RESUMO
PURPOSE: In metastatic renal cell carcinoma (mRCC), survival benefit associated with objective response rates of 16-20 % with high-dose interleukin-2 (HDIL-2) is well established and discussed. Based on recently emerged data on efficacy of cancer immunotherapy, we hypothesized that the survival benefit with HDIL-2 extends beyond those achieving objective responses, i.e., to those who achieve stable disease as the best response to treatment. MATERIALS AND METHODS: All sequential treatment naïve mRCC patients treated with HDIL-2 at the University of Utah (1988-2013) and University of Michigan (1997-2013) were included. Best responses on treatment were associated with survival outcomes using log-rank and COX regression with a landmark analysis at 2 months. RESULTS: 391 patients (75 % male; median age 55 years) were included and belonged to the following prognostic risk categories: 20 % good, 64 % intermediate, and 15 % poor. Best responses on treatment were complete response (9 %), partial response (10 %), stable disease (32 %), progressive disease (42 %), and not evaluable for response (7 %). No significant differences in progression-free survival (HR 0.74, 95 % CI 0.48-1.1, p = 0.14) or overall survival (HR 0.66, 95 % CI 0.39-1.09, p = 0.11) were observed between patients achieving partial response versus stable disease. Significant differences in progression-free survival (HR 0.13, 95 % CI 0.09-0.22, p < 0.0001) and overall survival (HR 0.33, 95 % CI 0.23-0.48, p < 0.0001) were observed between patients achieving stable disease compared to those with progressive disease and who were not evaluable. CONCLUSIONS: Survival benefit with HDIL-2 is achieved in ~50 % patients and extends beyond those achieving objective responses.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/uso terapêutico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Estudos de Coortes , Feminino , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/farmacologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Análise de SobrevidaRESUMO
Purpose. Circulating melanoma cells (CMCs) constitute a potentially important representation of time-resolved tumor biology in patients. To date, genomic characterization of CMCs has been limited due to the lack of a robust methodology capable of identifying them in a format suitable for downstream characterization. Here, we have developed a methodology to detect intact CMCs that enables phenotypic, morphometric and genomic analysis at the single cell level. Experimental design. Blood samples from 40 metastatic melanoma patients and 10 normal blood donors were prospectively collected. A panel of 7 chondroitin sulfate proteoglycan 4 (CSPG4)-specific monoclonal antibodies (mAbs) was used to immunocytochemically label CMCs. Detection was performed by automated digital fluorescence microscopy and multi-parametric computational analysis. Individual CMCs were captured by micromanipulation for whole genome amplification and copy number variation (CNV) analysis. Results. Based on CSPG4 expression and nuclear size, 1-250 CMCs were detected in 22 (55%) of 40 metastatic melanoma patients (0.5-371.5 CMCs ml(-1)). Morphometric analysis revealed that CMCs have a broad spectrum of morphologies and sizes but exhibit a relatively homogeneous nuclear size that was on average 1.5-fold larger than that of surrounding PBMCs. CNV analysis of single CMCs identified deletions of CDKN2A and PTEN, and amplification(s) of TERT, BRAF, KRAS and MDM2. Furthermore, novel chromosomal amplifications in chr12, 17 and 19 were also found. Conclusions. Our findings show that CSPG4 expressing CMCs can be found in the majority of advanced melanoma patients. High content analysis of this cell population may contribute to the design of effective personalized therapies in patients with melanoma.
