RESUMEN
Colorectal cancer (CRC) patients suffer from the second highest mortality among all cancer entities. In half of all CRC patients, colorectal cancer liver metastases (CRLM) can be observed. Metastatic colorectal cancer is associated with poor overall survival and limited treatment options. Even after successful surgical resection of the primary tumor, metachronous liver metastases occur in one out of eight cases. The only available curative intended treatment is hepatic resection, but metachronous CRLM frequently recur after approximately 1 year. In this study, we performed a proteome analysis of three recurrent liver metastases of a single CRC patient by mass spectrometry. Despite surgical resection of the primary CRC and adjuvant chemotherapy plus cetuximab treatment, the patient developed three metachronous CRLM which occurred consecutively after 9, 21 and 31 months. We identified a set of 1132 proteins expressed in the three metachronous CRLM, of which 481 were differentially regulated, including 81 proteins that were associated with the extracellular matrix (ECM). 56 ECM associated proteins were identified as upregulated in the third metastasis, 26 (46%) of which were previously described as negative prognostic markers in CRC, including tenascin C, nidogen 1, fibulin 1 and vitronectin. These data may reflect an ascending trend of malignancy from the first to the third metachronous colorectal cancer liver metastasis. Additionally, the results indicate different ECM phenotypes for recurrent metachronous metastasis, associated with different grades of malignancy and highlights the importance of individual analysis of molecular features in different, consecutive metastatic events in a single patient.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/metabolismo , Neoplasias Primarias Secundarias/patología , Compuestos Organoplatinos/administración & dosificación , Proteoma/metabolismoRESUMEN
BACKGROUND: The aim of this study was to compare 11 active surveillance (AS) protocols in contemporary European men treated with radical prostatectomy (RP) at the Martini-Clinic Prostate Cancer Center. PATIENTS AND METHODS: Analyzed were 3498 RP patients, from 2005 to 2016, who underwent ≥ 10 core biopsies and fulfilled at least 1 of 11 examined AS entry definitions. We tested proportions of AS eligibility, ineligibility, presence of primary Gleason 4/5, upstage, and combinations thereof at RP, as well as 5-year biochemical recurrence-free survival (BFS). RESULTS: The most and least stringent criteria were very low risk National Comprehensive Cancer Network and Royal Marsden with 18.8% and 96.1% of AS-eligible patients, respectively. Rates of primary Gleason 4/5 at RP, upstaging, or both features, respectively, ranged from 2.3% to 6.7%, 6.1% to 18.2%, and 7.1% to 21.0% for those 2 AS entry definitions. The range of individuals deemed AS-ineligible between the same 2 AS entry definitions, despite not harboring unfavorable pathology (primary Gleason pattern 4/5, upstage, or both), was 80.3% to 3.7%, 78.3% to 3.4%, and 77.8% to 3.4%, respectively. BFS rates showed narrow variability, with a range of 85.9% to 91.8%. CONCLUSION: Use of stringent AS entry definitions reduces the number of AS-eligible patients, which is related to a select range in individual entry parameters. Moreover, rates of unfavorable pathology at RP as much as tripled between most and least stringent AS entry definitions. However, less stringent AS entry definitions result in the lowest AS-ineligibility rates, in men without unfavorable pathology. BFS rates were virtually invariably high. Clinicians should know differences in key parameters underlying each AS entry definition, associated effect on rates of eligibility, and potential misclassification of individuals.
RESUMEN
PURPOSE: To investigate nuclear localized and tyrosine phosphorylated Stat5 (Nuc-pYStat5) as a marker of prognosis in node-negative breast cancer and as a predictor of response to antiestrogen therapy. PATIENTS AND METHODS: Levels of Nuc-pYStat5 were analyzed in five archival cohorts of breast cancer by traditional diaminobenzidine-chromogen immunostaining and pathologist scoring of whole tissue sections or by immunofluorescence and automated quantitative analysis (AQUA) of tissue microarrays. RESULTS: Nuc-pYStat5 was an independent prognostic marker as measured by cancer-specific survival (CSS) in patients with node-negative breast cancer who did not receive systemic adjuvant therapy, when adjusted for common pathology parameters in multivariate analyses both by standard chromogen detection with pathologist scoring of whole tissue sections (cohort I; n = 233) and quantitative immunofluorescence of a tissue microarray (cohort II; n = 291). Two distinct monoclonal antibodies gave concordant results. A progression array (cohort III; n = 180) revealed frequent loss of Nuc-pYStat5 in invasive carcinoma compared to normal breast epithelia or ductal carcinoma in situ, and general loss of Nuc-pYStat5 in lymph node metastases. In cohort IV (n = 221), loss of Nuc-pYStat5 was associated with increased risk of antiestrogen therapy failure as measured by univariate CSS and time to recurrence (TTR). More sensitive AQUA quantification of Nuc-pYStat5 in antiestrogen-treated patients (cohort V; n = 97) identified by multivariate analysis patients with low Nuc-pYStat5 at elevated risk for therapy failure (CSS hazard ratio [HR], 21.55; 95% CI, 5.61 to 82.77; P < .001; TTR HR, 7.30; 95% CI, 2.34 to 22.78; P = .001). CONCLUSION Nuc-pYStat5 is an independent prognostic marker in node-negative breast cancer. If confirmed in prospective studies, Nuc-pYStat5 may become a useful predictive marker of response to adjuvant hormone therapy.
Asunto(s)
Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal no Infiltrante/metabolismo , Proteínas de Neoplasias/fisiología , Proteínas Nucleares/fisiología , Factor de Transcripción STAT5/fisiología , Proteínas Supresoras de Tumor/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/tratamiento farmacológico , Carcinoma Intraductal no Infiltrante/mortalidad , Carcinoma Intraductal no Infiltrante/patología , Estudios de Cohortes , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Moduladores de los Receptores de Estrógeno/farmacología , Moduladores de los Receptores de Estrógeno/uso terapéutico , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Proteínas de Neoplasias/química , Proteínas Nucleares/química , Fosforilación , Fosfotirosina/química , Pronóstico , Procesamiento Proteico-Postraduccional , Factor de Transcripción STAT5/química , Análisis de Supervivencia , Insuficiencia del Tratamiento , Proteínas Supresoras de Tumor/química , Adulto JovenRESUMEN
Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. Here we show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells, have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia. These results suggest that alterations in calcium homeostasis can be driven by defects in gastric acidification, especially given that calcium gluconate supplementation fully rescues the phenotype of the Cckbr-mutant mice. Finally, mice deficient in Tcirg1, encoding a subunit of the vacuolar proton pump specifically expressed in both osteoclasts and parietal cells, show hypocalcemia and osteopetrorickets. Although neither Src- nor Cckbr-deficient mice have this latter phenotype, the combined deficiency of both genes results in osteopetrorickets. Thus, we find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification.