RESUMEN
BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).
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Antineoplásicos Inmunológicos , Melanoma , Terapia Neoadyuvante , Neoplasias Cutáneas , Humanos , Adyuvantes Inmunológicos , Progresión de la Enfermedad , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/cirugía , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Quimioterapia AdyuvanteRESUMEN
Ultraviolet radiation is an important etiologic factor in skin cancer and a better understanding of how solar stimulated light (SSL) affects signal transduction pathways in human skin which is needed in further understanding activated networks that could be targeted for skin cancer prevention. We utilized Reverse Phase Protein Microarray Analysis (RPPA), a powerful technology that allows for broad-scale and quantitative measurement of the activation/phosphorylation state of hundreds of key signaling proteins and protein pathways in sun-protected skin after an acute dose of two minimal erythema dose (MED) of SSL. RPPA analysis was used to map the altered cell signaling networks resulting from acute doses of solar simulated radiation (SSL). To that end, we exposed sun-protected skin in volunteers to acute doses of two MED of SSL and collected biopsies pre-SSL and post-SSL irradiation. Frozen biopsies were subjected to laser capture microdissection (LCM) and then assessed by RPPA. The activation/phosphorylation or total levels of 128 key signaling proteins and drug targets were selected for statistical analysis. Coordinate network-based analysis was performed on specific signaling pathways that included the PI3k/Akt/mTOR and Ras/Raf/MEK/ERK pathways. Overall, we found early and sustained activation of the PI3K-AKT-mTOR and MAPK pathways. Cell death and apoptosis-related proteins were activated at 5 and 24 h. Ultimately, expression profile patterns of phosphorylated proteins in the epidermal growth factor receptor (EGFR), AKT, mTOR, and other relevant pathways may be used to determine pharmacodynamic activity of new and selective topical chemoprevention agents administered in a test area exposed to SSL to determine drug-induced attenuation or reversal of skin carcinogenesis pathways.
RESUMEN
This small exploratory study was designed to test the hypothesis that thin melanoma lesions contain nuclei of two similar phenotypes, in different proportions. In lesions likely to progress to metastatic disease, one of these phenotypes predominates. Histopathological sections from 18 cases of thin melanomas which did not progress to metastasis, and from 10 cases which did progress were imaged and digitized at high resolution, with a total of 2084 and 1148 nuclei, respectively, recorded. Five karyometric features were used to discriminate between nuclei from indolent and from potentially metastatic lesions. For each case, the percentage of nuclei classified by the discriminant function as having come from a potentially metastatic lesion was determined and termed as case classification criterion. Standard histopathological criteria, such as ulceration and high mitotic index, indicated in this material the need for intensive therapy for only one of the 10 participants, as compared with 7/10 identified correctly by the karyometric measure. Using a case classification criterion threshold of 40%, the overall accuracy was 86% in the test set. The proportion of nuclei of an aggressive phenotype may lend itself as an effective prognostic clue for thin melanoma lesions. The algorithm developed in this training set appears to identify those patients at high risk for metastatic disease, and demonstrates a basis for a further study to assess the utility of prognostic clues for thin melanomas.
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Melanoma/complicaciones , Neoplasias Cutáneas/complicaciones , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Retrospectivos , Riesgo , Neoplasias Cutáneas/patologíaRESUMEN
Prevention of nonmelanoma skin cancers remains a health priority due to high costs associated with this disease. Diclofenac and difluoromethylornithine (DFMO) have demonstrated chemopreventive efficacy for cutaneous squamous cell carcinomas. We designed a randomized study of the combination of DFMO and diclofenac in the treatment of sun-damaged skin. Individuals with visible cutaneous sun damage were eligible. Subjects were randomized to one of the three groups: topical DFMO applied twice daily, topical diclofenac applied daily, or DFMO plus diclofenac. The treatment was limited to an area on the left forearm, and the duration of use was 90 days. We hypothesized that combination therapy would have increased efficacy compared with single-agent therapy. The primary outcome was change in karyometric average nuclear abnormality (ANA) in the treated skin. Individuals assessing the biomarkers were blinded regarding the treatment for each subject. A total of 156 subjects were randomized; 144 had baseline and end-of-study biopsies, and 136 subjects completed the study. The ANA unexpectedly increased for all groups, with higher values correlating with clinical cutaneous inflammation. Nearly all of the adverse events were local cutaneous effects. One subject had cutaneous toxicity that required treatment discontinuation. Significantly more adverse events were seen in the groups taking diclofenac. Overall, the study indicated that the addition of topical DFMO to topical diclofenac did not enhance its activity. Both agents caused inflammation on a cellular and clinical level, which may have confounded the measurement of chemopreventive effects. More significant effects may be observed in subjects with greater baseline cutaneous damage.