Assuntos
Genoma Humano/genética , Melanoma/genética , Melanoma/patologia , Células Neoplásicas Circulantes/patologia , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
OBJECTIVE: Ipilimumab is a fully human, anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody that has demonstrated antitumor activity in advanced melanoma. We evaluated the safety and efficacy of ipilimumab alone and in combination with dacarbazine (DTIC) in patients with unresectable, metastatic melanoma. METHODS: Chemotherapy-naïve patients were randomized in this multicenter, phase II study to receive ipilimumab at 3 mg/kg every 4 weeks for four doses either alone or with up to six 5-day courses of DTIC at 250 mg/m(2)/day. The primary efficacy endpoint was objective response rate. RESULTS: Seventy-two patients were treated per-protocol (ipilimumab plus DTIC, n = 35; ipilimumab, n = 37). The objective response rate was 14.3% (95% CI, 4.8-30.3) with ipilimumab plus DTIC and was 5.4% (95% CI, 0.7-18.2) with ipilimumab alone. At a median follow-up of 20.9 and 16.4 months for ipilimumab plus DTIC (n = 32) and ipilimumab alone (n = 32), respectively, median overall survival was 14.3 months (95% CI, 10.2-18.8) and 11.4 months (95% CI, 6.1-15.6); 12-month, 24-month, and 36-month survival rates were 62%, 24% and 20% for the ipilimumab plus DTIC group and were 45%, 21% and 9% for the ipilimumab alone group, respectively. Immune-related adverse events were, in general, medically manageable and occurred in 65.7% of patients in the combination group versus 53.8% in the monotherapy group, with 17.1% and 7.7% ≥grade 3, respectively. CONCLUSION: Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dacarbazina/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Dacarbazina/efeitos adversos , Dacarbazina/farmacocinética , Demografia , Feminino , Humanos , Ipilimumab , Estimativa de Kaplan-Meier , Subpopulações de Linfócitos/imunologia , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
Interleukin-2 (IL-2) is used to treat metastatic renal cell carcinoma and malignant melanoma, but its use is limited by the severe hypotension it produces. We have shown here that M40403, a superoxide dismutase (SOD) mimetic, blocked IL-2-induced hypotension and allowed the dose of IL-2 to be increased in mice. The reversal of IL-2-mediated hypotension was associated with an increase in plasma catecholamines. In addition, M40403 increased lymphokine-activated killer (LAK) cell cytotoxicity in vitro and in vivo, through inhibition of macrophage superoxide production. Treatment of methylcholanthrene-induced (Meth A) ascites tumors with IL-2 and > or =3 mg per kg body weight M40403 induced 50% complete remissions lasting for more than 200 d, which was longer than those of untreated mice (15-d median survival) or mice treated with IL-2 alone (22-d median). Growth of subcutaneous implants of RENCA renal carcinoma was also inhibited by the combination of IL-2 and M40403. These results established that M40403 prevented IL-2 from causing dose-limiting hypotension, while enhancing its anticancer activity.
Assuntos
Antineoplásicos/uso terapêutico , Hipotensão/induzido quimicamente , Interleucina-2/uso terapêutico , Mimetismo Molecular , Compostos Organometálicos/uso terapêutico , Superóxido Dismutase/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Catecolaminas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipotensão/prevenção & controle , Interleucina-2/toxicidade , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária , Macrófagos/imunologia , Macrófagos/metabolismo , Manganês , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Estrutura Molecular , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Superóxido Dismutase/química , Taxa de SobrevidaRESUMO
In the last 3 years there has been a dramatic increase in the treatment options for patients with metastatic renal cancer. In addition to the cytokines interferon and interleukin 2, recently approved agents include sorafenib, sunitinib, temsirolimus and bevacizumab. A plethora of agents that are likely to have clinical activity are currently in the development 'pipeline'. This brief review is intended to overview recent developments, and to identify advances that are likely to influence treatment decisions.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , HumanosRESUMO
PURPOSE: UV radiation is the major environmental risk factor for melanoma and a potent inducer of oxidative stress, which is implicated in the pathogenesis of several malignancies. We evaluated whether the thiol antioxidant N-acetylcysteine (NAC) could protect melanocytes from UV-induced oxidative stress/damage in vitro and from UV-induced melanoma in vivo. EXPERIMENTAL DESIGN: In vitro experiments used the mouse melanocyte line melan-a. For in vivo experiments, mice transgenic for hepatocyte growth factor and survivin, shown previously to develop melanoma following a single neonatal dose of UV irradiation, were given NAC (7 mg/mL; mother's drinking water) transplacentally and through nursing until 2 weeks after birth. RESULTS: NAC (1-10 mmol/L) protected melan-a cells from several UV-induced oxidative sequelae, including production of intracellular peroxide, formation of the signature oxidative DNA lesion 8-oxoguanine, and depletion of free reduced thiols (primarily glutathione). Delivery of NAC reduced thiol depletion and blocked formation of 8-oxoguanine in mouse skin following neonatal UV treatment. Mean onset of UV-induced melanocytic tumors was significantly delayed in NAC-treated compared with control mice (21 versus 14 weeks; P = 0.0003). CONCLUSIONS: Our data highlight the potential importance of oxidative stress in the pathogenesis of melanoma and suggest that NAC may be useful as a chemopreventive agent.
