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1.
Clin. transl. oncol. (Print) ; 24(10): 1903–1913, octubre 2022. ilus
Artigo em Inglês | IBECS | ID: ibc-207946

RESUMO

Introduction: Immunotherapy is an effective treatment method for cancer cells with humoral and cellular immune mechanisms of action but triggers an inflammatory response and disrupts standard protective immune tolerance. Early detection of immune-related adverse events (irAEs) on PET/CT is crucial for patient management and subsequent therapy decisions. In this study, we aimed to evaluate the impact of 18F-FDG PET/CT on detecting of irAEs in patients receiving immunotherapy.Patients and methodsForty-six patients with advanced RCC (n: 32), malign melanoma (n: 9), lung cancer (n: 4), and laryngeal carcinoma (n: 1), who underwent 18F-FDG PET/CT imaging for response assessment after immunotherapy, were enrolled in the study. Newly detected findings associated with irAEs on posttreatment PET/CT images were compared with the pretreatment PET/CT, both qualitatively and semi-quantitatively.ResultsTwenty-eight (61%) patients developed irAEs as observed on PET/CT. Enteritis/colitis was the most frequent irAE visualized on PET/CT with 13 patients (28.2%), followed by gastritis (17.3%), thyroiditis (13%), and myositis/arthritis (13%). Hepatitis (6.5%), pneumonitis (6.5%), sarcoid-like reaction (4.3%), and hypophysitis (4.3%) were observed to a lesser extent. The median time between the appearance of irAEs on PET/CT and the initiation of immunotherapy was 4.3 months. There were no significant differences in age, sex, and treatment response status of patients with and without irAEs.Conclusion18F-FDG PET/CT plays a fundamental role in cancer immunotherapy with the potential to show significant irAEs both in the diagnosis and in follow-up of irAEs. IrAEs were present on PET/CT images of more than half of the patients who received immunotherapy in our study. (AU)


Assuntos
Humanos , Fluordesoxiglucose F18 , Imunoterapia , Melanoma , Tomografia por Emissão de Pósitrons , Pacientes , Estudos Retrospectivos
2.
Clin. transl. oncol. (Print) ; 24(10): 2010–2020, octubre 2022. tab, graf
Artigo em Inglês | IBECS | ID: ibc-207956

RESUMO

Purpose: Immune Checkpoint Inhibitors (ICI) can be associated with thrombotic events, both venous and arterial (VTE/AT). However, there is a paucity of information regarding patients in routine clinical practice.Methods/patientsRetrospective, multicenter study promoted by the Thrombosis and Cancer Section of the Spanish Society of Medical Oncology (SEOM). Patients with melanoma and lung cancer who initiated ICI between 01/01/2015 and 31/12/2019 were recruited. Minimum follow-up was 6 months (unless it was not possible because of death). The primary objective was to calculate the incidence of ICI-associated VTE/AT and the secondary objectives included to analyze its impact on survival and to identify predictor variables for VTE/AT.Results665 patients with lung cancer were enrolled. The incidence of VTE/AT during follow-up was 8.4%. Median overall survival (OS) was lower in the VTE/AT group (12 months 95% CI 4.84–19.16 vs. 19 months 95% CI 16.11–21.9; p = 0.0049). Neutrophil/lymphocyte ratio (NLR) and anemia upon initiation of IT, as well as a history of thrombosis between cancer diagnosis and the start of ICI, were predictive variables for developing of VTE/AT (p < 0.05). 291 patients with melanoma were enrolled. There was a 5.8% incidence rate of VTE/AT during follow-up. Median OS was lower in the VTE/AT group (10 months 95% CI 0.0–20.27 vs. 29 months 95% CI 19.58–36.42; p = 0.034). NLR and lactate dehydrogenase (LDH) at the beginning of ICI were predictor variables for VTE/AT (p < 0.05).ConclusionsICI increases the risk of VTE/AT in patients with lung cancer and melanoma, which impact OS. (AU)


Assuntos
Humanos , Neoplasias Pulmonares , Oncologia , Melanoma , Trombose , Tromboembolia Venosa , Prognóstico , Estudos Retrospectivos
3.
J Transl Med ; 20(1): 391, 2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36058945

