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INTRODUCTION AND OBJECTIVES: Adjuvant platinum-based chemotherapy for completely resected non-small cell lung cancer is associated with modest improvement in survival; nevertheless, no validated biomarker exists for predicting the benefit or harm of adjuvant platinum-based chemotherapy. MATERIALS AND METHODS: We simultaneously measured 27 cytokines in operative tumor specimens from a discovery cohort (n = 97) by multiplex immunoassay; half of the patients received adjuvant platinum-based chemotherapy, and the other half were observed. We tested possible prognostic and predictive factors in multivariate Cox models for overall survival (OS) and relapse-free survival (RFS), and a tree-based method was applied to detect predictive factors with respect to RFS. The results were validated in an independent validation cohort (n = 93). RESULTS: Fifty-two of 97 (54 %) patients in the discovery cohort and 50 of 93 (54 %) in the validation cohort received adjuvant chemotherapy; forty-four (85 %) patients in the discovery cohort and 37 (74 %) in the validation cohort received four cycles as planned. In patients with low IL-1ß-expressing tumors, RFS and OS were worse after adjuvant chemotherapy than after observation. The limited effect of adjuvant chemotherapy for patients with low IL-1ß-expressing tumors was confirmed in the validation cohort. Additionally, RFS and OS were prolonged by adjuvant chemotherapy only in patients with high IL-1ß-expressing tumors in the validation cohort. CONCLUSIONS: This study identified and validated low tumor IL-1ß expression as a potential biomarker of a limited response to adjuvant platinum-based chemotherapy after complete resection of pulmonary adenocarcinoma. This finding has the potential to inform adjuvant treatment decisions.
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BACKGROUND: Immune checkpoint therapy has dramatically changed treatment options in patients with metastatic melanoma. However, a relevant part of patients still does not respond to treatment. Data regarding the prognostic or predictive significance of preexisting immune responses against tumour antigens are conflicting. Retrospective data suggested a higher clinical benefit of ipilimumab in melanoma patients with preexisting NY-ESO-1-specific immunity. PATIENTS AND METHODS: Twenty-five patients with previously untreated or treated metastatic melanoma and preexisting humoural immune response against NY-ESO-1 received ipilimumab at a dose of 10 mg/kg in week 1, 4, 7, 10 followed by 3-month maintenance treatment for a maximum of 48 weeks. Primary endpoint was the disease control rate (irCR, irPR or irSD) according to immune-related response criteria (irRC). Secondary endpoints included the disease control rate according to RECIST criteria, progression-free survival and overall survival (OS). Humoural and cellular immune responses against NY-ESO-1 were analysed from blood samples. RESULTS: Disease control rate according to irRC was 52%, irPR was observed in 36% of patients. Progression-free survival according to irRC was 7.8 months, according to RECIST criteria it was 2.9 months. Median OS was 22.7 months; the corresponding 1-year survival rate was 66.8%. Treatment-related grade 3 AEs occurred in 36% with no grade 4-5 AEs. No clear association was found between the presence of NY-ESO-1-specific cellular or humoural immune responses and clinical activity. CONCLUSION: Ipilimumab demonstrated clinically relevant activity within this biomarker-defined population. NY-ESO-1 positivity, as a surrogate for a preexisting immune response against tumour antigens, might help identifying patients with a superior outcome from immune checkpoint blockade. CLINICAL TRIAL INFORMATION: NCT01216696.
