RESUMEN
Therapy of BRAF-mutant melanoma with selective inhibitors of BRAF (BRAFi) and MEK (MEKi) represents a major clinical advance but acquired resistance to therapy has emerged as a key obstacle. To date, no clinical approaches successfully resensitize to BRAF/MEK inhibition. Here, we develop a therapeutic strategy for melanoma using bromosporine, a bromodomain inhibitor. Bromosporine (bromo) monotherapy produced significant anti-tumor effects against established melanoma cell lines and patient-derived xenografts (PDXs). Combinatorial therapy involving bromosporine and cobimetinib (bromo/cobi) showed synergistic anti-tumor effects in multiple BRAFi-resistant PDX models. The bromo/cobi combination was superior in vivo to standard BRAFi/MEKi therapy in the treatment-naive BRAF-mutant setting and to MEKi alone in the setting of immunotherapy-resistant NRAS- and NF1-mutant melanoma. RNA sequencing of xenografts treated with bromo/cobi revealed profound down-regulation of genes critical to cell division and mitotic progression. Bromo/cobi treatment resulted in marked DNA damage and cell-cycle arrest, resulting in induction of apoptosis. These studies introduce bromodomain inhibition, alone or combined with agents targeting the mitogen activated protein kinase pathway, as a rational therapeutic approach for melanoma refractory to standard targeted or immunotherapeutic approaches.
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Melanoma , Proteínas Proto-Oncogénicas B-raf , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Quinasas de Proteína Quinasa Activadas por Mitógenos , Proteínas Nucleares , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/metabolismo , Factores de TranscripciónRESUMEN
BACKGROUND: Technetium-99m-labeled Tilmanocept, a multivalent mannose, is readily internalized by the CD206 surface receptor on macrophages and dendritic cells which are abundantly present in lymph nodes. We want to examine the drainage patterns of Technetium-99m-labeled Tilmanocept to sentinel lymph nodes (SLNs) in melanoma patients following the 10% rule. METHODS: Multi-center retrospective review of patients with cutaneous melanoma undergoing SLN biopsy using Technetium-99m-labeled Tilmanocept between 2008 and 2014 was conducted. Statistical methods were used for data analyses. RESULTS: Of the 564 patients (mean age of 60.3 and 62% male) with preoperative lymphoscintigraphy showing at least one SLN, several primary tumor sites were included: 27% head/neck, 33% trunk, 21% upper extremity and 19% lower extremity. For the head/neck primary site, 36.5% of patients had multiple draining basins; for the trunk site, 36.4% of patients; for the upper extremity site, 13% of patients; and for the lower extremity, 27.4% of patients. A median of 3 (range 1-18) SLNs were identified and resected. Overall, 78% of patients had >1 SLN identified by Technetium-99m-labeled Tilmanocept. In a multivariate model, patients with >1 SLN were significantly associated with age, Breslow depth, tumor location and higher AJCC tumor stage. A total of 17.7% of patients (100/564) had a positive SLN identified. A total of 145 positive SLNs were identified out of 1,812 SLNs with a positive SLN rate of 8%. Positive SLN status was significantly associated with younger age, greater Breslow depth, mitosis rate, higher AJCC tumor stage, presence of ulceration and angiolymphatic invasion. CONCLUSIONS: Using the 10% rule, Technetium-99m-labeled Tilmanocept detects multiple SLNs in most melanoma patients.