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Diclofenaco/administración & dosificación , Eflornitina/administración & dosificación , Antebrazo/patología , Queratosis Actínica/prevención & control , Neoplasias Cutáneas/prevención & control , Piel/efectos de los fármacos , Administración Tópica , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Anticarcinógenos/administración & dosificación , Femenino , Estudios de Seguimiento , Antebrazo/efectos de la radiación , Humanos , Queratosis Actínica/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Piel/metabolismo , Piel/patología , Neoplasias Cutáneas/metabolismo , Luz Solar/efectos adversosRESUMEN
MicroRNAs (miRNAs) are small, noncoding RNAs that regulate protein levels posttranscriptionally. miRNAs play important regulatory roles in many cellular processes and have been implicated in several diseases. Recent studies have reported significant levels of miRNAs in a variety of body fluids, raising the possibility that miRNAs could serve as useful biomarkers. Here, changes in miRNA expression patterns are described in 2 different rodent models of glomerular injury (acute puromycin aminonucleoside nephropathy and passive Heymann nephritis). By employing 2 different modes of glomerular insult, oxidative stress and immune-mediated toxicity, miRNA changes in both isolated glomeruli as well as urine specimens allow for identification of urinary miRNA biomarkers that are suggestive of drug-induced injury specifically to the glomerulus. Subsets of glomerular urinary miRNAs associated with these different modes of glomerular toxicity seem to be dependent on the mechanism of the induced injury, while 9 miRNAs that changed early in both glomerular and urine specimens were common to both studies. We further show that the miRNAs identified as mechanism-specific early glomerular injury biomarkers target key pathways and transcripts relevant to the type of insult, while the insult-independent changes might serve as ideal glomerular injury biomarkers.
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Lesión Renal Aguda/orina , Modelos Animales de Enfermedad , Glomerulonefritis Membranosa/metabolismo , Glomérulos Renales/metabolismo , MicroARNs/orina , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/fisiopatología , Animales , Biomarcadores/metabolismo , Biomarcadores/orina , Progresión de la Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Glomerulonefritis Membranosa/inmunología , Glomerulonefritis Membranosa/patología , Glomerulonefritis Membranosa/fisiopatología , Complejo Antigénico de Nefritis de Heymann/química , Sueros Inmunes/toxicidad , Glomérulos Renales/inmunología , Glomérulos Renales/fisiopatología , Glomérulos Renales/ultraestructura , Captura por Microdisección con Láser , Masculino , Metabolómica/métodos , MicroARNs/metabolismo , Microscopía Electrónica de Transmisión , Estrés Oxidativo/efectos de los fármacos , Podocitos/efectos de los fármacos , Podocitos/inmunología , Podocitos/metabolismo , Podocitos/ultraestructura , Puromicina Aminonucleósido/toxicidad , Ratas Sprague-Dawley , Oveja DomésticaRESUMEN
The incidence of skin cancer is higher than all other cancers and continues to increase, with an average annual cost over $8 billion in the United States. As a result, identifying molecular pathway alterations that occur with UV exposure to strategize more effective preventive and therapeutic approaches is essential. To that end, we evaluated phosphorylation of proteins within the PI3K/Akt and MAPK pathways by immunohistochemistry in sun-protected skin after acute doses of physiologically relevant solar-simulated ultraviolet light (SSL) in 24 volunteers. Biopsies were performed at baseline, 5 minutes, 1, 5, and 24 hours after SSL irradiation. Within the PI3K/Akt pathway, we found activation of Akt (serine 473) to be significantly increased at 5 hours while mTOR (serine 2448) was strongly activated early and was sustained over 24 hours after SSL. Downstream, we observed a marked and sustained increase in phospho-S6 (serine 235/S236), whereas phospho-4E-BP1 (threonines 37/46) was increased only at 24 hours. Within the MAPK pathway, SSL-induced expression of phospho-p38 (threonine 180/tyrosine 182) peaked at 1 to 5 hours. ERK 1/2 was observed to be immediate and sustained after SSL irradiation. Phosphorylation of histone H3 (serine 10), a core structural protein of the nucleosome, peaked at 5 hours after SSL irradiation. The expression of both p53 and COX-2 was increased at 5 hours and was maximal at 24 hours after SSL irradiation. Apoptosis was significantly increased at 24 hours as expected and indicative of a sunburn-type response to SSL. Understanding the timing of key protein expression changes in response to SSL will aid in development of mechanistic-based approaches for the prevention and control of skin cancers.
