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1.
Ann Surg Oncol ; 31(3): 1865-1879, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37989956

RESUMO

In the last decade, immunotherapy has become the cornerstone in the management of patients with melanoma, the foremost cause of skin-cancer-related death in the USA. The emergence of immune checkpoint blockade as a crucial element in current immunotherapy and combination strategies has significantly transformed the treatments of resectable and advanced (unresectable or metastatic) melanoma. This paper reviews the landmark clinical trials that formed the basis of management of melanoma in the perioperative and metastatic setting. Furthermore, we discuss the rationale for the applications of PD-1 blockade and its combination with anti-CTLA-4 and anti-LAG-3. The review also explores new experimental combinations of PD-1 blockade with other immunomodulatory agents, including targeted therapies, anti-TIGIT antibodies, TLR-9 agonists, antiangiogenic agents, and mRNA vaccines.


Assuntos
Antineoplásicos , Melanoma , Humanos , Melanoma/tratamento farmacológico , Ipilimumab/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Nivolumabe/uso terapêutico , Antineoplásicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Receptor de Morte Celular Programada 1 , Antígeno CTLA-4 , Imunoterapia
2.
J Natl Compr Canc Netw ; 22(1D): e240002, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38244274

RESUMO

The NCCN Guidelines for Merkel Cell Carcinoma (MCC) provide recommendations for diagnostic workup, clinical stage, and treatment options for patients. The panel meets annually to discuss updates to the guidelines based on comments from expert review from panel members, institutional review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new page for locally advanced disease in the setting of clinical node negative status, entitled "Clinical N0 Disease, Locally Advanced MCC." This new algorithm page addresses locally advanced disease, and the panel clarifies the meaning behind the term "nonsurgical" by further defining locally advanced disease. In addition, the guideline includes the management of in-transit disease and updates to the systemic therapy options.


Assuntos
Carcinoma de Célula de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia
3.
J Natl Compr Canc Netw ; 21(11): 1181-1203, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37935106

RESUMO

Basal cell carcinoma (BCC) is the most common form of skin cancer in the United States. Due to the high frequency, BCC occurrences are not typically recorded, and annual rates of incidence can only be estimated. Current estimated rates are 2 million Americans affected annually, and this continues to rise. Exposure to radiation, from either sunlight or previous medical therapy, is a key player in BCC development. BCC is not as aggressive as other skin cancers because it is less likely to metastasize. However, surgery and radiation are prevalent treatment options, therefore disfigurement and limitation of function are significant considerations. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) outline an updated risk stratification and treatment options available for BCC.


Assuntos
Carcinoma Basocelular , Neoplasias Cutâneas , Humanos , Estados Unidos/epidemiologia , Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/epidemiologia , Carcinoma Basocelular/etiologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/etiologia , Luz Solar , Oncologia , Incidência
4.
J Surg Res ; 283: 274-281, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36423476

RESUMO

INTRODUCTION: Melanoma is the fifth most common cancer diagnosed in the United States, representing 5.6% of all new cancer cases. There are conflicting reports correlating a relationship between primarily outdoor occupations, associated with increased exposure to direct sunlight, and the incidence of cutaneous melanoma. Our objective was to outline and critically evaluate the relevant literature related to chronic occupational exposure to sunlight and risk of developing cutaneous melanoma. METHODS: The study protocol for this systematic review was submitted to the International Prospective Register of Systematic Reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. For each relevant study included, the following information was extracted: author names, publication year, study name, study design, age, exposure assessment, outcome, comparison, number of cases, case ascertainment, and descriptive and adjusted statistics. Study quality and evidence certainty was assessed using the Grading of Recommendations, Assessment, Development and Evaluations model. RESULTS: The initial database search yielded 1629 articles for review and following full-text screening, a total of 14 articles were included for final analysis. Of the studies included, seven articles were retrospective case control and seven were cohort studies. The studies did not report any differences in the likelihood of cutaneous melanoma development based upon membership in the outdoor versus indoor occupation groups included in each study. CONCLUSIONS: Overall, the articles included in this systematic review did not report an increased risk of developing cutaneous melanoma among individuals with outdoor occupations. Further investigation is required to determine if other occupational or life-style-related risk factors exist, to help support the development of individualized skin screening recommendations and improve the early detection of melanoma in all populations.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/epidemiologia , Luz Solar/efeitos adversos , Estudos Retrospectivos , Melanoma Maligno Cutâneo
5.
J Surg Oncol ; 127(4): 716-726, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36453464