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Melanoma , Ganglio Linfático Centinela , Neoplasias Cutáneas , Humanos , Masculino , Persona de Mediana Edad , Femenino , Ganglio Linfático Centinela/diagnóstico por imagen , Ganglio Linfático Centinela/cirugía , Ganglio Linfático Centinela/patología , Linfocintigrafia/métodos , Melanoma/diagnóstico por imagen , Melanoma/cirugía , Melanoma/patología , Biopsia del Ganglio Linfático Centinela/métodos , Radiofármacos , Pentetato de Tecnecio Tc 99m , Tecnecio , Metástasis Linfática/patología , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/cirugía , Neoplasias Cutáneas/patología , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/cirugía , Ganglios Linfáticos/patologíaRESUMEN
BACKGROUND: The significance of tumor-infiltrating lymphocytes (TILs) in melanoma is debated. This article presents a multicenter, retrospective study assessing the predictive and prognostic value of TILs. METHODS: The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with known TIL data. TILs were categorized as absent or present, which included nonbrisk (NB), brisk (B), and present but unspecified TIL levels. Clinicopathologic factors were correlated with TILs, sentinel lymph node (SLN) status, and melanoma-specific survival (MSS). RESULTS: Overall, 3203 patients were included. The median thickness was 1.5 mm, and 469 cases had SLN metastases. TILs were present in 2458 cases (76.7%), with NB, B, and unspecified TILs seen in 1691 (68.8%), 691 (28.1%), and 76 (3.1%), respectively. Multivariable analysis showed that the presence of TILs significantly predicted a negative SLN biopsy (P < .05). The median follow-up was 25.2 months. MSS was significantly better for cases with TILs than cases without TILs (P < .001). According to multivariable analysis, age, gender, thickness, mitotic rate, ulceration, lymphovascular invasion, and SLN status were significantly prognostic of MSS (all P values < .05). Although TILs were not prognostic of MSS, when multiple imputation was used and the SLN status was excluded, the presence of TILs was significantly prognostic of improved MSS (hazard ratio, 0.78; 95% confidence interval, 0.64-0.95; P = .0154). CONCLUSIONS: TILs are a favorable marker because their presence significantly predicts a negative SLN, and the absence of TILs may be a prognostic marker of worse survival in patients with a positive SLN but not a negative SLN. TILs may also serve as a prognostic marker of survival when the SLN status is not considered.
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Melanoma , Neoplasias Cutáneas , Humanos , Linfocitos Infiltrantes de Tumor , Melanoma/patología , Pronóstico , Estudios Retrospectivos , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: The relationship between tumor-infiltrating lymphocytes (TILs) and regression in melanoma is unknown. This report describes a large multicenter study assessing the association between TILs and regression. METHODS: The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with TILs and regression data. Clinicopathologic factors were correlated with regression and TIL status, sentinel lymph node (SLN) status, and overall survival (OS). RESULTS: The study enrolled 2450 patients. In 1811 cases, TILs (73.9%) were present, with regression present in 328 of these 1811 (18.1%) cases and in 49 (7.7%) of 639 cases without TILs. The presence of TILs was significantly associated with regression (p < 0.0001) as well as a negative SLN (p < 0.05). However, when TILs were stratified by regression status, only absence or presence of both TILs and regression were significantly associated with SLN metastases (p = 0.038). Although the presence of TILs was associated with OS (p < 0.05), regression status by itself was not (p = 0.2058 and 0.252, respectively). Furthermore, when TILs were stratified by regression status, only the presence of TILs with or without regression was significantly associated with improved OS (p = 0.0081 and 0.0137, respectively) versus the absence of both TILs and regression, with regression status not significantly affecting OS for patients with or without TILs (p = 0.2314 and 0.65, respectively). CONCLUSIONS: Regression is highly correlated with TILs, but only TILs are significantly associated with SLN metastasis and OS in melanoma patients, whereas regression is not. The impact of regression on outcomes ultimately appears dependent upon the absence or presence of TILs.
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Linfadenopatía , Melanoma , Neoplasias Cutáneas , Humanos , Metástasis Linfática/patología , Linfocitos Infiltrantes de Tumor/patología , Melanoma/patología , Pronóstico , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND AND OBJECTIVES: The prognostic significance of regression in predicting melanoma recurrences is unknown. We present a large multicenter study correlating regression with recurrence. METHODS: The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with regression data. Clinicopathologic factors were correlated with overall and first-site of recurrence and with recurrence-free survival (RFS). RESULTS: There were 4790 patients and the median follow-up was 39.6 months. Regression and recurrences were seen in 1081 (22.6%) and 773 (16.1%) cases, respectively. First-site locoregional and distant recurrences were seen in 412 (8.6%) and 352 (7.3%) patients, respectively. Regression was seen in 15.8% and 24.7% of all cases with and without recurrences (p < 0.0001), respectively, while regression was seen in 14.3% and 17.9% of first-site locoregional and distant recurrent cases, respectively, compared with 23.3% and 22.9% of patients with regression and without first-site locoregional and distant recurrences, respectively (p = 0.29). On multivariable analysis, after controlling for age, gender, thickness, ulceration, lymphovascular invasion, and sentinel lymph node status, regression significantly predicted improved RFS (p = 0.004) and fewer first-site regional recurrences (p = 0.017). CONCLUSION: Our data suggest that regression is a favorable prognostic marker in melanoma and predicts significantly better RFS and decreased first-site regional recurrences.