RESUMO

Advances in immune checkpoint and combination therapy have led to improvement in overall survival for patients with advanced melanoma. Improved understanding of the tumor, tumor microenvironment and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. Combination modalities with other immunotherapy agents, chemotherapy, radiotherapy, electrochemotherapy are also being explored to overcome resistance and to potentiate the immune response. In addition, novel approaches such as adoptive cell therapy, oncogenic viruses, vaccines and different strategies of drug administration including sequential, or combination treatment are being tested. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic theràapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers, but they have yet to be fully characterized and implemented clinically. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. Overall, the future research efforts in melanoma therapeutics and translational research should focus on several aspects including: (a) developing robust biomarkers to predict efficacy of therapeutic modalities to guide clinical decision-making and optimize treatment regimens, (b) identifying mechanisms of therapeutic resistance to immune checkpoint inhibitors that are potentially actionable, (c) identifying biomarkers to predict therapy-induced adverse events, and (d) studying mechanism of actions of therapeutic agents and developing algorithms to optimize combination treatments. During the Melanoma Bridge meeting (December 2nd-4th, 2021, Naples, Italy) discussions focused on the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine as well as the impact of COVID-19 pandemic on management of melanoma patients.


Assuntos
COVID-19 , Melanoma , Biomarcadores , Humanos , Imunoterapia/métodos , Itália , Melanoma/genética , Pandemias , Microambiente Tumoral
4.
J Transl Med ; 20(1): 403, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064556

RESUMO

BACKGROUND: The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood. OBJECTIVE: To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. METHODS: We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P < 5 × 10-8) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts. RESULTS: Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61-2.71, P = 2.08 × 10-8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77-3.21, P = 1.07 × 10-8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83-0.94, P = 6.93 × 10-5; I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78-0.90). CONCLUSION: We found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting.


Assuntos
Melanoma , Neoplasias Cutâneas , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Melanoma/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Cutâneas/genética , Raios Ultravioleta
5.
Commun Biol ; 5(1): 917, 2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068291

RESUMO

Pyroptosis, as a proinflammatory form of regulated cell death, plays an important role in multiple cancers. However, the diagnostic and prognostic values of pyroptosis and its interaction with tumor immunity in pan-cancer are still unclear. Here, we show an elevated general expression of 17 pyroptosis-associated genes of tumor patients with high-immune-activity and a reduced pyroptosis in low-immune-activity tumors. Moreover, pyroptosis is positively correlated with immune infiltration and immune-related signatures across 30 types of cancer. Furthermore, our experimental data suggest that pyroptosis directly modulate the expression of immune checkpoint molecules and cytokines. We generate a pyroptosis score model as a potential independent prognostic indicator in melanoma patients. Interestingly, 3 of pyroptosis-associated genes including CASP1, CASP4 and PYCARD, can predict the effectiveness of anti-PD-1 immunotherapy for patients with melanoma. Our study demonstrates that pyroptosis correlates with tumor immunity and prognosis, might be used as a potential target for immune therapy.


Assuntos
Melanoma , Piroptose , Citocinas/metabolismo , Humanos , Melanoma/genética , Prognóstico
6.
Sci Transl Med ; 14(661): eaax8933, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36070364

RESUMO

Brain metastasis is a complication of increasing incidence in patients with breast cancer at advanced disease stage. It is a severe condition characterized by a rapid decline in quality of life and poor prognosis. There is a critical clinical need to develop effective therapies to prevent and treat brain metastases. Here, we describe a unique and robust spontaneous preclinical model of breast cancer metastasis to the brain (4T1-BM2) in mice that has been instrumental in uncovering molecular mechanisms guiding metastatic dissemination and colonization of the brain. Key experimental findings were validated in the additional murine D2A1-BM2 model and in human MDA231-BrM2 model. Gene expression analyses and functional studies, coupled with clinical transcriptomic and histopathological investigations, identified connexins (Cxs) and focal adhesion kinase (FAK) as master molecules orchestrating breast cancer colonization of the brain. Cx31 promoted homotypic tumor cell adhesion, heterotypic tumor-astrocyte interaction, and FAK phosphorylation. FAK signaling prompted NF-κB activation inducing Lamc2 expression and laminin 332 (laminin 5) deposition, α6 integrin-mediated adhesion, and sustained survival and growth within brain parenchyma. In the MDA231-BrM2 model, the human homologous molecules CX43, LAMA4, and α3 integrin were involved. Systemic treatment with FAK inhibitors reduced brain metastasis progression. In conclusion, we report a spontaneous model of breast cancer metastasis to the brain and identified Cx-mediated FAK-NF-κB signaling as a mechanism promoting cell-autonomous and microenvironmentally controlled cell survival for brain colonization. Considering the limited therapeutic options for brain metastatic disease in cancer patients, we propose FAK as a therapeutic candidate to further pursue in the clinic.


Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Animais , Encéfalo/metabolismo , Neoplasias da Mama/genética , Conexinas/metabolismo , Feminino , Proteína-Tirosina Quinases de Adesão Focal/genética , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Melanoma , Camundongos , NF-kappa B/metabolismo , Qualidade de Vida , Neoplasias Cutâneas
7.
World J Surg Oncol ; 20(1): 287, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071438

RESUMO

BACKGROUND: Primary melanoma of the bladder is extremely rare and has been sporadically reported in case reports. Its incidence, diagnosis, treatment, and outcomes are still unclear. CASE PRESENTATION: We report a 67-year-old female patient who presented with hematuria and was diagnosed with primary melanoma of the bladder by transurethral resection. No distant metastasis was detected by fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT). After a multidisciplinary discussion, the patient received laparoscopic radical resection of the bladder tumor. There was no tumor recurrence or distant metastasis after 15 months of follow-up. CONCLUSION: Primary melanoma of the bladder is easily confused with urothelium carcinoma in morphology. The immunohistochemical is crucial in diagnosis. Because of a lack of in-depth understanding of primary melanoma of the bladder, the "gold standard" treatment has not been set. We would like to provide some rare information about it and discuss the proper treatment strategy for this rare disease.


Assuntos
Melanoma , Neoplasias da Bexiga Urinária , Idoso , Feminino , Humanos , Melanoma/patologia , Melanoma/cirurgia , Recidiva Local de Neoplasia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/patologia
8.
Biomed Res Int ; 2022: 4864485, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072469

RESUMO

Introduction: The purpose of this study is to use deep learning and machine learning to learn and classify patients with cutaneous melanoma with different prognoses and to explore the application value of deep learning in the prognosis of cutaneous melanoma patients. Methods: In deep learning, VGG-19 is selected as the network architecture and learning model for learning and classification. In machine learning, deep features are extracted through the VGG-19 network architecture, and the support vector machine (SVM) model is selected for learning and classification. Compare and explore the application value of deep learning and machine learning in predicting the prognosis of patients with cutaneous melanoma. Result: According to receiver operating characteristic (ROC) curves and area under the curve (AUC), the average accuracy of deep learning is higher than that of machine learning, and even the lowest accuracy is better than that of machine learning. Conclusion: As the number of learning increases, the accuracy of machine learning and deep learning will increase, but in the same number of cutaneous melanoma patient pathology maps, the accuracy of deep learning will be higher. This study provides new ideas and theories for computational pathology in predicting the prognosis of patients with cutaneous melanoma.


Assuntos
Aprendizado Profundo , Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/diagnóstico por imagem , Melanoma/patologia , Prognóstico , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/patologia
9.
Comput Intell Neurosci ; 2022: 6138490, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072725

RESUMO

One of the most prevalent diseases that can be initially identified by visual inspection and further identified with the use of dermoscopic examination and other testing is skin cancer. Since eye observation provides the earliest opportunity for artificial intelligence to intercept various skin images, some skin lesion classification algorithms based on deep learning and annotated skin photos display improved outcomes. The researcher used a variety of strategies and methods to identify and stop diseases earlier. All of them yield positive results for identifying and categorizing diseases, but proper disease categorization is still lacking. Computer-aided diagnosis is one of the most crucial methods for more accurate disease detection, although it is rarely used in dermatology. For Feature Extraction, we introduced Spectral Centroid Magnitude (SCM). The given dataset is classified using an enhanced convolutional neural network; the first stage of preprocessing uses a median filter, and the final stage compares the accuracy results to the current method.