RESUMO

BACKGROUND: Completion lymph node dissection (CLND) was the standard treatment for patients with melanoma with positive sentinel lymph nodes (SLN) until 2017 when data from the DeCOG-SLT and MLST-2 randomized trials challenged the survival benefit of this procedure. We assessed the contribution of patient, tumor and facility factors on the use of CLND in patients with surgically resected Stage III melanoma. METHODS: Using the National Cancer Database, patients who underwent surgical excision and were found to have a positive SLN from 2012 to 2017 were included. A multivariable mixed-effects logistic regression model with a random intercept for the facility was used to determine the effect of patient, tumor, and facility variables on the risk of CLND. Reference effect measures (REMs) were used to compare the contribution of contextual effects (unknown facility variables) versus measured variables on the variation in CLND use. RESULTS: From 2012 to 2017, the overall use of CLND decreased from 59.9% to 26.5% (p < 0.0001). Overall, older patients and patients with government-based insurance were less likely to undergo CLND. Tumor factors associated with a decreased rate of CLND included primary tumor location on the lower limb, decreasing depth, and mitotic rate <1. However, the contribution of contextual effects to the variation in CLND use exceeded that of the measured facility, tumor, time, and patient variables. CONCLUSIONS: There was a decrease in CLND use during the study period. However, there is still high variability in CLND use, mainly driven by unmeasured contextual effects.


Assuntos
Melanoma , Linfonodo Sentinela , Neoplasias Cutâneas , Humanos , Biópsia de Linfonodo Sentinela/métodos , Tipagem de Sequências Multilocus , Melanoma/patologia , Neoplasias Cutâneas/patologia , Excisão de Linfonodo/métodos , Linfonodo Sentinela/cirurgia , Linfonodo Sentinela/patologia
6.
Ann Surg Oncol ; 29(1): 415-424, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34494169

RESUMO

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. Our report describes the evolution of management and characteristics associated with recurrence, disease-specific survival (DSS) and overall survival (OS) in the treatment of MCC. METHODS: A single institution retrospective review of MCC and SEER data to determine factors associated with RFS, DSS, and OS using a multivariable Cox regression on inverse-probability weighted cohorts. RESULTS: One hundred fifty-nine patients were identified with a median age of 75. Of these, 96% were Caucasian and 60% male. Fifty-eight out of 159 (36%) of all patients were deceased with 21/58 (36%) dead from MCC with a median follow-up of 3.1 years. Institutionally, trends over time demonstrated an increased use of immunotherapy with a concomitant decrease in chemotherapy and decreased use of radiotherapy alone. Institutionally and nationally, there has been increased surgical nodal staging. Institutionally, factors associated with shorter DSS included advanced age, active cigarette smoker (p = 0.002), cT2 disease (p = 0.007), and MCC with unknown primary (p < 0.001). Institutionally, factors associated with shorter OS included ages ≥ 75 years (p < 0.001), an immunocompromised state (p < 0.001), truncal primary site (p = 0.002), and cT2 disease (HR 9.59, p < 0.001). CONCLUSION: Changing practice patterns in MCC management have been driven by the adoption of immunotherapy. Our study highlights that competing risks of mortality in MCC patients likely prevents OS from being an accurate surrogate outcome measure to understand factors associated with DSS.


