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1.
Cell ; 183(6): 1714-1731.e10, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33275901

RESUMO

Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to a lack of understanding of the relative importance of the key molecular events required to induce target degradation. Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive dataset provides chemical leads for ∼200 kinases and demonstrates that the current practice of starting from the highest potency binder is an ineffective method for discovering active compounds. We develop multitargeted degraders to answer fundamental questions about the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent. This work will not only fuel kinase degrader discovery, but also provides a blueprint for evaluating targeted degradation across entire gene families to accelerate understanding of TPD beyond the kinome.


Assuntos
Proteínas Quinases/metabolismo , Proteólise , Proteoma/metabolismo , Adulto , Linhagem Celular , Bases de Dados de Proteínas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Quinases/genética , Proteômica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Adulto Jovem
2.
Mol Cell ; 81(17): 3468-3480.e7, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34314700

RESUMO

HECT ubiquitin ligases play essential roles in metazoan development and physiology. The HECT ligase HUWE1 is central to the cellular stress response by mediating degradation of key death or survival factors, including Mcl1, p53, DDIT4, and Myc. Although mutations in HUWE1 and related HECT ligases are widely implicated in human disease, our molecular understanding remains limited. Here we present a comprehensive investigation of full-length HUWE1, deepening our understanding of this class of enzymes. The N-terminal ∼3,900 amino acids of HUWE1 are indispensable for proper ligase function, and our cryo-EM structures of HUWE1 offer a complete molecular picture of this large HECT ubiquitin ligase. HUWE1 forms an alpha solenoid-shaped assembly with a central pore decorated with protein interaction modules. Structures of HUWE1 variants linked to neurodevelopmental disorders as well as of HUWE1 bound to a model substrate link the functions of this essential enzyme to its three-dimensional organization.


Assuntos
Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/metabolismo , Microscopia Crioeletrônica/métodos , Células HEK293 , Humanos , Estresse Fisiológico/fisiologia , Relação Estrutura-Atividade , Proteínas Supressoras de Tumor/genética , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
3.
J Drugs Dermatol ; 16(10): 1047-1049, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29036261

RESUMO

Immunotherapy-induced vitiligo is an immune-related adverse event (irAE) observed in metastatic melanoma patients treated with immune checkpoint inhibitors that target the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) pathways. To date, the development of leukoderma, poliosis, and halo nevi during immunotherapy has largely been reported in metastatic melanoma patients. We report a case of immunotherapy-induced leukoderma presenting as halo nevi in a patient with non-small cell lung cancer (NSCLC) treated with atezolizumab, a programmed cell death ligand (PD-L1) antibody. Immunotherapy-induced vitiligo in metastatic melanoma patients may be associated with improved survival, but it remains to be determined whether its occurrence in non-melanoma cancers has the same prognostic significance.

J Drugs Dermatol. 2017;16(10):1047-1049.

.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nevo com Halo/diagnóstico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nevo com Halo/induzido quimicamente , Prognóstico , Vitiligo/diagnóstico , Vitiligo/etiologia
4.
J Transl Med ; 12: 342, 2014 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-25491880

RESUMO

BACKGROUND: Matrix metalloproteinase-23 (MMP-23) can block the voltage-gated potassium channel Kv1.3, whose function is important for sustained Ca(2+) signaling during T cell activation. MMP-23 may also alter T cell activity and phenotype through cleavage of proteins affecting cytokine and chemokine signaling. We therefore tested the hypothesis that MMP-23 can negatively regulate the anti-tumor T cell response in human melanoma. METHODS: We characterized MMP-23 expression in primary melanoma patients who received adjuvant immunotherapy. We examined the association of MMP-23 with the anti-tumor immune response - as assessed by the prevalence of tumor-infiltrating lymphocytes and Foxp3(+) regulatory T cells. Further, we examined the association between MMP-23 expression and response to immunotherapy. Considering also an in trans mechanism, we examined the association of melanoma MMP-23 and melanoma Kv1.3 expression. RESULTS: Our data revealed an inverse association between primary melanoma MMP-23 expression and the anti-tumor T cell response, as demonstrated by decreased tumor-infiltrating lymphocytes (TIL) (P = 0.05), in particular brisk TILs (P = 0.04), and a trend towards an increased proportion of immunosuppressive Foxp3(+) regulatory T cells (P = 0.07). High melanoma MMP-23 expression is also associated with recurrence in patients treated with immune biologics (P = 0.037) but not in those treated with vaccines (P = 0.64). Further, high melanoma MMP-23 expression is associated with shorter periods of progression-free survival for patients receiving immune biologics (P = 0.025). On the other hand, there is no relationship between melanoma MMP-23 and melanoma Kv1.3 expression (P = 0.27). CONCLUSIONS: Our data support a role for MMP-23 as a potential immunosuppressive target in melanoma, as well as a possible biomarker for informing melanoma immunotherapies.