Assuntos
Acetilcisteína/farmacologia , Melanócitos/metabolismo , Melanócitos/efeitos da radiação , Melanoma/tratamento farmacológico , Melanoma/etiologia , Neoplasias Induzidas por Radiação/tratamento farmacológico , Estresse Oxidativo , Animais , Anticarcinógenos/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dímeros de Pirimidina/química , Espécies Reativas de Oxigênio , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos da radiação , Raios UltravioletaRESUMO
For decades, options for the treatment for metastatic renal cancer have been limited and mostly ineffective. During this time, immunotherapy agents, such as IFN-alpha and IL-2, have represented the major treatment options. Over the last 3 years, advances in cancer biology have characterized important signaling pathways that regulate blood vessel growth and cell proliferation. These studies have identified a number of novel 'druggable' targets. Since 2004, this has resulted in regulatory approval of four additional agents that are active against renal cancer (bevacizumab, sorafenib, sunitinib and temsirolimus). A large number of additional candidate molecules that block the vascular endothelial growth factor and mTOR pathways have subsequently been identified. These agents are rapidly progressing through clinical testing in renal cancer and in other malignancies. This paper overviews the status of these investigational agents and anticipates areas of future research and development.
Assuntos
Antineoplásicos , Desenho de Fármacos , Neoplasias Renais/tratamento farmacológico , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Indústria Farmacêutica , Humanos , Neoplasias Renais/imunologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Metástase Neoplásica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/metabolismo , Serina-Treonina Quinases TOR , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
The incidence of CNS progression in patients with high-risk regional melanoma (stages IIIAN2a-IIIC) is not well characterized. Data from the S0008 trial provided an opportunity to examine the role of CNS progression in treatment failure and survival. All patients were surgically staged. Following wide excision and full regional lymphadenectomy, patients were randomized to receive adjuvant biochemotherapy (BCT) or high-dose interferon alfa-2B (HDI). CNS progression was retrospectively identified from data forms. Survival was measured from date of CNS progression. A total of 402 eligible patients were included in the analysis (BCT: 199, HDI: 203). Median follow-up (if alive) was over 7 years (range: 1 month to 11 years). The site of initial progression was identifiable in 80% of relapsing patients. CNS progression was a component of systemic melanoma relapse in 59/402 patients (15% overall). In 34/402 patients (9%) CNS progression represented the initial site of treatment failure. CNS progression was a component of initial progression in 27% of all patients whose melanoma relapsed (59/221). The risk of CNS progression was highest within 3 years of randomization. The difference in CNS progression rates between treatment arms was not significant (BCT = 25, HDI = 34, P = 0.24). Lymph node macrometastases strongly associated with CNS progression (P = 0.001), while ulceration and head and neck primaries were not significant predictors. This retrospective analysis of the S0008 trial identified a high brain metastasis rate (15%) in regionally advanced melanoma patients. Further studies are needed to establish whether screening plus earlier treatment would improve survival following CNS progression.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/secundário , Interferon-alfa/uso terapêutico , Melanoma/secundário , Melanoma/terapia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Cisplatino/administração & dosagem , Dacarbazina/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Linfonodos/patologia , Metástase Linfática , Masculino , Melanoma/complicações , Estadiamento de Neoplasias , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Neoplasias Cutâneas/complicações , Úlcera Cutânea/etiologia , Taxa de Sobrevida , Vimblastina/administração & dosagemRESUMO
