant therapy, such as chemotherapy and targeted therapies are mainly used for disseminated disease. Radiotherapy (RT) is a powerful treatment option used in more than 50% of cancer patients, however, conventional RT alone is unable to eradicate melanoma. Its general radioresistance is attributed to overexpression of repair genes in combination with cascades of biochemical repair mechanisms. A novel sophisticated technique based on synchrotron-generated, spatially fractionated RT, called Microbeam Radiation Therapy (MRT), has been shown to overcome these treatment limitations by allowing increased dose delivery. With MRT, a collimator subdivides the homogeneous radiation field into an array of co-planar, high-dose microbeams that are tens of micrometres wide and spaced a few hundred micrometres apart. Different preclinical models demonstrated that MRT has the potential to completely ablate tumours, or significantly improve tumour control while dramatically reducing normal tissue toxicity. Here, we discuss the role of conventional RT-induced immunity and the potential for MRT to enhance local and systemic anti-tumour immune responses. Comparative gene expression analysis from preclinical tumour models indicated a specific gene signature for an 'MRT-induced immune effect'. This focused review highlights the potential of MRT to overcome the inherent radioresistance of melanoma which could be further enhanced for future clinical use with combined treatment strategies, in particular, immunotherapy.


Assuntos
Melanoma/radioterapia , Animais , Terapia Combinada/métodos , Humanos , Imunidade/imunologia , Imunoterapia/métodos , Melanoma/imunologia , Melanoma/terapia , Radioterapia/métodos , Síncrotrons
15.
J Immunother Cancer ; 9(7)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34272309

RESUMO

The clinical and immunologic implications of the SARS-CoV-2 pandemic for patients with cancer receiving systemic anticancer therapy have introduced a multitude of clinical challenges and academic controversies. This review summarizes the current evidence, discussion points, and recommendations regarding the use of immune checkpoint inhibitors (ICIs) in patients with cancer during the SARS-CoV-2 pandemic, with a focus on patients with melanoma and renal cell carcinoma (RCC). More specifically, we summarize the theoretical concepts and available objective data regarding the relationships between ICIs and the antiviral immune response, along with recommended clinical approaches to the management of melanoma and RCC patient cohorts receiving ICIs throughout the course of the COVID-19 pandemic. Additional insights regarding the use of ICIs in the setting of current and upcoming COVID-19 vaccines and broader implications toward future pandemics are also discussed.


Assuntos
COVID-19/imunologia , Carcinoma de Células Renais/imunologia , Inibidores de Checkpoint Imunológico/imunologia , Neoplasias Renais/imunologia , Melanoma/imunologia , SARS-CoV-2/imunologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/uso terapêutico , Carcinoma de Células Renais/terapia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Neoplasias Renais/terapia , Melanoma/terapia , Pandemias/prevenção & controle , SARS-CoV-2/efeitos dos fármacos
16.
Nat Commun ; 12(1): 4098, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215730

RESUMO

Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. We hypothesized that the T cell receptor (TCR) repertoire of tumor infiltrating T lymphocytes could therefore be indicative of the functional state of these cells and determine disease course at different stages in cancer progression. Here we show that the diversity of the TCR of tumor infiltrating T cell at baseline is prognostic in various cancers, whereas the TCR clonality of T cell infiltrating metastatic melanoma pre-treatment is predictive for activity and efficacy of PD1 blockade immunotherapy.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Receptores de Antígenos de Linfócitos T , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Biópsia , Estudos de Coortes , Feminino , Humanos , Imunoterapia , Masculino , Melanoma/patologia , Melanoma/terapia , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Taxa de Sobrevida
17.
J Transl Med ; 19(1): 296, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238310

RESUMO

BACKGROUND: Immunotherapy is a revolutionary strategy in cancer therapy, but the resistance of which is one of the important challenges. Detecting the regulation of immune cells and biomarkers concerning immune checkpoint blockade (ICB) therapy is of great significance. METHODS: Here, we firstly constructed regulation networks for 11 immune cell clusters by integrating biological pathway data and single cell sequencing data in metastatic melanoma with or without ICB therapy. We then dissected these regulation networks and identified differently expressed genes between responders and non-responders. Finally, we trained and validated a logistic regression model based on ligands and receptors in the regulation network to predict ICB therapy response. RESULTS: We discovered the regulation of genes across eleven immune cell stats. Functional analysis indicated that these stat-specific networks consensually enriched in immune response corrected pathways and highlighted antigen processing and presentation as a core pathway in immune cell regulation. Furthermore, some famous ligands like SIRPA, ITGAM, CD247and receptors like CD14, IL2 and HLA-G were differently expressed between cells of responders and non-responders. A predictive model of gene sets containing ligands and receptors performed accuracy prediction with AUCs above 0.7 in a validation dataset suggesting that they may be server as biomarkers for predicting immunotherapy response. CONCLUSIONS: In summary, our study presented the gene-gene regulation landscape across 11 immune cell clusters and analysis of these networks revealed several important aspects and immunotherapy response biomarkers, which may provide novel insights into immune related mechanisms and immunotherapy response prediction.