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Eritema/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piel/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Rayos Ultravioleta/efectos adversos , Anciano , Relación Dosis-Respuesta en la Radiación , Eritema/etiología , Eritema/patología , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Transducción de Señal/efectos de la radiación , Piel/patología , Piel/efectos de la radiaciónRESUMEN
Orally administered small molecule agonists of soluble guanylate cyclase (sGC) induced increased numbers of osteoclasts, multifocal bone resorption, increased porosity, and new bone formation in the appendicular and axial skeleton of Sprague-Dawley rats. Similar histopathological bone changes were observed in both young (7- to 9-week-old) and aged (42- to 46-week-old) rats when dosed by oral gavage with 3 different heme-dependent sGC agonist (sGCa) compounds or 1 structurally distinct heme-independent sGCa compound. In a 7-day time course study in 7- to 9-week-old rats, bone changes were observed as early as 2 to 3 days following once daily compound administration. Bone changes were mostly reversed following a 14-day recovery period, with complete reversal after 35 days. The mechanism responsible for the bone changes was investigated in the thyroparathyroidectomized rat model that creates a low state of bone modeling and remodeling due to deprivation of thyroid hormone, calcitonin (CT), and parathyroid hormone (PTH). The sGCa compounds tested increased both bone resorption and formation, thereby increasing bone remodeling independent of calciotropic hormones PTH and CT. Based on these studies, we conclude that the bone changes in rats were likely caused by increased sGC activity.
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Desarrollo Óseo/efectos de los fármacos , Remodelación Ósea/efectos de los fármacos , Resorción Ósea/inducido químicamente , Osteoclastos/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/agonistas , Envejecimiento/fisiología , Animales , Resorción Ósea/patología , Huesos/patología , Calcitonina/deficiencia , Química Farmacéutica , GMP Cíclico/metabolismo , Guanilato Ciclasa , Hormona Paratiroidea/deficiencia , Ratas , Ratas Sprague-Dawley , Guanilil Ciclasa Soluble , Hormonas Tiroideas/deficienciaRESUMEN
Although cancer-mediated changes in hemostatic proteins unquestionably promote hypercoagulation, the effects of neoplasia on fibrinolysis in the circulation are less well defined. The goals of the present investigation were to determine if plasma obtained from patients with breast, lung, pancreas and colon cancer was less or more susceptible to lysis by tissue-type plasminogen activator (tPA) compared to plasma obtained from normal individuals. Archived plasma obtained from patients with breast (nâ=â18), colon/pancreas (nâ=â27) or lung (nâ=â19) was compared to normal individual plasma (nâ=â30) using a thrombelastographic assay that assessed fibrinolytic vulnerability to exogenously added tPA. Plasma samples were activated with tissue factor/celite, had tPA added, and had data collected until clot lysis occurred. Additional, similar samples had potato carboxypeptidase inhibitor added to assess the role played by thrombin-activatable fibrinolysis inhibitor in cancer-modulated fibrinolysis. Rather than inflicting a hypofibrinolytic state, the three groups of cancers demonstrated increased vulnerability to tPA (e.g. decreased time to lysis, increased speed of lysis, decreased clot lysis time). However, hypercoagulation manifested as increased speed of clot formation and strength compensated for enhanced fibrinolytic vulnerability, resulting in a clot residence time that was not different from normal individual thrombi. In sum, enhanced hypercoagulability associated with cancer was in part diminished by enhanced fibrinolytic vulnerability to tPA.