Assuntos
Imunoterapia , Metaloproteinases da Matriz/metabolismo , Melanoma/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melanoma/imunologia , Melanoma/terapia , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia , Adulto Jovem
5.
Cell Rep ; 42(5): 112496, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37167062

RESUMO

HUWE1 is a large, enigmatic HECT-domain ubiquitin ligase implicated in the regulation of diverse pathways, including DNA repair, apoptosis, and differentiation. How HUWE1 engages its structurally diverse substrates and how HUWE1 activity is regulated are unknown. Using unbiased quantitative proteomics, we find that HUWE1 targets substrates in a largely cell-type-specific manner. However, we identify C16orf72/HAPSTR1 as a robust HUWE1 substrate in multiple cell lines. Previously established physical and genetic interactions between HUWE1 and HAPSTR1 suggest that HAPSTR1 positively regulates HUWE1 function. Here, we show that HAPSTR1 is required for HUWE1 nuclear localization and nuclear substrate targeting. Nuclear HUWE1 is required for both cell proliferation and modulation of stress signaling pathways, including p53 and nuclear factor κB (NF-κB)-mediated signaling. Combined, our results define a role for HAPSTR1 in gating critical nuclear HUWE1 functions.


Assuntos
Ubiquitina-Proteína Ligases , Ubiquitina , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/genética , Linhagem Celular , Reparo do DNA , Núcleo Celular/metabolismo , Transdução de Sinais
6.
bioRxiv ; 2023 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-37873358

RESUMO

Small molecules that can induce protein degradation by inducing proximity between a desired target and an E3 ligase have the potential to greatly expand the number of proteins that can be manipulated pharmacologically. Current strategies for targeted protein degradation are mostly limited in their target scope to proteins with preexisting ligands. Alternate modalities such as molecular glues, as exemplified by the glutarimide class of ligands for the CUL4CRBN ligase, have been mostly discovered serendipitously. We recently reported a trans-labelling covalent glue mechanism which we named 'Template-assisted covalent modification', where an electrophile decorated small molecule binder of BRD4 was effectively delivered to a cysteine residue on an E3 ligase DCAF16 as a consequence of a BRD4-DCAF16 protein-protein interaction. Herein, we report our medicinal chemistry efforts to evaluate how various electrophilic modifications to the BRD4 binder, JQ1, affect DCAF16 trans-labeling and subsequent BRD4 degradation efficiency. We discovered a decent correlation between the ability of the electrophilic small molecule to induce ternary complex formation between BRD4 and DCAF16 with its ability to induce BRD4 degradation. Moreover, we show that a more solvent-exposed warhead presentation is optimal for DCAF16 recruitment and subsequent BRD4 degradation. Unlike the sensitivity of CUL4CRBN glue degraders to chemical modifications, the diversity of covalent attachments in this class of BRD4 glue degraders suggests a high tolerance and tunability for the BRD4-DCAF16 interaction. This offers a potential new avenue for a rational design of covalent glue degraders by introducing covalent warheads to known binders.

7.
bioRxiv ; 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36824856

RESUMO

Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics1-3. Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs4-6. The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism, which we term "template-assisted covalent modification". We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). BRD4BD2, in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 Å cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4BD2 have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16Cys58 covalent modification. Systematic mutagenesis of both DCAF16 and BRD4BD2 revealed that the loop conformation around BRD4His437, rather than specific side chains, is critical for stable interaction with DCAF16 and BD2 selectivity. Together our work establishes "template-assisted covalent modification" as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology.