Assuntos
Melanoma , Dermatopatias , Inteligência Artificial , Dermoscopia/métodos , Humanos , Melanoma/patologia , Pele/patologia
10.
Orv Hetil ; 163(36): 1422-1429, 2022 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-36057871

RESUMO

INTRODUCTION: Photodynamic therapy is indicated for the treatment of superficial basal cell carcinoma, Bowen's disease and actinic keratosis. Reactive oxygen radicals are released from the metabolite of the topically applied photosensitizer that is excited by light, which selectively leads to the destruction of tumor cells. The procedure can be performed with an artificial light source or with the use of sunlight. The latter is called daylight photodynamic therapy, which is an effective and painless procedure. OBJECTIVE: Our aim was to introduce daylight photodynamic therapy in actinic keratoses at our department and to optimize the treatment protocol for the local climatic conditions. METHOD: Three clinical trials were performed. The difference between the treatment protocols was between the incubation time of the photosensitizer on the skin and in the time patients spent under the sunlight. RESULTS: When using the international treatment protocol, 73% of the actinic keratoses showed complete, while 27% partial remission. By reducing the proportion of time patients spent outdoor, complete remission was achieved in two-thirds and partial remission in one-third of the lesions. At doses above 100 J/cm², severe erythema was observed 24 hours after the treatment. To avoid this, we calculated the time to be spent outdoor by dosimetry. Partial remission was achieved in 15%, complete remission in 85% of the actinic keratoses with good tolerability. DISCUSSION: The stepwise modification of the treatment protocol resulted in an effective and well-tolerated treatment in actinic keratoses under the local climatic conditions. CONCLUSION: The method has been successfully adapted in our clinic and is used in daily practice to treat actinic keratoses. Orv Hetil. 2022; 163(36): 1422-1429.


Assuntos
Ceratose Actínica , Melanoma , Fotoquimioterapia , Neoplasias Cutâneas , Humanos , Ceratose Actínica/tratamento farmacológico , Ceratose Actínica/patologia , Melanoma/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Resultado do Tratamento
11.
Cell Physiol Biochem ; 56(5): 457-483, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36057984

RESUMO

BACKGROUND/AIMS: Hypertension is treated primarily with angiotensin II (ATII) receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors (ACEIs). Both ATII and ACEIs can trigger signal transduction via ACE, and a possible correlation between ARB/ACEI therapy and an increased risk of cancer is highly controversial. The question of whether or not ACE as a potential signal transducer affects human melanoma (MV3) cell behavior prompted the present study. METHODS: Expression of ACE, ATII receptor types 1, 2 (AT1R, AT2R), COX2 and MMP2 in MV3 cells was examined by qPCR. AT1R, AT2R and ACE were inhibited with losartan, EMA401 and lisinopril, respectively. Adhesion, migration and invasiveness of MV3 cells seeded on a hepatocyte (Huh7) monolayer or a reconstituted collagen type I matrix were analyzed using video microscopy and Boyden chambers. Integrity of the Huh7 cell layer was confirmed by measuring transepithelial electrical resistance (TEER). ERK1/2 phosphorylation and MMP2 secretion were evaluated by Western blotting. MMP2 activity was inhibited with ARP-100. RESULTS: Losartan, EMA401 and lisinopril stimulated MV3 melanoma cell migration and invasion in a coculture model with Huh7 cells while leaving proliferation and adhesion largely unaffected. The drugs did not interfere with TEER of the hepatocyte monolayer nor with MV3 cell proliferation, but tended to increase the phosphorylation of ERK1/2 and the expression of both COX2 and MMP2. Lisinopril caused a significant increase in MV3 cells' MMP2 secretion and an accelerated MV3 cell-mediated TEER breakdown. The MMP2 inhibitor ARP-100 could antagonize the lisinopril-stimulated invasion of the hepatocyte layer. CONCLUSION: Lisinopril stimulates MV3 cell invasion by increasing the expression and secretion of MMP2.


Assuntos
Lisinopril , Melanoma , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Ciclo-Oxigenase 2 , Humanos , Lisinopril/farmacologia , Losartan/farmacologia , Metaloproteinase 2 da Matriz , Melanoma/tratamento farmacológico , Melanoma/metabolismo
12.
Comput Math Methods Med ; 2022: 4261329, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36060650