Cyclin-dependent kinase inhibitor 2A (CDKN2A or p16) is the major melanoma predisposition gene. In order to evaluate the candidacy for genetic testing of CDKN2A mutations among melanoma prone families, it is important to identify characteristics that predict a high likelihood of carrying a CDKN2A mutation. We primarily used a unique Utah genealogical resource to identify independent melanoma prone families whom we tested for mutations in CDKN2A, cyclin-dependent kinase 4, and alternate reading frame. We sampled 60 families which met the inclusion criteria of two or more affected first-degree relatives. We found four different pathogenic CDKN2A mutations in five families, mutations of uncertain significance in two families, and known polymorphisms in three families. One of the mutations of uncertain significance, 5' untranslated region -25C>T, has not been previously described. Among our population-based set of Utah families, the prevalence of CDKN2A mutations was 8.2% (4/49); the overall prevalence when physician-referred pedigrees were also considered was between 8.3% (5/60) and 10% (6/60). Having four or more first- or second-degree relatives with melanoma, or a family member with > or =3 primary melanomas, correlated strongly with carrying a CDKN2A mutation. We observed a significantly elevated rate of pancreatic cancer in one of four families with a deleterious CDKN2A mutation.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Melanoma/genética , Mutação , Neoplasias Cutâneas/genética , Sequência de Bases , Ilhas de CpG , Humanos , Dados de Sequência Molecular , Neoplasias Primárias Múltiplas/genética , Neoplasias Pancreáticas/genéticaRESUMO
PURPOSE: The nucleoside analog 5-aza-2'-deoxycytidine (5-aza-CdR, decitabine) is a potent inhibitor of DNA methylation in vitro. Cellular treatment with this agent induces the re-expression of methylation-silenced genes. It remains unclear to what extent this compound inhibits DNA methylation in vivo. A clinical study was designed to examine the molecular effects and toxicity of a continuous 1-week intravenous infusion of decitabine in solid tumor patients. METHODS: Ten patients with refractory solid tumors were included in this study. Decitabine was administered at 2 mg/m(2)/d [DOSAGE ERROR CORRECTED] via continuous infusion for 168 hours. Quantitative polymerase chain reaction and high performance liquid chromatography were utilized to measure promoter-specific and global DNA methylation in peripheral-blood cells before and after treatment. RESULTS: Transient grade III/IV neutropenia (two patients) and grade II thrombocytopenia (one patient) was observed at the lowest planned dose step (2 mg/m2/d for 7 days). Nonhematologic toxicities were not observed. Quantitative polymerase chain reaction demonstrated significant MAGE-1 promoter hypomethylation by 14 days after the start of treatment in all 13 treatment cycles examined. Significant genomic DNA hypomethylation was also seen by day 14 in 11 of 13 treatment cycles analyzed. Genomic DNA methylation reverted to baseline levels by 28 to 35 days after the start of treatment, demonstrating that inhibition of DNA methylation by decitabine is transient. CONCLUSION: A 168-hour continuous infusion of decitabine is well tolerated and results in the inhibition of promoter-specific and genomic DNA methylation in vivo. This treatment schedule is suitable for evaluation of decitabine in combination with agents whose activity may be enhanced by the reversal of DNA methylation-mediated gene silencing.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Metilação de DNA , Inativação Gênica , Neoplasias/tratamento farmacológico , Regiões Promotoras Genéticas/genética , Idoso , Idoso de 80 Anos ou mais , Metilases de Modificação do DNA/antagonistas & inibidores , Decitabina , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias/patologiaRESUMO
PURPOSE: Familial melanoma patients are reported to present with thinner melanomas, to be younger at the time of diagnosis, and to have a greater likelihood of developing multiple primary tumors. We sought to determine whether melanomas that occur in a familial setting demonstrate different prognostic and survival statistics relative to sporadic melanoma. PATIENTS AND METHODS: This population-based study used the Utah Cancer Registry and Utah Population Database to objectively evaluate prognostic and survival statistics of the familial melanoma population. From 1973 to 1999, there were 7,785 cases of invasive melanoma identified through the Utah Cancer Registry. These were linked to the Utah Population Database, resulting in 2,659 subjects with family-history information from which a familiality score could be calculated. Cases scored in the top ninth percentile were assigned as high familial risk, and the remaining 91% were considered low familial risk. RESULTS: Multivariate logistic-regression analysis found no association between sex, Breslow depth, Clark level, or survival and the familial status. Age at first diagnosis of invasive melanoma was slightly lower in the high-familial-risk group (57 v 60 years; P = .03). High-familial-risk subjects had more melanomas diagnosed at age 30 or younger (12% v 6%; P < .001). A significant difference in the overall number of individuals with two or more primary malignant melanomas was not detected among the groups (P = .2). CONCLUSION: These data suggest that melanomas occurring in the context of an underlying inherited susceptibility do not have a significantly different biologic behavior.