8.
Cancer ; 118(17): 4184-92, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22246969

RESUMO

BACKGROUND: In patients with multiple primary melanomas (MPM), mean tumor thickness tends to decrease from the first melanoma to the second melanoma, and prognosis may be improved compared with the prognosis for patients who have a single primary melanoma (SPM). In this study, the authors compared the clinicopathologic features of patients with MPM and SPM to better characterize the differences between these 2 groups and to determine whether or not there is an inherent difference in tumor aggression. METHODS: In total, 788 patients with melanoma who were enrolled prospectively in the Interdisciplinary Melanoma Cooperative Group database from 2002 to 2008 were studied. Patients with SPM and with MPM were compared with regard to clinical and primary melanoma characteristics. RESULTS: Of 788 patients with melanoma, 61 patients (7.7%) had 2 or more primary melanomas. The incidence of developing a second primary melanoma 1 year and 5 years after initial melanoma diagnosis was 4.1% and 8.7%, respectively, and most of the risk accumulated within the first year. The incidence of MPM was greater in patients aged ≥60 years than in those aged ≤60 years. The absence or presence of mitosis and other tumor characteristics did not differ significantly between patients with SPM and patients with MPM (P = .61). CONCLUSIONS: No difference was observed in the presence or absence of mitoses, a marker of tumor proliferation, in SPM and MPM. Because it has been demonstrated that the presence of mitosis is a powerful prognostic marker, the current findings suggested that the tumors behave similarly in patients with SPM and patients with MPM. The authors concluded that differences in tumor thickness and prognosis between SPM and MPM more likely are caused by factors other than tumor biology, such as increased surveillance.


Assuntos
Melanoma/patologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Cutâneas/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitose , Prognóstico
9.
Mod Pathol ; 25(7): 1000-10, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22425909

RESUMO

The sentinel lymph node is the initial site of metastasis. Downregulation of antitumor immunity has a role in nodal progression. Our objective was to investigate the relationship between immune modulation and sentinel lymph node positivity, correlating it with outcome in melanoma patients. Lymph node/primary tissues from melanoma patients prospectively accrued and followed at New York University Medical Center were evaluated for the presence of regulatory T cells (Foxp3(+)) and dendritic cells (conventional: CD11c(+), mature: CD86(+)) using immunohistochemistry. Primary melanoma immune cell profiles from sentinel lymph node-positive/-negative patients were compared. Logistic regression models inclusive of standard-of-care/immunological primary tumor characteristics were constructed to predict the risk of sentinel lymph node positivity. Immunological responses in the positive sentinel lymph node were also compared with those in the negative non-sentinel node from the same nodal basin and matched negative sentinel lymph node. Decreased immune response was defined as increased regulatory T cells or decreased dendritic cells. Associations between the expression of these immune modulators, clinicopathological variables, and clinical outcome were evaluated using univariate/multivariate analyses. Primary tumor conventional dendritic cells and regression were protective against sentinel lymph node metastasis (odds ratio=0.714, 0.067; P=0.0099, 0.0816, respectively). Antitumor immunity was downregulated in the positive sentinel lymph node with an increase in regulatory T cells compared with the negative non-sentinel node from the same nodal basin (P=0.0005) and matched negative sentinel lymph node (P=0.0002). The positive sentinel lymph node also had decreased numbers of conventional dendritic cells compared with the negative sentinel lymph node (P<0.0001). Adding sentinel lymph node regulatory T cell expression improved the discriminative power of a recurrence risk assessment model using clinical stage. Primary tumor regression was associated with prolonged disease-free (P=0.025) and melanoma-specific (P=0.014) survival. Our results support an assessment of local immune profiles in both the primary tumor and sentinel lymph node to help guide therapeutic decisions.