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Antígenos de Neoplasias/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Proteínas de la Membrana/inmunología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunidad Humoral , Masculino , Melanoma/mortalidad , Persona de Mediana Edad , Neoplasias Cutáneas/mortalidad , Melanoma Cutáneo MalignoRESUMEN
In recent years, percutaneous radiofrequency ablation (RFA) has been developed as a new tool in the treatment of non-small-cell lung cancer (NSCLC) in non-surgical patients. There is growing evidence that RFA-mediated necrosis can modulate host immune responses. Here we analysed serum inflammatory factors as well as immunosuppressive cells in the peripheral blood to discover possible prognostic indicators. Peripheral blood and serum samples were collected before RFA and within 3 months after the treatment in a total of 12 patients. Inflammatory cytokines and growth factors were measured in serum by the Bio-Plex assay. Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs ) were evaluated in the peripheral blood via flow cytometry. In patients developing local or lymphogenic tumour relapse (n=4), we found an early significant increase in the concentration of tumour necrosis factor (TNF)-α as well as chemokine (C-C motif) ligand (CCL)-2 and CCL-4 compared to patients without relapse (n=4) and healthy donors (n=5). These changes were associated with an elevated activity of circulating MDSC indicated by an increased nitric oxide (NO) production in these cells. Elevated serum levels of TNF-α, CCL-2 and CCL-4 associated with an increased NO production in circulating MDSCs might be an early indicator of the incomplete RFA and subsequently a potential tumour relapse in NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Mediadores de Inflamación/sangre , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/inmunología , Células Mieloides/inmunología , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Ablación por Catéter , Recuento de Células , Femenino , Humanos , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Pronóstico , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Carga TumoralRESUMEN
There are 2 stages of alopecia, anagen and telogen effluvium, both of which may be associated with medication-related alopecia. We describe massive hair loss in a 51-year-old woman during treatment with Seroxat (paroxetine), which remitted after it was discontinued. Pathological mechanisms of drug-associated alopecia are complex and have yet to be fully elucidated.
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Alopecia/inducido químicamente , Antidepresivos de Segunda Generación/efectos adversos , Trastorno Depresivo/tratamiento farmacológico , Paroxetina/efectos adversos , Femenino , Humanos , Persona de Mediana EdadRESUMEN
Psychogenic polydipsia and its frequent complication, water intoxication, are well-known to psychologists. There are biochemical and psychiatric theories of psychogenic polydipsia which often correlate with each other. A 48-year-old man with chronic paranoid schizophrenia developed symptoms of psychogenic polydipsia. This provoked disturbances in electrolyte balance, resulting in a rapid decrease in serum sodium concentration and eventual death. There is a paucity of information and little awareness of this problem in the professional literature.
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Conducta de Ingestión de Líquido , Esquizofrenia Paranoide/complicaciones , Intoxicación por Agua/complicaciones , Resultado Fatal , Humanos , Masculino , Persona de Mediana Edad , Psicología del Esquizofrénico , Sodio/sangre , Desequilibrio Hidroelectrolítico/etiologíaRESUMEN
Economical methods by which gene function may be analysed on a genomic scale are relatively scarce. To fill this need, we have developed a transposon-tagging strategy for the genome-wide analysis of disruption phenotypes, gene expression and protein localization, and have applied this method to the large-scale analysis of gene function in the budding yeast Saccharomyces cerevisiae. Here we present the largest collection of defined yeast mutants ever generated within a single genetic background--a collection of over 11,000 strains, each carrying a transposon inserted within a region of the genome expressed during vegetative growth and/or sporulation. These insertions affect nearly 2,000 annotated genes, representing about one-third of the 6,200 predicted genes in the yeast genome. We have used this collection to determine disruption phenotypes for nearly 8,000 strains using 20 different growth conditions; the resulting data sets were clustered to identify groups of functionally related genes. We have also identified over 300 previously non-annotated open reading frames and analysed by indirect immunofluorescence over 1,300 transposon-tagged proteins. In total, our study encompasses over 260,000 data points, constituting the largest functional analysis of the yeast genome ever undertaken.
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Elementos Transponibles de ADN , Técnicas Genéticas , Genoma Fúngico , Saccharomyces cerevisiae/genética , Algoritmos , Escherichia coli/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/fisiología , Perfilación de la Expresión Génica , Datos de Secuencia Molecular , Mutagénesis , Análisis de Secuencia por Matrices de Oligonucleótidos , Sistemas de Lectura Abierta , Fenotipo , Reacción en Cadena de la Polimerasa , Transformación GenéticaRESUMEN
Priapism or pathological, prolonged erection, is a rare adverse effect sometimes associated with psychotropic medication and is due to alpha adrenergic receptor blockade. Priapism in a 44-year-old mental patient receiving risperidone is described. Urinary retention was relieved by catheterization, followed by saline irrigations. Priapism was relieved when a hematoma was evacuated from his penis. This may be the first description of priapism following risperidone alone, since a previous report included a patient receiving risperidone together with 2 other psychotropic medications. Priapism should be looked for in men receiving risperidone, a novel antipsychotic medication.