Assuntos
Predisposição Genética para Doença , Melanoma/genética , Sistema de Registros/estatística & dados numéricos , Neoplasias Cutâneas/genética , Adulto , Idoso , Bases de Dados Factuais , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Prognóstico , Fatores Sexuais , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Utah/epidemiologiaRESUMO
Conditional survival (CS) is a clinically useful prediction measure which adjusts a patient's prognosis based on their duration of survival since initiation of therapy. CS has been described in numerous malignancies, and recently described in patients with metastatic renal cell carcinoma (mRCC) who received vascular endothelial growth factor tyrosine kinase inhibitor (VEGFTKI) therapy. However, CS has been not reported in the context of mRCC treated with high-dose interleukin-2 therapy (HDIL-2). A total of 176 patients with histologically confirmed metastatic clear cell RCC (mccRCC) treated with HDIL-2 at the University of Utah Huntsman Cancer Institute from 1988-2012 were evaluated. Using the Heng/IMDC model, they were stratified by performance status and prognostic risk groups. Two-year CS was defined as the probability of surviving an additional two years from initiation of HDIL-2 to 18 months after the start of HDIL-2 at three-month intervals. The median overall survival (OS) was 19.9 months. Stratifying patients into favourable (n = 35; 20%), intermediate (n = 110; 63%), and poor (n = 31; 18%) prognostic groups resulted in median OS of 47.5 (HR 0.57, 95% CI 0.35-0.88, p = 0.0106 versus intermediate), 19.6 (HR 0.33, 95% CI 0.10-0.33, p < 0.0001 versus poor), and 8.8 (HR 5.34, 95% CI 3.00-9.62, p < 0.0001 versus favourable) months respectively. Two-year overall CS increased from 43% at therapy initiation to 100% at 18 months. These results have significant ramifications in prognostication. Furthermore, it is important when counseling patients with mccRCC who have completed treatment with HDIL-2 and are in active follow-up.
RESUMO
PURPOSE: Although metastases to the fetus via the placenta are rare, melanoma is the most common culprit. When it occurs, maternally derived melanoma metastasis in the infant is almost invariably fatal. PATIENTS AND METHODS: This article reviews current guidelines for placental evaluation in pregnant women with metastatic melanoma and presents surveillance recommendations for their infants. Comprehensive literature reviews were performed on melanoma in pregnancy and melanoma metastasis to the placenta and fetus. The use of interferon alfa in the pediatric population was also reviewed. A comprehensive search of the MEDLINE database (1966 to 2002) was performed. Articles were reviewed and additional references were obtained from the bibliographies. Translation of non-English articles was performed, and authors of previous publications were contacted. RESULTS: Eighty-seven patients with placental or fetal metastasis were identified. Twenty-seven occurrences were attributed to melanoma (31%). The fetus was affected in six of 27 melanoma patients (22%), with five of six infants dying of disease. The use of high-dose interferon alfa adjuvant therapy in pediatric patients has not been reported. CONCLUSION: The placentas of women with known or suspected metastatic melanoma should be carefully examined grossly and histologically by pathologists. With placental involvement, fetal risk of melanoma metastasis is approximately 22%. Neonates delivered with concomitant placental involvement should be considered a high-risk population. The risk-benefit ratio of adjuvant treatment for a potentially affected infant should be carefully weighed.