Assuntos
Linfonodos/imunologia , Linfonodos/patologia , Melanoma/imunologia , Melanoma/patologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Adulto , Idoso , Área Sob a Curva , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática/imunologia , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Curva ROC , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/mortalidade
10.
J Transl Med ; 10: 155, 2012 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-22857597

RESUMO

BACKGROUND: Identification of melanoma patients at high risk for recurrence and monitoring for recurrence are critical for informed management decisions. We hypothesized that serum microRNAs (miRNAs) could provide prognostic information at the time of diagnosis unaccounted for by the current staging system and could be useful in detecting recurrence after resection. METHODS: We screened 355 miRNAs in sera from 80 melanoma patients at primary diagnosis (discovery cohort) using a unique quantitative reverse transcription-PCR (qRT-PCR) panel. Cox proportional hazard models and Kaplan-Meier recurrence-free survival (RFS) curves were used to identify a miRNA signature with prognostic potential adjusting for stage. We then tested the miRNA signature in an independent cohort of 50 primary melanoma patients (validation cohort). Logistic regression analysis was performed to determine if the miRNA signature can determine risk of recurrence in both cohorts. Selected miRNAs were measured longitudinally in subsets of patients pre-/post-operatively and pre-/post-recurrence. RESULTS: A signature of 5 miRNAs successfully classified melanoma patients into high and low recurrence risk groups with significant separation of RFS in both discovery and validation cohorts (p = 0.0036, p = 0.0093, respectively). Significant separation of RFS was maintained when a logistic model containing the same signature set was used to predict recurrence risk in both discovery and validation cohorts (p < 0.0001, p = 0.033, respectively). Longitudinal expression of 4 miRNAs in a subset of patients was dynamic, suggesting miRNAs can be associated with tumor burden. CONCLUSION: Our data demonstrate that serum miRNAs can improve accuracy in identifying primary melanoma patients with high recurrence risk and in monitoring melanoma tumor burden over time.


Assuntos
Biomarcadores Tumorais/sangue , Melanoma/genética , MicroRNAs/sangue , Neoplasias Cutâneas/genética , Feminino , Humanos , Masculino , Melanoma/sangue , Pessoa de Meia-Idade , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/sangue
11.
Oncology ; 80(3-4): 181-7, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21701232

RESUMO

OBJECTIVE: Previous melanoma studies evaluating prognostic factors of survival at recurrence have focused on primary tumor characteristics and clinical variables at first recurrence. We examined the prognostic relevance of recurrent tumor proliferation. METHODS: 114 melanoma patients with available recurrent tissues who were prospectively enrolled at New York University Medical Center were studied. Standard of care prognostic variables (e.g. stage at initial diagnosis and lactate dehydrogenase level) and recurrent tissue expression of proliferative marker Ki-67 were evaluated for their association with overall survival. RESULTS: High Ki-67 expression was observed in 57 (50%) of the 114 recurrent melanomas. On univariate analysis, the median overall survival of patients whose recurrent tumors overexpressed Ki-67 was significantly shorter than that of patients whose recurrent tumors had low Ki-67 expression (3.6 vs. 9.5 years, p = 0.03). On multivariate analysis, a high proliferative index of the recurrent melanoma remained an independent predictor of worse overall survival, controlling for stage at initial diagnosis, disease-free survival, and stage at first recurrence [HR = 2.09 (95% CI 1.24-3.54), p = 0.006]. CONCLUSIONS: Our results demonstrate the prognostic relevance of tumor proliferation in recurrent melanoma patients. Data also support restratification of risk assessment upon recurrence that considers tumor biology in addition to clinical variables evaluated as part of the standard of care.


Assuntos
Antígeno Ki-67/metabolismo , Melanoma/mortalidade , Melanoma/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , L-Lactato Desidrogenase/sangue , Masculino , Melanoma/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Neoplasias Cutâneas/metabolismo
12.
J Community Health ; 36(3): 461-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21080042

RESUMO

Minority melanoma patients have worse survival. In this study, we evaluated the impact of socioeconomic and demographic factors on minority melanoma patients presenting to two different New York City hospitals (one public and one private) managed by the same multidisciplinary team. Sociodemographic and clinicopathologic characteristics were retrieved for melanoma patients presenting to Bellevue Hospital Center (BHC), a public hospital, and the New York University Cancer Institute (NYUCI), a private cancer center. Socioeconomic data was obtained from the United States Census Bureau database. The Kruskal-Wallis and chi-square tests were used to evaluate the associations between race/ethnicity and continuous and categorical variables (e.g. income, stage at presentation), respectively. Minorities comprised 2% (27/1296) of melanoma patients at the NYUCI compared to 42% (50/119) at BHC. Those presenting to the NYUCI were more likely to have a higher median household income (P = 0.05), a higher educational level (P = 0.04), and an earlier stage at presentation (P = 0.02) than those at BHC. NYUCI patients were predominantly covered by commercial insurance (70%), whereas Medicaid (62%) was common among BHC patients. Only 19% of Hispanic patients at BHC chose English as their preferred language. Our data demonstrate that language and health care system factors affect melanoma presentation in minorities.