Assuntos
Carcinoma de Célula de Merkel , Radioterapia (Especialidade) , Neoplasias Cutâneas , Idoso , Carcinoma de Célula de Merkel/terapia , Feminino , Humanos , Imunoterapia , Masculino , Estudos Retrospectivos , Neoplasias Cutâneas/terapia
7.
Semin Cancer Biol ; 65: 114-122, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31911188

RESUMO

Advances in immunotherapy, most notably antibodies targeting the inhibitory immune receptors cytotoxic T-lymphocyte associated protein 4 (CTLA-4/CD152), programmed death protein 1 (PD-1/CD279) and programmed death-ligand 1 (PD-L1/B7H1/CD274) have become effective standard therapies in advanced malignancies including melanoma,1-4 merkel cell carcinoma5, urological cancers6-8, non-small cell lung cancer9-11, mis-match repair (MMR) deficient tumors12, and Hodgkin lymphoma with response rates ranging from 25 to 60% in the first and second line settings13,14. FDA approval has also been given for treatment for hepatocellular carcinoma, gastric cancer, triple negative breast cancer, cervical and head and neck cancers with response rates closer to 15 %15. Additionally, some clinical efficacy has been observed in ovarian cancer, mesothelioma, prostate cancer, diffuse large B cell lymphoma, follicular lymphoma, and both cutaneous and peripheral T-cell lymphoma. However, despite these successes, most patients will initially fail to respond to treatment and almost half of initial responders will develop secondary resistance to immunotherapy and progress. Moreover, many prevalent solid organ tumors remain resistant to immunotherapy including colorectal, pancreatic and hepatobiliary cancers. Therefore, new therapies are needed to increase both initial and durable response rates and to develop new mechanistic insights into pathways of immune resistance so that immunotherapy may become more widely available as a therapeutic option in common malignancies.


Assuntos
Antineoplásicos/uso terapêutico , Epigênese Genética/imunologia , Repressão Epigenética/imunologia , Neoplasias/terapia , Antineoplásicos/imunologia , Antígeno B7-H1/efeitos adversos , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Terapia Combinada , Humanos , Imunoterapia/efeitos adversos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
10.
Ann Surg ; 259(2): 204-12, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23673766

RESUMO

OBJECTIVE: To validate the 2010 American Joint Committee on Cancer (AJCC) and 2006 European Neuroendocrine Tumor Society (ENETS) tumor staging systems for pancreatic neuroendocrine tumors (PanNETs) using the largest, single-institution series of surgically resected patients in the literature. BACKGROUND: The natural history and prognosis of PanNETs have been poorly defined because of the rarity and heterogeneity of these neoplasms. Currently, there are 2 main staging systems for PanNETs, which can complicate comparisons of reports in the literature and thereby hinder progress against this disease. METHODS: Univariate and multivariate analyses were conducted on the prognostic factors of survival using 326 sporadic, nonfunctional, surgically resected PanNET patients who were cared for at our institution between 1984 and 2011. Current and proposed models were tested for survival prognostication validity as measured by discrimination (Harrel's c-index, HCI) and calibration. RESULTS: Five-year overall-survival rates for AJCC stages I, II, and IV are 93% (88%-99%), 74% (65%-83%), and 56% (42%-73%), respectively, whereas ENETS stages I, II, III, and IV are 97% (92%-100%), 87% (80%-95%), 73% (63%-84%), and 56% (42%-73%), respectively. Each model has an HCI of 0.68, and they are no different in their ability to predict survival. We developed a simple prognostic tool just using grade, as measured by continuous Ki-67 labeling, sex, and binary age that has an HCI of 0.74. CONCLUSIONS: Both the AJCC and ENETS staging systems are valid and indistinguishable in their survival prognostication. A new, simpler prognostic tool can be used to predict survival and decrease interinstitutional mistakes and uncertainties regarding these neoplasms.