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Fibrinólisis/efectos de los fármacos , Neoplasias/sangre , Activador de Tejido Plasminógeno/farmacología , Adulto , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Neoplasias del Colon/sangre , Neoplasias del Colon/patología , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Neoplasias/patología , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/patología , Adulto JovenRESUMEN
Colon and pancreatic cancer are associated with significant thrombophilia. Colon and pancreas tumor cells have an increase in hemeoxygenase-1 (HO-1) activity, the endogenous enzyme responsible for carbon monoxide production. Given that carbon monoxide enhances plasmatic coagulation, we determined if patients undergoing resection of colon and pancreatic tumors had an increase in endogenous carbon monoxide and plasmatic hypercoagulability. Patients with colon (n = 17) and pancreatic (n = 10) tumors were studied. Carbon monoxide was determined by the measurement of carboxyhemoglobin (COHb). A thrombelastographic method to assess plasma coagulation kinetics and formation of carboxyhemefibrinogen (COHF) was utilized. Nonsmoking patients with colon and pancreatic tumors had abnormally increased COHb concentrations of 1.4 ± 0.9 and 1.9 ± 0.7%, respectively, indicative of HO-1 upregulation. Coagulation analyses comparing both tumor groups demonstrated no significant differences in any parameter; thus the data were combined for the tumor groups for comparison with 95% confidence interval values obtained from normal individuals (n = 30) plasma. Seventy percent of tumor patients had a velocity of clot formation greater than the 95% confidence interval value of normal individuals, with 53% of this hypercoagulable group also having COHF formation. Further, 67% of tumor patients had clot strength that exceeded the normal 95% confidence interval value, and 56% of this subgroup had COHF formation. Finally, 63% of all tumor patients had COHF formation. Future investigation of HO-1-derived carbon monoxide in the pathogenesis of colon and pancreatic tumor-related thrombophilia is warranted.
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Pruebas de Coagulación Sanguínea/métodos , Carboxihemoglobina/metabolismo , Neoplasias del Colon/sangre , Hemo-Oxigenasa 1/metabolismo , Neoplasias Pancreáticas/sangre , Tromboelastografía/métodos , Adulto , Coagulación Sanguínea , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Fully phosphorothioate antisense oligonucleotides (ASOs) with locked nucleic acids (LNAs) improve target affinity, RNase H activation and stability. LNA modified ASOs can cause hepatotoxicity, and this risk is currently not fully understood. In vitro cytotoxicity screens have not been reliable predictors of hepatic toxicity in non-clinical testing; however, mice are considered to be a sensitive test species. To better understand the relationship between nucleotide sequence and hepatotoxicity, a structure-toxicity analysis was performed using results from 2 week repeated-dose-tolerability studies in mice administered LNA-modified ASOs. ASOs targeting human Apolipoprotien C3 (Apoc3), CREB (cAMP Response Element Binding Protein) Regulated Transcription Coactivator 2 (Crtc2) or Glucocorticoid Receptor (GR, NR3C1) were classified based upon the presence or absence of hepatotoxicity in mice. From these data, a random-decision forest-classification model generated from nucleotide sequence descriptors identified two trinucleotide motifs (TCC and TGC) that were present only in hepatotoxic sequences. We found that motif containing sequences were more likely to bind to hepatocellular proteins in vitro and increased P53 and NRF2 stress pathway activity in vivo. These results suggest in silico approaches can be utilized to establish structure-toxicity relationships of LNA-modified ASOs and decrease the likelihood of hepatotoxicity in preclinical testing.