Assuntos
Doenças Fetais/patologia , Melanoma/congênito , Melanoma/secundário , Doenças Placentárias/patologia , Complicações Neoplásicas na Gravidez/patologia , Feminino , Humanos , Incidência , Recém-Nascido , Masculino , Melanoma/epidemiologia , Melanoma/mortalidade , Metástase Neoplásica , Neoplasias/congênito , Neoplasias/epidemiologia , Neoplasias/mortalidade , Neoplasias/patologia , Gravidez , Resultado da Gravidez , Risco , Taxa de SobrevidaRESUMO
Phenotypic characteristics of members of a melanoma prone kindred with a V126D CDKN2A gene mutation were monitored over approximately 15 y. Thirty-eight previously studied subjects were recruited. Participants underwent a complete skin examination by the same dermatologist who examined them initially. The size and location of all nevi were recorded on a body map diagram. Total nevus number (TNN) and total nevus density (TND) were determined. CDKN2A sequencing verified 13 mutation carriers and 16 non-carriers. Nine participants were spouse controls without a history of melanoma and did not carry a CDKN2A mutation. Mutation carriers demonstrated a greater mean TNN and TND at initial and follow-up examinations compared with non-carriers and continued to develop nevi rather than show nevus regression seen in non-carriers and spouse controls. Non-carriers showed an intermediate nevus phenotype between mutation carriers and spouse controls. Four of the 13 mutation carriers and one non-carrier have developed invasive melanoma. Over a 15-y interval, TNN and TND were increased in mutation carriers compared with non-carriers and spouse controls. Continued accumulation of nevi in mutation carriers supports a nevogenic role for this CDKN2A mutation. An intermediate nevus phenotype in non-carrier family members suggests the presence of additional modifier genes.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Melanoma/genética , Nevo/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Criança , Meio Ambiente , Saúde da Família , Feminino , Seguimentos , Heterozigoto , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Mutação PuntualRESUMO
Nitric oxide (NO*) synthesis is induced within many tumors. The time course of NO* synthesis was evaluated during intra-peritoneal Meth A fibrosarcoma progression. While increasing macrophage recruitment into ascites was noted, inducible nitric oxide synthase (iNOS) antigen and function peaked between days 3-6 after tumor implantation. The capacity of cells to respond to LPS and IFNgamma stimulation was markedly depressed on day 9 and 11. Cellular proliferation correlated in an inverse fashion with levels of NO* synthesis. Electron paramagnetic resonance spectroscopy and nitrotyrosine immunostaining failed to show accumulation of characteristic target cell lesions induced by NO*. These findings lead us to conclude that NO* production was increasingly suppressed during Meth A tumor progression. Depression of NO* production did not correlate with levels of the inhibitory cytokines TGFbeta and IL-10, but could be partially overcome by addition of sepiapterin (a tetrahydrobiopterin prodrug). Thus, depletion of essential co-factors necessary for iNOS function may contribute to depressed NO* responses during cancer progression.
Assuntos
Ascite/metabolismo , Citocinas/metabolismo , Fibrossarcoma/metabolismo , Óxido Nítrico/biossíntese , Fagócitos/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Espectroscopia de Ressonância de Spin Eletrônica , Repressão Enzimática/efeitos dos fármacos , Imuno-Histoquímica , Lipopolissacarídeos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Nitritos/metabolismo , Pterinas/farmacologia , Fatores de TempoRESUMO
Nitric oxide (NO*) synthesis is induced within many tumors. The timecourse of NO* synthesis was evaluated during intraperitoneal Meth A fibrosarcoma progression. While increasing macrophage recruitment into ascites was noted, inducible nitric oxide synthase (iNOS) antigen and function peaked between days 3-6 after tumor implantation. The capacity of cells to respond to LPS and IFNgamma stimulation was markedly depressed on day 9 and 11. Cellular proliferation correlated in an inverse fashion with levels of NO* synthesis. Electron paramagnetic resonance spectroscopy and nitrotyrosine immunostaining failed to show accumulation of characteristic target cell lesions induced by NO*. These findings lead us to conclude that NO* production was increasingly suppressed during Meth A tumor progression. Depression of NO* production did not correlate with levels of the inhibitory cytokines TGFbeta and IL-10, but could be partially overcome by addition of sepiapterin (a tetrahydrobiopterin prodrug). Thus, depletion of essential co-factors necessary for iNOS function may contribute to depressed NO* responses during cancer progression.