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Melanoma/mortalidad , Recurrencia Local de Neoplasia/epidemiología , Anciano , Femenino , Humanos , Metástasis Linfática , Masculino , Melanoma/patología , Persona de Mediana Edad , Ganglio Linfático Centinela/patología , Ganglio Linfático Centinela/cirugíaRESUMEN
BACKGROUND: Sentinel lymph node biopsy (SLNB) is recommended for intermediate thickness melanoma, but for thick melanoma, guidelines are less definitive about the use of SLNB in this population. We present a study on thick melanoma evaluating for prognostic factors. PATIENTS AND METHODS: The Sentinel Lymph Node Working Group database was queried for thick (> 4 mm) melanoma cases that had a SLNB from 1993 to 2018. Clinicopathologic characteristics were correlated with SLN status and melanoma-specific survival (MSS). RESULTS: There were 1235 patients. Median follow-up was 28 months. Median thickness was 5.9 mm, with 956, 175, and 104 cases presenting thickness > 4-8, > 8-12, and > 12 mm, respectively. SLN metastases were seen in 439 of 1235 (35.5%) cases and in 33.9%, 40.6%, and 42.3% of melanomas > 4-8, > 8-12, and > 12 mm, respectively. In each thickness group, MSS was significantly worse for SLN-positive compared with SLN-negative cases (all P < 0.005). Multivariable analysis showed that SLN metastasis, male gender, increasing thickness, lymphovascular invasion, and microsatellitosis significantly predicted worse MSS for melanomas > 4-8 mm, with SLN metastasis showing the greatest risk (HR 2.17, 95% CI 1.64-2.87, P < 0.0001). For melanomas > 8 mm, only SLN metastasis significantly predicted MSS (> 8-12 mm: HR 3.93, 95% CI 2.00-7.73, P < 0.0001; > 12 mm: HR 3.58, 95% CI 1.56-8.22, p < 0.0027). CONCLUSIONS: Thick melanoma patients with SLN metastasis have significantly worse MSS compared with SLN-negative patients, even in the thickest cases, and SLN status is the most powerful and/or only predictor of MSS. Given these results, SLNB shows important prognostic value in this population and is indicated for clinically localized thick melanoma.
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Melanoma , Ganglio Linfático Centinela , Neoplasias Cutáneas , Humanos , Masculino , Melanoma/cirugía , Pronóstico , Estudios Retrospectivos , Ganglio Linfático Centinela/cirugía , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/cirugíaRESUMEN
Cancer metastasis may be regarded as a progressive process from its inception in the primary tumor microenvironment to distant sites by way of the lymphovascular system. Although this type of tumor dissemination often occurs in an orderly fashion via the sentinel lymph node (SLN), acting as a possible gateway to the regional lymph nodes, bone marrow, and peripheral blood and ultimately to distant metastatic sites, this is not a general rule as tumor cells may enter the blood and spread to distant sites, bypassing the SLN. Methods of detecting micrometastatic cancer cells in the SLN, bone marrow, and peripheral blood of patients have been established. Patients with cancer cells in their SLN, bone marrow, or peripheral blood have worse clinical outcomes than patients with no evidence of spread to these compartments. The presence of these cells also has important biologic implications for disease progression and the clinician's understanding of the process of cancer metastasis. Further characterization of these micrometastatic cancer cells at each stage and site of metastasis is needed to design novel selective therapies for a more "personalized" treatment.