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Oligonucleótidos Antisentido/toxicidad , Oligonucleótidos/toxicidad , Animales , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Motivos de Nucleótidos , Oligonucleótidos/química , Oligonucleótidos/metabolismo , Oligonucleótidos Antisentido/química , Oligonucleótidos Antisentido/metabolismo , Proteínas/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Development of LNA gapmers, antisense oligonucleotides used for efficient inhibition of target RNA expression, is limited by non-target mediated hepatotoxicity issues. In the present study, we investigated hepatic transcription profiles of mice administered non-toxic and toxic LNA gapmers. After repeated administration, a toxic LNA gapmer (TS-2), but not a non-toxic LNA gapmer (NTS-1), caused hepatocyte necrosis and increased serum alanine aminotransferase levels. Microarray data revealed that, in addition to gene expression patterns consistent with hepatotoxicity, 17 genes in the clathrin-mediated endocytosis (CME) pathway were altered in the TS-2 group. TS-2 significantly down-regulated myosin 1E (Myo1E), which is involved in release of clathrin-coated pits from plasma membranes. To map the earliest transcription changes associated with LNA gapmer-induced hepatotoxicity, a second microarray analysis was performed using NTS-1, TS-2, and a severely toxic LNA gapmer (HTS-3) at 8, 16, and 72 h following a single administration in mice. The only histopathological change observed was minor hepatic hypertrophy in all LNA groups across time points. NTS-1, but not 2 toxic LNA gapmers, increased immune response genes at 8 and 16 h but not at 72 h. TS-2 significantly perturbed the CME pathway only at 72 h, while Myo1E levels were decreased at all time points. In contrast, HTS-3 modulated DNA damage pathway genes at 8 and 16 h and also modulated the CME pathway genes (but not Myo1E) at 16 h. Our results may suggest that different LNAs modulate distinct transcriptional genes and pathways contributing to non-target mediated hepatotoxicity in mice.
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Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Endocitosis/efectos de los fármacos , Hígado/efectos de los fármacos , Oligonucleótidos Antisentido/toxicidad , Oligonucleótidos/toxicidad , Transcriptoma/efectos de los fármacos , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Clatrina/metabolismo , Endocitosis/genética , Perfilación de la Expresión Génica , Inyecciones Subcutáneas , Hígado/patología , Masculino , Ratones , Ratones Endogámicos , Datos de Secuencia Molecular , Oligonucleótidos/química , Oligonucleótidos/genética , Oligonucleótidos/metabolismo , Oligonucleótidos Antisentido/química , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/metabolismoRESUMEN
Reverse phase protein microarray analysis was used to identify cell signaling derangements in squamous cell carcinoma (SCC) compared with actinic keratosis (AK) and upper inner arm (UIA). We analyzed two independent tissue sets with isolation and enrichment of epithelial cells by laser capture microdissection. Set 1 served as a pilot and a means to identify protein pathway activation alterations that could be further validated in a second independent set. Set 1 was comprised of 4 AK, 13 SCC, and 20 UIA. Set 2 included 15 AK, 9 SCCs, and 20 UIAs. Activation of 51 signaling proteins, known to be involved in tumorigenesis, were assessed for set 1 and showed that the MEK-ERK [mitogen-activated protein (MAP)/extracellular signal-regulated (ERK; MEK)] pathway was activated in SCC compared with AK and UIA, and that epidermal growth factor receptor (EGFR) and mTOR pathways were aberrantly activated in SCC. Unsupervised two-way hierarchical clustering revealed that AK and UIA shared a common signaling network activation architecture while SCC was dramatically different. Statistical analysis found that prosurvival signaling through phosphorylation of ASK and 4EBP1 as well as increased Bax and Bak expression was higher in AK compared with UIA. We expanded pathway network activation mapping in set 2 to 101 key signaling proteins, which corroborated activation of MEK-ERK, EGFR, and mTOR pathways through discovery of a number of upstream and downstream signaling molecules within these pathways to conclude that SCC is indeed a pathway activation-driven disease. Pathway activation mapping of SCC compared with AK revealed several interconnected networks that could be targeted with drug therapy for potential chemoprevention and therapeutic applications.