Assuntos
Ascite/metabolismo , Citocinas/metabolismo , Fibrossarcoma/metabolismo , Macrófagos/metabolismo , Óxido Nítrico/biossíntese , Animais , Ascite/patologia , Fibrossarcoma/imunologia , Citometria de Fluxo , Imunofluorescência , Imuno-Histoquímica , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/imunologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II , Análise Espectral , Fatores de TempoRESUMO
BACKGROUND: Trebananib, an investigational peptibody, binds to angiopoietin 1 and 2, thereby blocking their interaction with Tie2. PATIENTS AND METHODS: This open-label phase I study examined trebananib 3 mg/kg or 10 mg/kg intravenous (I.V.) once weekly plus sorafenib 400 mg twice per day or sunitinib 50 mg once per day in advanced RCC. Primary end points were adverse event incidence and pharmacokinetics. RESULTS: Thirty-seven patients were enrolled. During trebananib plus sorafenib administration (n = 17), the most common treatment-related adverse events (TRAEs) included rash (n = 12; 71%), diarrhea (n = 12; 71%), hypertension (n = 11; 65%), and fatigue (n = 11; 65%); grade ≥ 3 TRAEs (n = 7; 41%); and 2 patients (12%) had peripheral edema. During trebananib plus sunitinib administration (n = 19), the most common TRAEs included diarrhea (n = 14; 74%), fatigue (n = 13; 68%), hypertension (n = 11; 58%), and decreased appetite (n = 11; 58%); grade ≥ 3 TRAEs (n = 13; 68%); and 8 (42%) patients had peripheral edema. Trebananib did not appear to alter the pharmacokinetics of sorafenib or sunitinib. No patient developed anti-trebananib antibodies. Objective response rates were 29% (trebananib plus sorafenib) and 53% (trebananib plus sunitinib). CONCLUSION: The toxicities of trebananib 3 mg/kg or 10 mg/kg I.V. plus sorafenib or sunitinib in RCC were similar to those of sorafenib or sunitinib monotherapy, with peripheral edema being likely specific to the combinations. Antitumor activity was observed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Proteínas Angiogênicas/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Feminino , Humanos , Indóis/administração & dosagem , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Pirróis/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Sorafenibe , Sunitinibe , Resultado do TratamentoRESUMO
Merkel cell carcinoma (MCC) is a highly aggressive skin malignancy. The growing incidence and recognition of this cancer in elderly or immunosuppressed individuals suggests that it is becoming an increasing clinical challenge. MCC recently has been demonstrated to have a probable viral pathogenesis related to a novel member of the polyomavirus (termed Merkel cell polyomavirus [MCV]). The molecular pathogenesis of viral carcinogenesis is currently being worked out in MCC. Current diagnostic and therapeutic strategies are discussed, with an eye toward the future development of molecularly targeted treatments.