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Médula Ósea/patología , Micrometástasis de Neoplasia , Células Neoplásicas Circulantes , Neoplasias de la Mama/patología , Humanos , Escisión del Ganglio Linfático , Metástasis Linfática , Melanoma/patología , Biopsia del Ganglio Linfático CentinelaRESUMEN
BACKGROUND: Mitotic rate is a strong, independent prognostic factor in patients with melanoma. However, incorporating it into the melanoma staging system has proved challenging. METHODS: The prognostic impact of mitotic rate was assessed in a melanoma cohort comprising 5050 patients from 2 geographically distinct populations. Computer-generated cut points for mitotic rate were constructed to determine its impact on melanoma-associated survival using Kaplan-Meier and multivariate regression analyses. The impact of mitotic rate also was assessed in randomly split training and validation sets. RESULTS: Mitotic rate had a nonlinear impact on survival, as evidenced by unequally spaced cut points. An index incorporating these cut points that was constructed from one population produced significantly more accurate predictions of survival in the other population than using the entire scale of mitotic rate. An index constructed from the combined cohort was found to be independently predictive of survival, with an impact comparable to that of ulceration. Optimal high-versus-low cut points for mitotic rate were generated separately for each T category (<2 mitoses/mm2 vs ≥2 mitoses/mm2 for T1 melanoma, <4 mitoses/mm2 vs ≥4 mitoses/mm2 for T2 melanoma, <6 mitoses/mm2 vs ≥6/mitoses/mm2 for T3 melanoma, and <7 mitoses/mm2 vs ≥7 mitoses/mm2 for T4 melanoma). Using Kaplan-Meier analysis, elevated mitotic rate was found to have an impact on survival comparable to that of ulceration within each T category. Application of the index for mitotic rate that was constructed from the training data set demonstrated an independent impact in the validation data set, with a significance similar to that of ulceration. CONCLUSIONS: The results of the current study demonstrated the comparable prognostic impact of mitotic rate and ulceration, providing support for its reincorporation into the T category.
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Melanoma/genética , Índice Mitótico/métodos , Femenino , Humanos , Masculino , Melanoma/mortalidad , Estadificación de Neoplasias , PronósticoRESUMEN
BACKGROUND: Patient-derived xenograft (PDX) mouse tumour models can predict response to therapy in patients. Predictions made from PDX cultures (PDXC) would allow for more rapid and comprehensive evaluation of potential treatment options for patients, including drug combinations. METHODS: We developed a PDX library of BRAF-mutant metastatic melanoma, and a high-throughput drug-screening (HTDS) platform utilising clinically relevant drug exposures. We then evaluated 34 antitumor agents across eight melanoma PDXCs, compared drug response to BRAF and MEK inhibitors alone or in combination with PDXC and the corresponding PDX, and investigated novel drug combinations targeting BRAF inhibitor-resistant melanoma. RESULTS: The concordance of cancer-driving mutations across patient, matched PDX and subsequent PDX generations increases as variant allele frequency (VAF) increases. There was a high correlation in the magnitude of response to BRAF and MEK inhibitors between PDXCs and corresponding PDXs. PDXCs and corresponding PDXs from metastatic melanoma patients that progressed on standard-of-care therapy demonstrated similar resistance patterns to BRAF and MEK inhibitor therapy. Importantly, HTDS identified novel drug combinations to target BRAF-resistant melanoma. CONCLUSIONS: The biological consistency observed between PDXCs and PDXs suggests that PDXCs may allow for a rapid and comprehensive identification of treatments for aggressive cancers, including combination therapies.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Melanoma/tratamiento farmacológico , Animales , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Melanoma/enzimología , Melanoma/genética , Melanoma/patología , Ratones , Mutación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Distribución Aleatoria , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The article "Intraoperative Imaging with a Portable Gamma Camera May Reduce the False-Negative Rate for Melanoma Sentinel Lymph Node Surgery," written by Stanley P. Leong et al., was originally published electronically on the publisher's internet portal (currently SpringerLink) on August 13, 2018, without open access.