Assuntos
Tumores Neuroendócrinos/patologia , Nomogramas , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Técnicas de Apoio para a Decisão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Reprodutibilidade dos Testes , Análise de Sobrevida , Carga Tumoral
11.
JCO Precis Oncol ; 8: e2300702, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38662983

RESUMO

PURPOSE: Melanocortin-1 receptor (MC1R) plays a critical role in human pigmentation and DNA repair mechanisms. MC1R-targeting agents are being investigated in clinical trials in patients with melanoma, yet large studies investigating the rate and degree of MC1R expression in primary and metastatic human melanoma tissue are lacking. METHODS: Using tissue microarrays containing three large cohorts of 225 cases of benign nevi, 189 with primary melanoma, and 271 with metastatic melanoma, we applied quantitative immunofluorescence and immunohistochemistry to comprehensively study MC1R protein expression. RESULTS: We show a stepwise elevation of MC1R expression in different stages of melanoma progression (nevi, primary, metastasis). Higher MC1R expression was seen in deeper (>1 mm) primary lesions and ulcerated lesions and was associated with shorter survival in primary and metastatic tumors. On multivariable analysis, Breslow thickness, male sex, and chronic sun exposure were independent predictors of worse overall survival in the primary melanoma cohort. CONCLUSION: Our data suggest that MC1R might be a valuable drug target in aggressive melanoma. Additional studies are warranted to determine its functional significance in melanoma progression and its utility as a predictive biomarker in patients receiving MC1R-directed therapies.


Assuntos
Biomarcadores Tumorais , Progressão da Doença , Melanoma , Receptor Tipo 1 de Melanocortina , Neoplasias Cutâneas , Humanos , Melanoma/patologia , Melanoma/metabolismo , Receptor Tipo 1 de Melanocortina/genética , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Idoso , Adulto
12.
J Immunother Cancer ; 12(3)2024 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-38519058

RESUMO

BACKGROUND: Desmoplastic melanoma (DM) is a rare melanoma subtype characterized by dense fibrous stroma, a propensity for local recurrence, and a high response rate to programmed cell death protein 1 (PD-1) blockade. Occult sentinel lymph node positivity is significantly lower in both pure and mixed DM than in conventional melanoma, underscoring the need for better prognostic biomarkers to inform therapeutic strategies. METHODS: We assembled a tissue microarray comprising various cores of tumor, stroma, and lymphoid aggregates from 45 patients with histologically confirmed DM diagnosed between 1989 and 2018. Using a panel of 62 validated immune-oncology markers, we performed digital spatial profiling using the NanoString GeoMx platform and quantified expression in three tissue compartments defined by fluorescence colocalization (tumor (S100+/PMEL+/SYTO+), leukocytes (CD45+/SYTO+), and non-immune stroma (S100-/PMEL-/CD45-/SYTO+)). RESULTS: We observed higher expression of immune checkpoints (lymphocyte-activation gene 3 [LAG-3] and cytotoxic T-lymphocyte associated protein-4 [CTLA-4]) and cancer-associated fibroblast (CAF) markers (smooth muscle actin (SMA)) in the tumor compartments of pure DMs than mixed DMs. When comparing lymphoid aggregates (LA) to non-LA tumor cores, LAs were more enriched with CD20+B cells, but non-LA intratumoral leukocytes were more enriched with macrophage/monocytic markers (CD163, CD68, CD14) and had higher LAG-3 and CTLA-4 expression levels. Higher intratumoral PD-1 and LA-based LAG-3 expression appear to be associated with worse survival. CONCLUSIONS: Our proteomic analysis reveals an intra-tumoral population of SMA+CAFs enriched in pure DM. Additionally, increased expressions of immune checkpoints (LAG-3 and PD-1) in LA and within tumor were associated with poorer prognosis. These findings might have therapeutic implications and help guide treatment selection in addition to informing potential prognostic significance.