RESUMO

Skin cutaneous melanoma (SKCM) is a common malignant skin cancer. Early diagnosis could effectively reduce SKCM patient's mortality to a large extent. We managed to construct a model to examine the prognosis of SKCM patients. The methylation-related data and clinical data of The Cancer Gene Atlas- (TCGA-) SKCM were downloaded from TCGA database. After preprocessing the methylation data, 21,861 prognosis-related methylated sites potentially associated with prognosis were obtained using the univariate Cox regression analysis and multivariate Cox regression analysis. Afterward, unsupervised clustering was used to divide the patients into 4 clusters, and weighted correlation network analysis (WGCNA) was applied to construct coexpression modules. By overlapping the CpG sites between the clusters and turquoise model, a prognostic model was established by LASSO Cox regression and multivariate Cox regression. It was found that 9 methylated sites included cg01447831, cg14845689, cg20895058, cg06506470, cg09558315, cg06373660, cg17737409, cg21577036, and cg22337438. After constructing the prognostic model, the performance of the model was validated by survival analysis and receiver operating characteristic (ROC) curve, and the independence of the model was verified by univariate and multivariate regression. It was represented that the prognostic model was reliable, and riskscore could be used as an independent prognostic factor in SKCM patients. At last, we combined clinical data and patient's riskscore to establish and testify the nomogram that could determine patient's prognosis. The results found that the reliability of the nomogram was relatively good. All in all, we constructed a prognostic model that could determine the prognosis of SKCM patients and screened 9 key methylated sites through analyzing data in TCGA-SKCM dataset. Finally, a prognostic nomogram was established combined with clinical diagnosed information and riskscore. The results are significant for improving the prognosis of SKCM patients in the future.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/genética , Metilação , Prognóstico , Reprodutibilidade dos Testes , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
13.
J Int Adv Otol ; 18(5): 455-458, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36063100

RESUMO

Mucosal melanoma originating from the eustachian tube is very rare, and only 15 cases were reported so far. In this study, we report a case of mucosal melanoma from the eustachian tube which was surgically managed, followed by chemoradiotherapy. A 53-year-old man presented with a history of recurrent idiopathic hemotympanum and a dark red mass in the nasopharynx protruding from the eustachian tube orifice. Under an impression of mucosal melanoma from the eustachian tube, en-bloc surgical removal was performed using the infratemporal fossa approach type C combined with a transnasal endoscopic approach followed by postoperative chemoradiotherapy. However, the disease progressed to lung metastasis, and the patient died of the disease at 13 months postoperatively. The presenting case showed a poor progression despite a margin-free surgical resection followed by chemoradiotherapy. Additional trial of new treatment options is necessary to improve the poor prognosis.


Assuntos
Neoplasias da Orelha , Tuba Auditiva , Melanoma , Neoplasias da Orelha/patologia , Neoplasias da Orelha/cirurgia , Endoscopia , Tuba Auditiva/cirurgia , Humanos , Masculino , Melanoma/patologia , Melanoma/radioterapia , Pessoa de Meia-Idade
14.
Dan Med J ; 69(9)2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-36065888

RESUMO

INTRODUCTION: The incidence of thin and early-stage melanoma is increasing in many populations, but the clinical significance of these lesions remains partly unknown. METHODS: Firstly, melanoma deaths in Denmark (2009-2018) were followed back to establish melanoma debut in these persons. Secondly, using national registries of cancer incidence and mortality, 27,036 persons with thin or early-stage melanoma were followed-up for melanoma death. RESULTS: It is estimated that in 11% of the persons who died from melanoma, the debut was a thin or early-stage melanoma. On follow-up of persons with thin or early-stage melanoma, the 20-year risk of dying from melanoma was 3%. CONCLUSION: The absolute risk of melanoma death after a diagnosis with thin or early-stage melanoma is low. A subgroup of patients who are at a high risk may possibly be identified by a combination of stage, thickness, ulceration and dermal mitoses. FUNDING: none. TRIAL REGISTRATION: not relevant.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Incidência , Sistema de Registros , Fatores de Risco , Neoplasias Cutâneas/patologia
17.
Dis Markers ; 2022: 1930185, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36046379