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Carcinoma de Células Escamosas/metabolismo , Transducción de Señal , Neoplasias Cutáneas/metabolismo , Piel/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Progresión de la Enfermedad , Femenino , Humanos , Captura por Microdisección con Láser , Masculino , Persona de Mediana Edad , Fosforilación , Pronóstico , Estudios Prospectivos , Neoplasias Cutáneas/patología , Adulto JovenAsunto(s)
Carcinoma de Células Escamosas/secundario , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Quinazolinas/uso terapéutico , Neoplasias Cutáneas/patología , Axila , Biopsia con Aguja , Carcinoma de Células Escamosas/cirugía , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Clorhidrato de Erlotinib , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Hombro , Neoplasias Cutáneas/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: On the basis of retrospective experience at individual centers, it appears that patients with stage IV melanoma who undergo complete resection have a favorable outcome compared with patients with disseminated stage IV disease. The Southwest Oncology Group (SWOG) performed a prospective trial in patients with metastatic melanoma who were enrolled before complete resection of their metastatic disease and provided prospective outcomes in the cooperative group setting. METHODS: Based on their physical examination and radiologic imaging studies, patients with a stage IV melanoma judged amenable to complete resection underwent surgery within 28 days of enrollment. All eligible patients were followed with scans (computed tomography or positron emission tomography) every 6 months until relapse and death. RESULTS: Seventy-seven patients were enrolled from 18 different centers. Of those, 5 patients were ineligible; 2 had stage III disease alone; and 3 had no melanoma in their surgical specimen. In addition, 8 eligible patients had incompletely resected tumor. Therefore, the primary analysis included 64 completely resected patients. Twenty patients (31%) had visceral disease. With a median follow-up of 5 years, the median relapse-free survival was 5 months (95% CI, 3-7 months) whereas median overall survival was 21 months (95% CI, 16-34 months). Overall survivals at 3 and 4 years were 36% and 31%, respectively. CONCLUSIONS: In a prospective multicenter setting, appropriately selected patients with stage IV melanoma achieved prolonged overall survival after complete surgical resection. Although median relapse-free survival was only 5 months, patients could still frequently undergo subsequent surgery for isolated recurrences. This patient population is appropriate for aggressive surgical therapy and for trials evaluating adjuvant therapy.
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Melanoma/patología , Melanoma/cirugía , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Selección de Paciente , Tomografía de Emisión de Positrones , Pronóstico , Estudios Prospectivos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Estados UnidosRESUMEN
Cutaneous squamous cell carcinoma (SCC) occurs commonly and can metastasize. Identification of specific molecular aberrations and mechanisms underlying the development and progression of cutaneous SCC may lead to better prognostic and therapeutic approaches and more effective chemoprevention strategies. To identify genetic changes associated with early stages of cutaneous SCC development, we analyzed a series of 40 archived skin tissues ranging from normal skin to invasive SCC. Using high-resolution array-based comparative genomic hybridization, we identified deletions of a region on chromosome 10q harboring the INPP5A gene in 24% of examined SCC tumors. Subsequent validation by immunohistochemistry on an independent sample set of 71 SCC tissues showed reduced INPP5A protein levels in 72% of primary SCC tumors. Decrease in INPP5A protein levels seems to be an early event in SCC development, as it also is observed in 9 of 26 (35%) examined actinic keratoses, the earliest stage in SCC development. Importantly, further reduction of INPP5A levels is seen in a subset of SCC patients as the tumor progresses from primary to metastatic stage. The observed frequency and pattern of loss indicate that INPP5A, a negative regulator of inositol signaling, may play a role in development and progression of cutaneous SCC tumors.