Assuntos
Melanoma , Humanos , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/metabolismo , Antígeno CTLA-4/uso terapêutico , Microambiente Tumoral , Actinas/metabolismo , Proteômica , Biomarcadores Tumorais/metabolismo
13.
JAMA Oncol ; 10(3): 342-351, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38175659

RESUMO

Importance: While immunotherapy is being used in an expanding range of clinical scenarios, the incidence of immunotherapy initiation at the end of life (EOL) is unknown. Objective: To describe patient characteristics, practice patterns, and risk factors concerning EOL-initiated (EOL-I) immunotherapy over time. Design, Setting, and Participants: Retrospective cohort study using a US national clinical database of patients with metastatic melanoma, non-small cell lung cancer (NSCLC), or kidney cell carcinoma (KCC) diagnosed after US Food and Drug Administration approval of immune checkpoint inhibitors for the treatment of each disease through December 2019. Mean follow-up was 13.7 months. Data analysis was performed from December 2022 to May 2023. Exposures: Age, sex, race and ethnicity, insurance, location, facility type, hospital volume, Charlson-Deyo Comorbidity Index, and location of metastases. Main Outcomes and Measures: Main outcomes were EOL-I immunotherapy, defined as immunotherapy initiated within 1 month of death, and characteristics of the cohort receiving EOL-I immunotherapy and factors associated with its use. Results: Overall, data for 242 371 patients were analyzed. The study included 20 415 patients with stage IV melanoma, 197 331 patients with stage IV NSCLC, and 24 625 patients with stage IV KCC. Mean (SD) age was 67.9 (11.4) years, 42.5% were older than 70 years, 56.0% were male, and 29.3% received immunotherapy. The percentage of patients who received EOL-I immunotherapy increased over time for all cancers. More than 1 in 14 immunotherapy treatments in 2019 were initiated within 1 month of death. Risk-adjusted patients with 3 or more organs involved in metastatic disease were 3.8-fold more likely (95% CI, 3.1-4.7; P < .001) to die within 1 month of immunotherapy initiation than those with lymph node involvement only. Treatment at an academic or high-volume center rather than a nonacademic or very low-volume center was associated with a 31% (odds ratio, 0.69; 95% CI, 0.65-0.74; P < .001) and 30% (odds ratio, 0.70; 95% CI, 0.65-0.76; P < .001) decrease in odds of death within a month of initiating immunotherapy, respectively. Conclusions and Relevance: Findings of this cohort study show that the initiation of immunotherapy at the EOL is increasing over time. Patients with higher metastatic burden and who were treated at nonacademic or low-volume facilities had higher odds of receiving EOL-I immunotherapy. Tracking EOL-I immunotherapy can offer insights into national prescribing patterns and serve as a harbinger for shifts in the clinical approach to patients with advanced cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Melanoma , Humanos , Masculino , Idoso , Feminino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos de Coortes , Estudos Retrospectivos , Neoplasias Pulmonares/tratamento farmacológico , Disparidades em Assistência à Saúde , Imunoterapia , Morte
14.
Front Oncol ; 14: 1336441, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38380358

RESUMO

Background: Immunotherapy agents are approved for adjuvant treatment of stage III melanoma; however, evidence for survival benefit in early stage III disease is lacking. Current guidelines for adjuvant immunotherapy utilization in stage IIIA rely on clinician judgment, creating an opportunity for significant variation in prescribing patterns. This study aimed to characterize current immunotherapy practice variations and to compare patient outcomes for different prescribing practices in stage IIIA melanoma. Study design: Patients with melanoma diagnosed from 2015-2019 that met American Joint Committee on Cancer 8th edition criteria for stage IIIA and underwent resection were identified in the National Cancer Database. Multiple imputation by chained equations replaced missing values. Factors associated with receipt of adjuvant immunotherapy were identified. Multivariable Cox proportional hazards regression compared overall survival across groups. Results: Of 4,432 patients included in the study, 34% received adjuvant immunotherapy. Patients had lower risk-adjusted odds of receiving immunotherapy if they were treated at an academic center (OR=0.48, 95%CI=0.33-0.72, p<0.001 vs. community facility) or at a high-volume center (OR=0.69, 0.56-0.84, p<0.001 vs. low-volume). Immunotherapy receipt was not associated with risk-adjusted survival (p=0.095). Moreover, patients treated at high-volume centers experienced longer overall risk-adjusted survival than those treated at low-volume centers (HR=0.52, 0.29-0.93, p=0.030). Risk-adjusted survival trended toward being longer at academic centers than at community centers, but the difference was not statistically significant. Conclusion: Academic and high-volume centers utilize significantly less adjuvant immunotherapy in stage IIIA melanoma than community and low-volume centers without compromise in overall survival. These findings suggest that this population may benefit from more judicious immunotherapy utilization.

15.
Res Sq ; 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38464315

RESUMO

Effective anti-tumor immunity is largely driven by cytotoxic CD8+ T cells that can specifically recognize tumor antigens. However, the factors which ultimately dictate successful tumor rejection remain poorly understood. Here we identify a subpopulation of CD8+ T cells which are tumor antigen-specific in patients with melanoma but resemble KIR+CD8+ T cells with a regulatory function (Tregs). These tumor antigen-specific KIR+CD8+ T cells are detectable in both the tumor and the blood, and higher levels of this population are associated with worse overall survival. Our findings therefore suggest that KIR+CD8+ Tregs are tumor antigen-specific but uniquely suppress anti-tumor immunity in patients with melanoma.

16.
Front Oncol ; 13: 1217816, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37476373

RESUMO

Merkel cell carcinoma (MCC) is a rare tumor with a high risk of recurrence after definitive therapy; however, the optimal duration of surveillance is unclear. First recurrences typically occur within 3 years. National guidelines recommend that patients undergo physical examination and imaging for surveillance during this time period. However, the duration of surveillance beyond this is not defined. Here, we describe a case of a patient developing a recurrence of MCC 7 years after the primary diagnosis with interval in-transit and regional lymph node metastases 15 months following the treatment of the primary MCC. Such late recurrences are rare, largely not reported, and the risk factors contributing to late recurrences are not well described. This case highlights the possibility of late recurrences of MCC after an initial in-transit and nodal recurrence and underscores the importance of identifying predictors of recurrence that may better guide the duration of surveillance.

17.
Cureus ; 15(2): e34742, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36909026

RESUMO

Objective In this study, we aimed to compare the clinical outcomes between older and younger patients with melanoma and to evaluate for differences in tumor genetic makeup that might explain differences in clinical behavior between older and younger cohorts. Materials and methods A consecutive sample of patients diagnosed with melanoma at a single institution from 1984 to 2019 was categorized by age into younger, middle, and older cohorts. Tumor characteristics, melanoma-specific survival, and recurrence-free survival were assessed while accounting for differential follow-up and death from other causes using Kaplan-Meier analysis with log-rank testing. Results A total of 4378 patients were included in the study. Older patients presented with a higher incidence of T3 and T4 tumors, and a lower incidence of T1 tumors (p<0.001). The same group of patients had a lower nodal positivity at any given Breslow thickness (p<0.01). Melanoma-specific survival was lower for older patients with T2 tumors (p=0.046). There was no difference in recurrence-free survival among all age groups and tumor thicknesses (p>0.05). For patients with a given genetic profile, the melanoma-specific survival and recurrence-free survival were equivalent across ages. BRAF was the most common driver in the younger group, while NRAS and other mutations increased in prevalence as age rose. Conclusions Older adults have decreased melanoma-specific survival for T2 tumors and lower nodal positivity, suggesting a different pattern of metastatic progression. The mutational drivers of cutaneous melanoma change with age and may play a role in the different metastatic progression as well as the differential melanoma-specific survival across all age cohorts.

18.
Res Sq ; 2023 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-37790306

RESUMO

Melanocortin-1 receptor (MC1R) plays a critical role in human pigmentation and DNA repair mechanisms. MC1R-targeting agents are being investigated in clinical trials in melanoma patients, yet large studies investigating the rate and degree of MC1R expression in primary and metastatic human melanoma tissue are lacking. Using tissue microarrays containing three large cohorts of 225 cases of benign nevi, 189 with primary melanoma, and 271 with metastatic melanoma, we applied quantitative immunofluorescence and immunohistochemistry to comprehensively study MC1R protein expression. We show a stepwise elevation of MC1R expression in different stages of melanoma progression (nevi, primary, metastasis). Higher MC1R expression was seen in deeper (>1 mm) primary lesions, ulcerated lesions, and mucosal melanomas compared to cutaneous melanomas and was associated with shorter survival in primary and metastatic tumors. On multi-variable analysis, Breslow thickness, ulceration, male sex, and chronic sun exposure were independent predictors of worse overall survival in the primary melanoma cohort. In the metastatic melanoma cohort, MC1R expression and mucosal melanomas were independent predictors of inferior overall survival. Our data suggest that MC1R might be a valuable drug target in aggressive melanoma. Additional studies are warranted to determine its functional significance in melanoma progression and its utility as a predictive biomarker in patients receiving MC1R-directed therapies.