RESUMO

Uveal melanoma (UM) is an intraocular malignancy in adults in which approximately 50% of patients develop metastatic diseases and have a poor clinical outcome. Immunotherapies are quickly becoming a need, and recent research has produced some amazing achievements in this area. In the current investigation, an attempt was made to evaluate the prognostic usefulness of KDELR3 in UM, particularly its connection with tumor-infiltrating lymphocytes (TILs). The expression patterns of mRNAs and related clinical data of 80 UM patients were obtained from The Cancer Genome Atlas (TCGA). By using RT-PCR, we were able to investigate whether or not UM cells and D78 cells expressed KDELR3. The Kaplan-Meier approach, as well as univariate and multivariate tests, was utilized in order to investigate the potential predictive significance of KDELR3 expression. The associations between KDELR3 and TILs and immunological checkpoints were analyzed in order to evaluate the effect that KDELR3 may have on UM immunotherapy. On the basis of the differential expression of KDELR3, a distribution of the half-maximal inhibitory concentration (IC50) of various targeted medicines was observed. In this study, we found that the expression of KDELR3 was distinctly increased in most types of tumors. In addition, KDELR3 was highly expressed in UM cells. Moreover, patients with high KDELR3 expression exhibited a shorter overall survival and disease-free survival than those with low KDELR3 expression. Multivariate analyses confirmed that KDELR3 expression was an independent prognostic factor for overall survival and disease-free survival in patients with UM. Furthermore, KDELR3 expression was demonstrated to be positively correlated with macrophage M1, T cell CD8, T cell follicular helper, dendritic cell resting, and T cell CD4 memory activated. Meanwhile, the expression of KDELR3 was related to several immune checkpoints. The IC50 of AP-24534, BHG712, bleomycin, camptothecin, cisplatin, cytarabine, GSK1070916, and tipifarnib was higher in the KDELR3 high-expression group. In conclusion, KDELR3 may be applied as a potential diagnostic and prognostic biomarker for UM patients.


Assuntos
Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Adulto , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Melanoma , Prognóstico , Neoplasias Uveais
18.
Int J Mol Sci ; 23(17)2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36076924

RESUMO

Nearly 100,000 individuals are expected to be diagnosed with melanoma in the United States in 2022. Treatment options for late-stage metastatic disease up until the 2010s were few and offered only slight improvement to the overall survival. The introduction of B-RAF inhibitors and anti-CTLA4 and anti-PD-1/PD-L1 immunotherapies into standard of care brought measurable increases in the overall survival across all stages of melanoma. Despite the improvement in the survival statistics, patients treated with targeted therapies and immunotherapies are subject to very serious side effects, the development of drug resistance, and the high costs of treatment. This leaves room for the development of novel approaches as well as for the exploration of novel combination therapies for the treatment of metastatic melanoma. One such approach is targeting melanin pigment with radionuclide therapy. Advances in melanin-targeting radionuclide therapy of melanoma can be viewed from two spheres: (1) radioimmunotherapy (RIT) and (2) radiolabeled small molecules. The investigation of mechanisms of the action and efficacy of targeting melanin in melanoma treatment by RIT points to the involvement of the immune system such as complement dependent cytotoxicity. The combination of RIT with immunotherapy presents synergistic killing in mouse melanoma models. The field of radiolabeled small molecules is focused on radioiodinated compounds that have the ability to cross the cellular membranes to access intracellular melanin and can be applied in both therapy and imaging as theranostics. Clinical applications of targeting melanin with radionuclide therapies have produced encouraging results and clinical work is on-going. Continued work on targeting melanin with radionuclide therapy as a monotherapy, or possibly in combination with standard of care agents, has the potential to strengthen the current treatment options for melanoma patients.


Assuntos
Melaninas , Melanoma , Animais , Imunoterapia , Melanoma/radioterapia , Camundongos , Radioimunoterapia/métodos , Radioisótopos/uso terapêutico
19.
J Immunother Cancer ; 10(9)2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36100309