RESUMEN
BACKGROUND: Factors that predict melanoma recurrence after a negative sentinel lymph node biopsy (SLNB) are not well-defined. We evaluated melanoma recurrence patterns, factors prognostic for recurrence, and the impact of recurrence on outcomes after a negative SLNB. METHODS: The Sentinel Lymph Node Working Group database was evaluated from 1996 to 2016 for negative SLNB melanoma patients. Clinicopathologic characteristics were correlated with recurrence, overall survival (OS), and melanoma-specific survival (MSS). RESULTS: Median follow-up was 32.1 months. Recurrences developed in 558 of 5351 negative SLN patients (10.4%). First-site of recurrence included a local or in-transit recurrence (LITR) in 221 cases (4.1%), nodal recurrence (NR) in 109 cases (2%), and distant recurrence (DR) in 220 cases (4.1%). On multivariable analysis, age, thickness, head/neck or lower extremity primary, and microsatellitosis significantly predicted for an LITR as first-site. Having an LITR as first-site significantly predicted for a subsequent NR and DR, and significantly predicted for worse OS and MSS. Furthermore, thickness and head/neck or lower extremity primary significantly predicted for an NR as first-site, while a prior LITR significantly predicted for a subsequent NR. Factors significantly predictive for a DR included thickness, head/neck or trunk primary, ulceration, and lymphovascular invasion. Patients with any type of locoregional recurrence were at higher risk for a DR. CONCLUSIONS: Recurrences occur in 10.4% of negative SLN patients, with LITR and DR being the most common types. Importantly, having an LITR significantly predicts for a subsequent NR and DR, and is prognostic for worse survival after a negative SLNB.
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Neoplasias de Cabeza y Cuello/patología , Escisión del Ganglio Linfático/mortalidad , Melanoma/patología , Recurrencia Local de Neoplasia/patología , Biopsia del Ganglio Linfático Centinela/mortalidad , Ganglio Linfático Centinela/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Masculino , Melanoma/cirugía , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/cirugía , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Ganglio Linfático Centinela/cirugía , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Microsatellitosis (mS) in melanoma has been considered a marker of unfavorable tumor biology, leading to the current American Joint Committee on Cancer staging of IIIB/C/D disease, despite few investigative studies of this entity limited by the small sample sizes and incomplete nodal microstaging. We sought to better characterize outcomes and prognostic factors in a multi-institutional cohort of patients with mS and nodal microstaging. METHODS: The Sentinel Lymph Node Working Group cohort included 414 mS patients who underwent sentinel lymph node (SLN) biopsy. Cox regression analysis was used to evaluate the prognostic significance of established clinicopathologic characteristics. Melanoma-specific survival (MSS) of patients with mS was compared with 3002 similarly staged patients from the Surveillance, Epidemiology, and End Results (SEER) Program registry. RESULTS: The median age of the mS cohort was 64.9 years; 39.6% were female. Median thickness was 3 mm, 40.6% of cases were ulcerated, and the SLN positivity rate was 46.7%. Increasing thickness, male sex, and SLN positivity were significantly associated with poorer MSS. Stage IIIB/C/D 5-year MSS rates were 86.3% (95% confidence interval [CI] 79.4-93.3%), 54.1% (95% CI 45.4-59.7%), and 44.2% (95% CI 25.4-63.0%), respectively. MSS survival for the stage IIIB mS cohort was significantly better than a similarly staged SEER cohort (5-year MSS of 70.1%, 95% CI 66.0-74.2%), while no significant difference was observed for the stage IIIC or D cohorts. CONCLUSIONS: SLN metastases are common and are a significant prognostic factor in patients with mS. Survival in stage IIIB patients with mS was considerably more favorable than their stage would otherwise suggest, which has important implications for decisions regarding adjuvant therapy for patients with mS.