Assuntos
Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/terapia , Infecções por Polyomavirus/complicações , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/virologia , Ensaios Clínicos como Assunto , Humanos , Polyomavirus/genética , Polyomavirus/metabolismo , Infecções por Polyomavirus/patologia , Infecções por Polyomavirus/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/virologiaRESUMO
A message from ASCO'S President. It has been forty years since President Richard Nixon signed the National Cancer Act of 1971, which many view as the nation's declaration of the "War on Cancer." The bill has led to major investments in cancer research and significant increases in cancer survival. Today, two-thirds of patients survive at least five years after being diagnosed with cancer compared with just half of all diagnosed patients surviving five years after diagnosis in 1975. The research advances detailed in this year's Clinical Cancer Advances demonstrate that improvements in cancer screening, treatment, and prevention save and improve lives. But although much progress has been made, cancer remains one of the world's most serious health problems. In the United States, the disease is expected to become the nation's leading cause of death in the years ahead as our population ages. I believe we can accelerate the pace of progress, provided that everyone involved in cancer care works together to achieve this goal. It is this viewpoint that has shaped the theme for my presidential term: Collaborating to Conquer Cancer. In practice, this means that physicians and researchers must learn from every patient's experience, ensure greater collaboration between members of a patient's medical team, and involve more patients in the search for cures through clinical trials. Cancer advocates, insurers, and government agencies also have important roles to play. Today, we have an incredible opportunity to improve the quality of cancer care by drawing lessons from the real-world experiences of patients. The American Society of Clinical Oncology (ASCO) is taking the lead in this area, in part through innovative use of health information technology. In addition to our existing quality initiatives, ASCO is working with partners to develop a comprehensive rapid-learning system for cancer care. When complete, this system will provide physicians with personalized, real-time information that can inform the care of every patient with cancer as well as connect patients with their entire medical teams. The rapid learning system will form a continuous cycle of learning: securely capturing data from every patient at the point of care, drawing on evidence-based guidelines, and evaluating quality of care against those standards and the outcomes of other patients. Clinical trials are another area in which collaboration is critical. Increasing clinical trial participation will require commitment across the cancer community from physicians, patients, insurers, hospitals, and industry. A 2010 report by the Institute of Medicine described challenges to participation in trials by both physicians and patients and provided recommendations for revitalizing clinical trials conducted through the National Cancer Institute's Cooperative Group Program. ASCO has pledged its support for the full implementation of these recommendations. More broadly, ASCO recently outlined a bold vision for translational and clinical cancer research for the next decade and made recommendations to achieve that vision. Accelerating Progress Against Cancer: ASCO's Blueprint for Transforming Clinical and Translational Research, released in November, calls for a research system that takes full advantage of today's scientific and technologic opportunities and sets a high-level agenda for policy makers, regulators, and advocates. Cancer research has transformed cancer care in the past forty years, and this year's Clinical Cancer Advances illustrates how far we have come in the past year alone. We now have a tremendous opportunity to use today's knowledge and collaborate across all facets of cancer care to conquer this deadly disease. Michael P. Link, MD President American Society of Clinical Oncology.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Ensaios Clínicos como Assunto/tendências , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Qualidade de Vida , Assistência Terminal , Adulto , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Criança , Aprovação de Drogas , Detecção Precoce de Câncer/métodos , Escolaridade , Feminino , Predisposição Genética para Doença , Reforma dos Serviços de Saúde , Política de Saúde/tendências , Acessibilidade aos Serviços de Saúde , Disparidades em Assistência à Saúde , Cuidados Paliativos na Terminalidade da Vida , Humanos , Imunoterapia , Masculino , Oncologia/tendências , Mutação , Neoplasias/metabolismo , Neoplasias/mortalidade , Neoplasias/prevenção & controle , Medicina de Precisão , Prevenção Primária/métodos , Radioterapia Adjuvante , Pesquisa/tendências , Prevenção Secundária/métodos , Fatores Socioeconômicos , Tomografia Computadorizada por Raios X , Estados Unidos/epidemiologiaRESUMO
Disseminated metastatic disease, including brain metastases, is commonly encountered in malignant melanoma. The classical treatment approach for melanoma brain metastases has been neurosurgical resection followed by whole brain radiotherapy. Traditionally, if lesions were either too numerous or surgical intervention would cause substantial neurologic deficits, patients were either treated with whole brain radiotherapy or referred to hospice and supportive care. Chemotherapy has not proven effective in treating brain metastases. Improvements in surgery, radiosurgery, and new drug discoveries have provided a wider range of treatment options. Additionally, recently discovered mutations in the melanoma genome have led to the development of "targeted therapy." These vastly improved options are resulting in novel treatment paradigms for approaching melanoma brain metastases in patients with and without systemic metastatic disease. It is therefore likely that improved survival can currently be achieved in at least a subset of melanoma patients with brain metastases.