RESUMO

BACKGROUND: A vaccine containing 6 melanoma-associated peptides to stimulate helper T cells (6MHP) is safe, immunogenic, and clinically active. A phase I/II trial was designed to evaluate safety and immunogenicity of 6MHP vaccines plus programmed death 1 (PD-1) blockade. PARTICIPANTS AND METHODS: Participants with advanced melanoma received 6MHP vaccines in an incomplete Freund's adjuvant (6 vaccines over 12 weeks). Pembrolizumab was administered intravenously every 3 weeks. Tumor biopsies at baseline and day 22 were analyzed by multiplex immunohistochemistry. Primary end points were safety (Common Terminology Criteria for Adverse Events V.4.03) and immunogenicity (ex vivo interferon-γ ELISpot assay). Additional end points included changes in the tumor microenvironment (TME) and clinical outcomes. RESULTS: Twenty-two eligible participants were treated: 6 naïve to PD-1 antibody (Ab) and 16 PD-1 Ab-experienced. Median follow-up was 24.4 months. Most common treatment-related adverse events (any grade) included injection site reactions, fatigue, anemia, lymphopenia, fever, elevated aspartate aminotransferase, pruritus, and rash. Treatment-related dose-limiting toxicities were observed in 3 (14%) participants, which did not cross the study safety bound. A high durable T cell response (Rsp) to 6MHP was detected in only one participant, but twofold T cell Rsps to 6MHP were detected in 7/22 (32%; 90% CI (16% to 52%)) by week 13. Objective clinical responses were observed in 23% (1 complete response, 4 partial responses), including 4/6 PD-1 Ab-naïve (67%) and 1/16 PD-1 Ab-experienced (6%). Overall survival (OS) was longer for PD-1 Ab-naïve than Ab-experienced participants (HR 6.3 (90% CI (2.1 to 28.7)). In landmark analyses at 13 weeks, OS was also longer for those with T cell Rsps (HR 6.5 (90% CI (2.1 to 29.2)) and for those with objective clinical responses. TME evaluation revealed increased densities of CD8+ T cells, CD20+ B cells, and Tbet+ cells by day 22. CONCLUSIONS: Treatment with the 6MHP vaccine plus pembrolizumab was safe, increased intratumoral lymphocytes, and induced T cell Rsps associated with prolonged OS. The low T cell Rsp rate in PD-1 Ab-experienced participants corroborates prior murine studies that caution against delaying cancer vaccines until after PD-1 blockade. The promising objective response rate and OS in PD-1 Ab-naïve participants support consideration of a larger study in that setting.


Assuntos
Vacinas Anticâncer , Melanoma , Linfócitos T CD8-Positivos , Humanos , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1 , Microambiente Tumoral , Vacinas de Subunidades/uso terapêutico
20.
Clin Cancer Res ; 28(18): 4121-4130, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36106402

RESUMO

PURPOSE: Adjuvant immunotherapy produces durable benefit for patients with resected melanoma, but many develop recurrence and/or immune-related adverse events (irAE). We investigated whether baseline serum autoantibody (autoAb) signatures predicted recurrence and severe toxicity in patients treated with adjuvant nivolumab, ipilimumab, or ipilimumab plus nivolumab. EXPERIMENTAL DESIGN: This study included 950 patients: 565 from CheckMate 238 (408 ipilimumab versus 157 nivolumab) and 385 from CheckMate 915 (190 nivolumab versus 195 ipilimumab plus nivolumab). Serum autoAbs were profiled using the HuProt Human Proteome Microarray v4.0 (CDI Laboratories, Mayaguez, PR). Analysis of baseline differentially expressed autoAbs was followed by recurrence and severe toxicity signature building for each regimen, testing of the signatures, and additional independent validation for nivolumab using patients from CheckMate 915. RESULTS: In the nivolumab independent validation cohort, high recurrence score predicted significantly worse recurrence-free survival [RFS; adjusted HR (aHR), 3.60; 95% confidence interval (CI), 1.98-6.55], and outperformed a model composed of clinical variables including PD-L1 expression (P < 0.001). Severe toxicity score was a significant predictor of severe irAEs (aHR, 13.53; 95% CI, 2.59-86.65). In the ipilimumab test cohort, high recurrence score was associated with significantly worse RFS (aHR, 3.21; 95% CI, 1.38-7.45) and severe toxicity score significantly predicted severe irAEs (aHR, 11.04; 95% CI, 3.84-37.25). In the ipilimumab plus nivolumab test cohort, high autoAb recurrence score was associated with significantly worse RFS (aHR, 6.45; 95% CI, 1.48-28.02), and high severe toxicity score was significantly associated with severe irAEs (aHR, 23.44; 95% CI, 4.10-212.50). CONCLUSIONS: Baseline serum autoAb signatures predicted recurrence and severe toxicity in patients treated with adjuvant immunotherapy. Prospective testing of the signatures that include datasets with longer follow-up and rare but more severe toxicities will help determine their generalizability and potential clinical utility. See related commentary by Hassel and Luke, p. 3914.


Assuntos
Adjuvantes Imunológicos , Protocolos de Quimioterapia Combinada Antineoplásica , Autoanticorpos , Melanoma , Adjuvantes Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Autoanticorpos/sangue , Humanos , Inibidores de Checkpoint Imunológico , Ipilimumab , Nivolumabe , Estudos Prospectivos
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