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Melanoma/patología , Repeticiones de Microsatélite , Biopsia del Ganglio Linfático Centinela/mortalidad , Ganglio Linfático Centinela/patología , Neoplasias Cutáneas/patología , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melanoma/mortalidad , Melanoma/cirugía , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Programa de VERF , Ganglio Linfático Centinela/cirugía , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/cirugía , Tasa de SupervivenciaRESUMEN
BACKGROUND: Completion lymph node dissection (CLND) for sentinel lymph node (SLN) disease in melanoma patients is debated. We evaluated the impact of CLND on survival and assessed for predictors of nonsentinel node metastasis (positive CLND). METHODS: Positive SLN melanoma patients were retrospectively identified in the Sentinel Lymph Node Working Group database. Clinicopathological factors were correlated with CLND status, overall survival (OS), and melanoma-specific survival (MSS). RESULTS: There were 953 positive SLN patients of whom 831 (87%) had CLND. Positive CLND was seen in 141 (17%) cases and was associated with worse OS and MSS (both P < 0.001). CLND was not performed (No-CLND) in 122 of 953 positive SLN cases (13%), of whom 100 had follow-up and 18 (18%) developed a nodal recurrence (NR). No significant differences in OS and MSS were seen comparing CLND with No-CLND (P = 0.084, P = 0.161, respectively) and comparing positive CLND with No-CLND NR patients (P = 0.565, P = 0.998, respectively). Gender, primary site, ulceration, and number of positive SLNs were correlated with nonsentinel node metastasis. CONCLUSIONS: Performance of CLND provides prognostic information but is not associated with a survival benefit. Clinical variables can predict a positive CLND in patients who may be at high risk of recurrence.
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Escisión del Ganglio Linfático/estadística & datos numéricos , Melanoma/mortalidad , Melanoma/cirugía , Adulto , Anciano , Bases de Datos Factuales , Femenino , Humanos , Metástasis Linfática , Masculino , Melanoma/patología , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Biopsia del Ganglio Linfático Centinela , Tasa de SupervivenciaRESUMEN
BACKGROUND: Preoperative imaging and intraoperative gamma probe (GP) localization is standard for identifying sentinel lymph nodes (SLNs) in melanoma patients. The aim of this prospective Institutional Review Board-approved study was to investigate whether an intraoperative portable gamma camera (PGC) improves SLN detection over the GP. METHODS: Lymphoscintigraphy and single photon emission computed tomography/computed tomography were performed after injection of 99mTc-Tilmanocept in melanoma patients (≥ 18 years, Breslow thickness ≥ 1.0 mm). A GP was used to localize the SLNs in each basin, which was explored by the GP to ensure that the operative field was < 10% counts of the hottest SLN. The PGC was then used after a negative GP screening. Any residual hotspots identified by the PGC were considered as additional SLNs and were removed following the 10% rule. RESULTS: Preoperative imaging of 100 patients identified 138 SLN basins, with 306 SLNs being identified by conventional surgery. The PGC localized 89 additional SLNs in 54 patients. Thus, the PGC identified an additional 23% of SLNs [95% confidence interval (CI) 18-27%]. Four of these 89 SLNs showed micrometastasis in four patients, in two of whom the only tumor-positive SLN was identified by the PGC, preventing two false-negative cases. Thus, the null hypothesis that the PGC did not detect additional positive SLNs was rejected (p = 0.000). The overall SLN positive rate was 9.9% (39/395, 95% CI 6-12), and the overall patient positive rate was increased using the PGC, from 25 to 27% (27/100). CONCLUSIONS: Intraoperative PGC imaging yielded additional SLNs in a significant number of patients over GP alone. Identification of these additional SLNs resulted in upstaging of four patients with two patients being converted from a negative to a positive status, thus, preventing two false-negative cases.