Assuntos
Biomarcadores Tumorais , Melanoma , Biomarcadores Tumorais/genética , Humanos , Imunoterapia , Melanoma/genética , Melanoma/terapia
18.
Molecules ; 26(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199757

RESUMO

The innovative strategy of using nanoparticles in radiotherapy has become an exciting topic due to the possibility of simultaneously improving local efficiency of radiation in tumors and real-time monitoring of the delivered doses. Yttrium oxide (Y2O3) nanoparticles (NPs) are used in material science to prepare phosphors for various applications including X-ray induced photodynamic therapy and in situ nano-dosimetry, but few available reports only addressed the effect induced in cells by combined exposure to different doses of superficial X-ray radiation and nanoparticles. Herein, we analyzed changes induced in melanoma cells by exposure to different doses of X-ray radiation and various concentrations of Y2O3 NPs. By evaluation of cell mitochondrial activity and production of intracellular reactive oxygen species (ROS), we estimated that 2, 4, and 6 Gy X-ray radiation doses are visibly altering the cells by inducing ROS production with increasing the dose while at 6 Gy the mitochondrial activity is also affected. Separately, high-concentrated solutions of 25, 50, and 100 µg/mL Y2O3 NPs were also found to affect the cells by inducing ROS production with the increase of concentration. Additionally, the colony-forming units assay evidenced a rather synergic effect of NPs and radiation. By adding the NPs to cells before irradiation, a decrease of the number of proliferating cell colonies was observed with increase of X-ray dose. DNA damage was evidenced by quantifying the γ-H2AX foci for cells treated with Y2O3 NPs and exposed to superficial X-ray radiation. Proteomic profile confirmed that a combined effect of 50 µg/mL Y2O3 NPs and 6 Gy X-ray dose induced mitochondria alterations and DNA changes in melanoma cells.


Assuntos
Melanoma/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ítrio/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Humanos , Melanoma/terapia , Mitocôndrias/efeitos dos fármacos , Nanopartículas , Tamanho da Partícula , Fotoquimioterapia , Proteômica
19.
J Mater Chem B ; 9(23): 4710-4717, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34076029

RESUMO

Locoregional drug delivery has emerged as a promising solution to the problems associated with intravenously administered antitumor agents, such as systemic toxicity and insufficient drug accumulation at tumor sites. Herein, we have developed an adhesive nanoparticle (NP)-based drug delivery system, using natural bioadhesive tannic acid (TA) and metal ions (Fe3+), for locoregional photothermal and antiangiogenic synergistic cancer therapy. In this study, a new near-infrared (NIR) photothermal agent indocyanine green (IR820) and an antiangiogenic agent sorafenib (SRF) were co-encapsulated in a TA-Fe complex (SIF@TA-Fe). The SIF@TA-Fe NPs exhibited super adhesion, antiangiogenesis, and efficient cellular uptake. Moreover, SIF@TA-Fe NPs showed a synergistic antitumor effect in vivo, including high tumor inhibition rate, excellent survival extension, and low risk of recurrence, resulting from the prolonged retention of the NPs in the tumor. Thus, this adhesive SIF@TA-Fe NP-based therapeutic system provides a promising approach for locoregional drug delivery of combined cancer therapy.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Melanoma/terapia , Metais/química , Nanopartículas/química , Fenóis/química , Fototerapia/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/farmacologia , Adesão Celular/efeitos dos fármacos , Terapia Combinada , Sistemas de Liberação de Medicamentos/métodos , Células Endoteliais da Veia Umbilical Humana , Humanos , Melanoma/tratamento farmacológico , Camundongos
20.
Theranostics ; 11(14): 6936-6949, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093863

RESUMO

Substantial progress has been made with cancer immunotherapeutic strategies in recent years, most of which mainly rely on enhancing the T cell response. However, sufficient tumor antigen information often cannot be presented to T cells, resulting in a failed effector T cell response. The innate immune system can effectively recognize tumor antigens and then initiate an adaptive immune response. Here, we developed a spontaneous multifunctional hydrogel (NOCC-CpG/OX-M, Ncom Gel) vaccine to amplify the innate immune response and harness innate immunity to launch and maintain a powerful adaptive immune response. Methods: Ncom Gel was formed by a Schiff base reaction between CpG-modified carboxymethyl chitosan (NOCC-CpG) and partially oxidized mannan (OX-M). The effects of the Ncom Gel vaccine on DCs and macrophages in vitro and antigen-specific humoral immunity and cellular immunity in vivo were studied. Furthermore, the antitumor immune response of the Ncom Gel vaccine and its effect on the tumor microenvironment were evaluated. Results: The Ncom Gel vaccine enhanced antigen presentation to T cells by facilitating DC uptake and maturation and inducing macrophages to a proinflammatory subtype, further leading to a T cell-mediated adaptive immune response. Moreover, the innate immune response could be amplified via the promotion of antigen-specific antibody production. The Ncom Gel vaccine reversed the tumor immune microenvironment to an inflamed phenotype and showed a significant antitumor response in a melanoma model. Conclusions: Our research implies the potential application of injectable hydrogels as a platform for tumor immunotherapy. The strategy also opens up a new avenue for multilayered cancer immunotherapy.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Vacinas Anticâncer/imunologia , Hidrogéis/química , Hidrogéis/farmacologia , Imunidade Inata/efeitos dos fármacos , Imunoterapia/métodos , Melanoma/imunologia , Microambiente Tumoral/efeitos dos fármacos , Imunidade Adaptativa/imunologia , Animais , Linhagem Celular Tumoral , Quitosana/química , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Hidrogéis/síntese química , Inflamação/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Mananas/química , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Ovalbumina/imunologia , Reologia , Bases de Schiff/química , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
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