Assuntos
Disparidades nos Níveis de Saúde , Melanoma/etnologia , Grupos Minoritários/estatística & dados numéricos , Neoplasias Cutâneas/etnologia , Classe Social , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/estatística & dados numéricos , População Negra/estatística & dados numéricos , Feminino , Hispânico ou Latino/estatística & dados numéricos , Hospitais Privados/estatística & dados numéricos , Hospitais Públicos/estatística & dados numéricos , Humanos , Seguro Saúde/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Fatores Socioeconômicos , Adulto Jovem
13.
J Transl Med ; 8: 19, 2010 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-20178639

RESUMO

BACKGROUND: Increased levels of cryptic collagen epitope HU177 in the sera of melanoma patients have been shown to be associated with thicker primary melanomas and with the nodular histologic subtype. In this study, we investigate the association between HU177 shedding in the sera and clinical outcome in terms of disease-free survival (DFS) and overall survival (OS). METHODS: Serum samples from 209 patients with primary melanoma prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group at the New York University Langone Medical Center (mean age = 58, mean thickness = 2.09 mm, stage I = 136, stage II = 41, stage III = 32, median follow-up = 54.9 months) were analyzed for HU177 concentration using a validated ELISA assay. HU177 serum levels at the time of diagnosis were used to divide the study cohort into two groups: low and high HU177. DFS and OS were estimated by Kaplan-Meier survival analysis, and the log-rank test was used to compare DFS and OS between the two HU177 groups. Multivariate Cox proportional hazards regression models were employed to examine the independent effect of HU177 category on DFS and OS. RESULTS: HU177 sera concentrations ranged from 0-139.8 ng/ml (mean and median of 6.2 ng/ml and 3.7 ng/ml, respectively). Thirty-eight of the 209 (18%) patients developed recurrences, and 34 of the 209 (16%) patients died during follow-up. Higher HU177 serum level was associated with an increased rate of melanoma recurrence (p = 0.04) and with increasing mortality (p = 0.01). The association with overall survival remained statistically significant after controlling for thickness and histologic subtype in a multivariate model (p = 0.035). CONCLUSIONS: Increased shedding of HU177 in the serum of primary melanoma patients is associated with poor prognosis. Further studies are warranted to determine the clinical utility of HU177 in risk stratification compared to the current standard of care.


Assuntos
Colágeno , Epitopos , Melanoma/sangue , Melanoma/diagnóstico , Melanoma/patologia , Adulto , Idoso , Colágeno/sangue , Colágeno/imunologia , Intervalo Livre de Doença , Epitopos/sangue , Epitopos/imunologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Recidiva , Análise de Sobrevida
14.
Melanoma Res ; 23(6): 461-7, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24165034

RESUMO

To better identify melanoma patients who are, at the time of primary melanoma diagnosis, at high risk of developing brain metastases, primary melanoma characteristics were examined as risk factors for brain metastasis development. In a study of two patient cohorts, clinicopathological characteristics prospectively collected at primary cutaneous melanoma diagnosis for patients with/without brain metastasis were assessed in univariate and multivariate analyses using data from two prospectively collected databases: the Melanoma Cooperative Group (MCG) (1972-1982) and the Interdisciplinary Melanoma Cooperative Group (IMCG) (2002-2009). Candidate risk factors were evaluated in association with time to brain metastasis using either the log-rank test or Cox proportional hazards regression analysis with/without considering competing risks. Out of 2341 total patients included in the study, 222 (9.5%) developed brain metastases (median follow-up: 98 months). The median time to brain metastases was 30.5 months and the median survival time after brain metastases was 4 months. Increased hazard ratios (HRs) for brain metastasis were found among thicker (logarithmic value in mm) (MCG: HR=1.97, P<0.0001; IMCG: HR=1.31, P=0.018), ulcerated (MCG: HR=1.93, P=0.01; IMCG: HR=3.14, P<0.0001), and advanced-stage (MCG: HR=2.08, P=0.008; IMCG: HR=2.56, P=0.0002) primary melanomas on the basis of multivariate Cox regression analysis assuming the presence of competing risks. Primary cutaneous melanoma thickness, ulceration, and stage were identified and validated as risk factors associated with time to melanoma brain metastasis.


Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Melanoma/diagnóstico , Melanoma/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Fatores de Risco , Resultado do Tratamento , Adulto Jovem , Melanoma Maligno Cutâneo
15.
Am J Surg Pathol ; 37(6): 882-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23629443

RESUMO

The prognostic value of mitotic rate in melanoma is increasingly recognized, particularly in thin melanoma in which the presence or absence of a single mitosis/mm can change staging from T1a to T1b. Still, accurate mitotic rate calculation (mitoses/mm) on hematoxylin and eosin (H&E)-stained sections can be challenging. Antimonoclonal mitotic protein-2 (MPM-2) and antiphosphohistone-H3 (PHH3) are 2 antibodies reported to be more mitosis-specific than other markers of proliferation such as Ki-67. We used light microscopy and computer-assisted image analysis software to quantify MPM-2 and PHH3 staining in melanoma. We then compared mitotic rates by each method with conventional H&E-based mitotic rate for correlation with clinical outcomes. Our study included primary tissues from 190 nonconsecutive cutaneous melanoma patients who were prospectively enrolled at New York University Langone Medical Center with information on age, gender, and primary tumor characteristics. The mitotic rate was quantified manually by light microscopy of corresponding H&E-stained, MPM-2-stained, and PHH3-stained sections. Computer-assisted image analysis was then used to quantify immunolabeled mitoses on the previously examined PHH3 and MPM-2 slides. We then analyzed the association between mitotic rate and both progression-free and melanoma-specific survival. Univariate analysis of PHH3 found significant correlation between increased PHH3 mitotic rate and decreased progression-free survival (P=0.04). Computer-assisted image analysis enhanced the correlation of PHH3 mitotic rate with progression-free survival (P=0.02). Regardless of the detection method, neither MPM-2 nor PHH3 offered significant advantage over conventional H&E determination of mitotic rate.


Assuntos
Interpretação de Imagem Assistida por Computador/métodos , Melanoma/patologia , Índice Mitótico/métodos , Estadiamento de Neoplasias/métodos , Neoplasias Cutâneas/patologia , Adulto , Biomarcadores Tumorais/análise , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Neoplasias Cutâneas/mortalidade
17.
Neuro Oncol ; 14(7): 849-58, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22561799

RESUMO

Melanoma brain metastasis that develops as the isolated first visceral site challenges the current paradigm of tumor progression in which brain metastasis is regarded as the final stage. Here we test the hypothesis that melanoma patients who develop brain metastasis as the isolated first visceral site have distinct clinicopathological features at the time of primary melanoma diagnosis. Cutaneous melanoma patients enrolled in 2 prospectively collected databases were studied (Cohort 1: 1972-1982, Cohort 2: 2002-2009). Patients who developed brain metastasis as isolated first visceral site were compared with (1) all other patients, (2) patients who developed visceral metastasis: extracranial only or extracranial and brain, and (3) patients who progressed to other isolated visceral sites first. Two hundred seven of 2280 (9.1%) patients developed brain metastasis (median follow-up, 5.2 y). Seventy-four of 207 (35.7%) brain metastasis patients progressed to brain metastasis as the isolated first visceral site. These patients presented with primaries that were thinner and had no mitosis compared with all other visceral metastasis patients (Fisher's combined P = .02, .05, respectively), and there was a significant difference in American Joint Committee on Cancer stage distribution at initial melanoma diagnosis (combined P = .02). Post-visceral metastasis survival, however, was shorter in patients with brain metastasis as isolated first visceral site than in patients with visceral metastasis: extracranial and brain (combined P = .03). Brain metastasis as isolated first visceral site is a distinct clinicopathological entity. Studies are needed to better understand the biological factors driving this phenotype at the time of primary melanoma diagnosis and to determine its clinical implications.


Assuntos
Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Melanoma/mortalidade , Melanoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto Jovem
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