19.
JCI Insight ; 8(7)2023 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-36821392

RESUMO

Targeting tumor-associated blood vessels to increase immune infiltration may enhance treatment effectiveness, yet limited data exist regarding anti-angiogenesis effects on the tumor microenvironment (TME). We hypothesized that dual targeting of angiogenesis with immune checkpoints would improve both intracranial and extracranial disease. We used subcutaneous and left ventricle melanoma models to evaluate anti-PD-1/anti-VEGF and anti-PD-1/lenvatinib (pan-VEGFR inhibitor) combinations. Cytokine/chemokine profiling and flow cytometry were performed to assess signaling and immune-infiltrating populations. An in vitro blood-brain barrier (BBB) model was utilized to study intracranial treatment effects on endothelial integrity and leukocyte transmigration. Anti-PD-1 with either anti-VEGF or lenvatinib improved survival and decreased tumor growth in systemic melanoma murine models; treatment increased Th1 cytokine/chemokine signaling. Lenvatinib decreased tumor-associated macrophages but increased plasmacytoid DCs early in treatment; this effect was not evident with anti-VEGF. Both lenvatinib and anti-VEGF resulted in decreased intratumoral blood vessels. Although anti-VEGF promoted endothelial stabilization in an in vitro BBB model, while lenvatinib did not, both regimens enabled leukocyte transmigration. The combined targeting of PD-1 and VEGF or its receptors promotes enhanced melanoma antitumor activity, yet their effects on the TME are quite different. These studies provide insights into dual anti-PD-1 and anti-angiogenesis combinations.


Assuntos
Melanoma , Compostos de Fenilureia , Animais , Camundongos , Linhagem Celular Tumoral , Citocinas/farmacologia , Melanoma/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/imunologia , Receptor de Morte Celular Programada 1/imunologia
20.
Heliyon ; 9(8): e18459, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37534012

RESUMO

Background: The onset of the COVID-19 pandemic led to substantial alterations in healthcare delivery and access. In this study, we aimed to evaluate the impact of COVID-19 on the presentation and surgical care of patients with gastrointestinal (GI) cancers. Methods: All patients who underwent GI cancer surgery at a large, tertiary referral center between March 15, 2019 and March 15, 2021 were included. March 15, 2020 was considered the start of the COVID-19 pandemic. Changes in patient, tumor, and treatment characteristics before the pandemic compared to during the pandemic were evaluated. Results: Of 522 patients that met study criteria, 252 (48.3%) were treated before the COVID-19 pandemic. During the first COVID-19 wave, weekly volume of GI cancer cases was one-third lower than baseline (p = 0.041); during the second wave, case volume remained at baseline levels (p = 0.519). There were no demographic or tumor characteristic differences between patients receiving GI cancer surgery before versus during COVID-19 (p > 0.05 for all), and no difference in rate of emergency surgery (p > 0.9). Patients were more likely to receive preoperative chemotherapy during the first six months of the pandemic compared to the subsequent six months (35.6% vs. 15.5%, p < 0.001). Telemedicine was rapidly adopted at the start of the pandemic, rising from 0% to 47% of GI surgical oncology visits within two months. Conclusions: The COVID-19 pandemic caused an initial disruption to the surgical care of GI cancers, but did not compromise stage at presentation. Preoperative chemotherapy and telemedicine were utilized to mitigate the impact of a high COVID-19 burden on cancer care.

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