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Cámaras gamma , Cuidados Intraoperatorios , Melanoma/cirugía , Ganglio Linfático Centinela/cirugía , Neoplasias Cutáneas/cirugía , Cirugía Asistida por Computador/métodos , Adulto , Anciano , Anciano de 80 o más Años , Reacciones Falso Negativas , Femenino , Estudios de Seguimiento , Humanos , Linfocintigrafia , Masculino , Melanoma/diagnóstico por imagen , Melanoma/patología , Persona de Mediana Edad , Micrometástasis de Neoplasia , Pronóstico , Estudios Prospectivos , Ganglio Linfático Centinela/diagnóstico por imagen , Ganglio Linfático Centinela/patología , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/secundarioRESUMEN
BACKGROUND: Melanoma brain metastasis is associated with an extremely poor prognosis, with a median overall survival of 4-5 months. Since 2011, the overall survival of patients with stage IV melanoma has been significantly improved with the advent of new targeted therapies and checkpoint inhibitors. We analyze the survival outcomes of patients diagnosed with brain metastasis after the introduction of these novel drugs. METHODS: We performed a retrospective analysis of our melanoma center database and identified 79 patients with brain metastasis between 2011 and 2015. RESULTS: The median time from primary melanoma diagnosis to brain metastasis was 3.2 years. The median overall survival duration from the time of initial brain metastasis was 12.8 months. Following a diagnosis of brain metastasis, 39 (49.4%), 28 (35.4%), and 24 (30.4%) patients were treated with anti-CTLA-4 antibody, anti-PD-1 antibody, or BRAF inhibitors (with or without a MEK inhibitor), with a median overall survival of 19.2 months, 37.9 months and 12.7 months, respectively. Factors associated with significantly reduced overall survival included male sex, cerebellar metastasis, higher number of brain lesions, and treatment with whole-brain radiation therapy. Factors associated with significantly longer overall survival included treatment with craniotomy, stereotactic radiosurgery, or with anti-PD-1 antibody after initial diagnosis of brain metastasis. CONCLUSIONS: These results show a significant improvement in the overall survival of patients with melanoma brain metastasis in the era of novel therapies. In addition, they suggest the activity of anti-PD-1 therapy specifically in the setting of brain metastasis.
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Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Melanoma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Antígeno CTLA-4/antagonistas & inhibidores , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Sentinel lymph nodes (SLNs), being the first nodes to receive lymph from a primary tumour and the preferential site of initial tumour metastases, are intensively exposed to the bioactive products of tumour cells and other associated cells. This makes them ideal for studies of the factors that determine selective tissue susceptibility to metastases. We postulate that tumour-induced immune modulation of SLNs facilitates lymph-node metastases by inhibiting the generation of tumour-specific cytotoxic T cells that are active against tumour cells of primary and metastatic melanomas. Immune modulation of the lymph nodes can be reversed by granulocyte/macrophage colony-stimulating factor (GM-CSF), a finding that has implications for the future therapy of lymph-node metastases.
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Metástasis Linfática/inmunología , Metástasis Linfática/patología , Neoplasias/inmunología , Neoplasias/patología , Animales , Movimiento Celular , Células Dendríticas/citología , Células Dendríticas/inmunología , Humanos , Neoplasias/metabolismo , Neoplasias/terapia , Biopsia del Ganglio Linfático CentinelaRESUMEN
Although melanomas with mutant v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) can now be effectively targeted, there is no molecular target for most melanomas expressing wild-type BRAF. Here, we show that the activation of Pleckstrin homology domain-interacting protein (PHIP), promotes melanoma metastasis, can be used to classify a subset of primary melanomas, and is a prognostic biomarker for melanoma. Systemic, plasmid-based shRNA targeting of Phip inhibited the metastatic progression of melanoma, whereas stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged the survival of tumor-bearing mice. The human PHIP gene resides on 6q14.1, and although 6q loss has been observed in melanoma, the PHIP locus was preserved in melanoma cell lines and patient samples, and its overexpression was an independent adverse predictor of survival in melanoma patients. In addition, a high proportion of PHIP-overexpressing melanomas harbored increased PHIP copy number. PHIP-overexpressing melanomas include tumors with wild-type BRAF, neuroblastoma RAS viral (v-ras) oncogene homolog, and phosphatase and tensin homolog, demonstrating PHIP activation in triple-negative melanoma. These results describe previously unreported roles for PHIP in predicting and promoting melanoma metastasis, and in the molecular classification of melanoma.