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Carcinoma de Células Escamosas/genética , Monoéster Fosfórico Hidrolasas/genética , Neoplasias Cutáneas/genética , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/patología , Hibridación Genómica Comparativa , Dosificación de Gen , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Inositol Polifosfato 5-Fosfatasas , Análisis de Secuencia por Matrices de Oligonucleótidos , Monoéster Fosfórico Hidrolasas/metabolismo , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patologíaRESUMEN
The chemopreventive and antitumor properties of perillyl alcohol (POH) that were studied preclinically indicate that topical POH inhibits both UVB-induced murine skin carcinogenesis (squamous cell tumor models) and 7,12-dimethylbenz(a)anthracene-induced murine melanoma (transgenic models involving tyrosinase-driven Ras). A previous phase 1 clinical trial in participants with normal-appearing skin showed that topical POH cream was well tolerated at a dose of 0.76% (w/w). Here, we performed a 3-month, double-blind, randomized, placebo-controlled phase 2a trial of two different doses of topical POH in individuals with sun-damaged skin. Participants applied POH cream twice daily to each dorsal forearm. Baseline and end-of-study biopsies were taken from each participant to evaluate whether the topical application of POH was effective in reversing actinic damage as evidenced by normalization of quantitative skin histopathologic scores and change in nuclear chromatin pattern as measured by karyometric analysis. There was a borderline reduction in the histopathologic score of the lower-dose POH group compared with the placebo (P = 0.1), but this was not observed in the high-dose group. However, in the high-dose group, a statistically significant reduction in the proportion of nuclei deviating from normal was observed by the use of karyometric analysis (P < 0.01). There was no statistical significance shown in the lower-dose group. No changes were observed in p53 expression, cellular proliferation (by proliferating cell nuclear antigen expression), or apoptosis in either treatment group compared with the placebo group. These results suggest that whereas our karyometric analyses can detect a modest effect of POH in sun-damaged skin, improved delivery into the epidermis may be necessary.
Asunto(s)
Antineoplásicos/administración & dosificación , Monoterpenos/administración & dosificación , Neoplasias Cutáneas/prevención & control , Administración Tópica , Anciano , Apoptosis/efectos de los fármacos , Quimioprevención/métodos , Cromatina/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Inmunohistoquímica , Cariotipificación , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Non-well-differentiated cutaneous squamous cell carcinomas may display a more aggressive behavior. It is important to better define prognostic criteria for these tumors. METHODS: This was a retrospective case-control analysis of a squamous cell carcinoma database. Patients with non-well-differentiated and well-differentiated tumors were matched based on site of tumor, age, and immunocompromised status. Comparisons included demographics, histology, immunohistochemical protein expressions (Ki-67, p53, E-cadherin, cyclin D1), and clinical outcomes. RESULTS: Demographic features were similar between cases (n=30) and controls (n=30). Non-well-differentiated tumors were larger (1.8 cm versus 1.3 cm, P=0.08), deeper (0.81 cm versus 0.32 cm, P<0.0001), and had greater recurrence (P=0.003). Non-well-differentiated tumors showed increased proliferation rate, Ki-67 index (77% versus 61%, P=0.001); no significant difference in activity of p53, E-cadherin, and cyclin D1 between the two groups. CONCLUSIONS: Tumor differentiation and depth are important pathologic and prognostic criteria for cutaneous squamous cell carcinoma. Immunohistochemistry helps describe patterns of biomarker protein expression and may exemplify aggressive subtypes.
Asunto(s)
Carcinoma de Células Escamosas/patología , Neoplasias Cutáneas/patología , Piel/patología , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Humanos , Masculino , Pronóstico , Estudios Retrospectivos , Piel/metabolismo , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/metabolismoRESUMEN
Epidermal cysts are common, benign, intradermal or subcutaneous, typically asymptomatic masses, ranging from 1 to 4 cm in size. They may occur anywhere in the body, with a predilection for the face, neck, and trunk. Transformation to squamous-cell carcinoma is rare. We present a case of a 61-year-old male patient with a large, growing mass in his posterior left gluteal region. Given the concern for a malignancy, he was referred to a surgical oncologist. Magnetic resonance imaging (MRI) without contrast was performed due to poor renal function and revealed a large cystic mass in the left gluteal subcutaneous soft tissues that was subsequently excised. Pathological examination revealed an epidermal inclusion cyst that measured 17.8 × 13.18 × 5.8 cm. To our knowledge, this is the largest epidermal inclusion cyst reported in the English literature.
RESUMEN
BACKGROUND: Families with a melanoma history are at risk of melanoma. Melanoma survival improves when people are aware of their risk and ways to modify it. We explored at-risk families' perceived risk communication from healthcare providers. METHODS: Qualitative description. RESULTS: Participants perceived: (1) few provider discussions of melanoma risk or risk-modifying behaviors; (2) a desire to trust information from providers; (3) the healthcare system constrains communication; and (4) concerns about provider competence and caring regarding worrisome lesions. CONCLUSIONS: Providers should provide clear, comprehensive, accurate, and consistent messages about melanoma to persons at high risk; messages also convey competence and caring.