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Biomarcadores de Tumor/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Melanoma Experimental/metabolismo , Melanoma Experimental/secundario , Melanoma/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Animales , Secuencia de Bases , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/genética , Melanoma/genética , Melanoma/secundario , Melanoma Experimental/genética , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , ARN Interferente Pequeño/genética , Transducción de SeñalRESUMEN
PURPOSE: We have previously reported that older patients with clinical stage I and II primary cutaneous. Melanoma had lower survival rates compared to younger patients. We postulated that the incidence of nodal metastasis would therefore be higher among older melanoma patients. METHODS: The expanded American Joint Committee on Cancer melanoma staging database contains a cohort of 7,756 melanoma patients who presented without clinical evidence of regional lymph node or distant metastasis and who underwent a sentinel node biopsy procedure as a component of their staging assessment. RESULTS: Although older patients had primary melanoma features associated with more aggressive biology, we paradoxically observed a significant decrease in the incidence of sentinel node metastasis as patient age increased. Overall, the highest incidence of sentinel node metastasis was 25.8 % in patients under 20 years of age, compared to 15.5 % in patients 80 years and older (p < 0.001). In contrast, 5-year mortality rates for clinical stage II patients ranged from a low of 20 % for those 20-40 years of age up to 38 % for those over 70 years of age. Patient age was an independent predictor of sentinel node metastasis in a multifactorial analysis (p < 0.001). CONCLUSIONS: Patients with clinical stage I and II melanoma under 20 years of age had a higher incidence of sentinel lymph node metastasis but, paradoxically, a more favorable survival outcome compared to all other age groups. In contrast, patients >70 years had the most aggressive primary melanoma features and a higher mortality rate compared to all other age groups but a lower incidence of sentinel lymph node metastasis.
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Ganglios Linfáticos/patología , Melanoma/mortalidad , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/mortalidad , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Escisión del Ganglio Linfático , Ganglios Linfáticos/cirugía , Metástasis Linfática , Masculino , Melanoma/patología , Melanoma/cirugía , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/secundario , Tasa de Supervivencia , Estados Unidos , Adulto JovenRESUMEN
Melanoma excision requires wide margins, leaving large defects. Surgical dogma has taught that definitive reconstruction of melanoma defects be performed after permanent pathology results, with skin grafts favored. However, this results in an open wound and the need for a second operation. The advantages of immediate reconstruction with flaps are single-stage surgery, high patient satisfaction, no period of disfigurement, and cost savings. Our purpose was to evaluate rate of positive margins and local recurrence after immediate reconstruction of head and neck melanoma (HNM) defects with flaps to determine safety of this approach. We prospectively followed all patients with HNM treated at a single center from January 2010 to June 2012 and collected patient and tumor data and reconstruction type. Outcomes assessed were permanent pathology margins and local recurrence rate. Risk factors for positive margins were assessed. Seventy-six patients with HNM were treated with wide excision and immediate flap reconstruction with a mean age of 59 years. Five patients had melanoma in situ and 71 had invasive melanoma. There was a 15.4% ulceration rate. Median thickness for invasive melanoma was 2.2 mm. Mean excision margin was 1.4 cm. Median follow-up was 2 years; 5.3% of patients had positive margins on permanent pathology after reconstruction and 3 were reexcised with negative margins. Local recurrence rate was 2.6% with no recurrence in patients with previous reexcised positive margins. Significant risk factors for positive margins were melanoma in situ excised with 5-mm margins (P=0.012) and desmoplastic melanoma (P<0.02). Immediate flap reconstruction after excision of HNM can be safely performed with low positive margin and local recurrence rates. This should be offered to patients, especially those with primary melanomas with distinct borders and excision margins greater than or equal to 1 cm.
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Neoplasias de Cabeza y Cuello/cirugía , Melanoma/cirugía , Procedimientos de Cirugía Plástica/métodos , Neoplasias Cutáneas/cirugía , Colgajos Quirúrgicos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Cancer cells within a population are heterogeneous due to genomic mutations or epigenetic changes. The immune response to cancer especially the T cell repertoire within the cancer microenvionment is important to the control and growth of cancer cells. When a cancer clone breaks through the surveillance of the immune system, it wins the battle to overcome the host's immune system. In this review, the complicated profile of the cancer microenvironment is emphasized. The molecular evidence of immune responses to cancer has been recently established. Based on these molecular mechanisms of immune interactions with cancer, clinical trials based on checkpoint inhibition therapy against CTLA-4 and/or PD-1 versus PD-L1 have been successful in the treatment of melanoma, lung cancer and other types of cancer. The diversity of the T cell repertoire is described and the tumor infiltrating lymphocytes within the cancer may be expanded ex vivo and infused back to the patient as a treatment modality for adoptive immunotherapy.