RESUMO
BACKGROUND: Research shows disparities in cancer outcomes by ethnicity or socio-economic status. Therefore, it is the aim of our study to perform a matched-pair analysis which compares the outcome of German and non-German (in the following described as 'foreign') cancer patients being treated at the Center for Integrated Oncology (CIO) Köln Bonn at the University Hospital of Bonn between January 2010 and June 2016. METHODS: During this time, 6314 well-documented patients received a diagnosis of cancer. Out of these patients, 219 patients with foreign nationality could be matched to German patients based on diagnostic and demographic criteria and were included in the study. All of these 438 patients were well characterized concerning survival data (Overall survival, Progression-free survival and Time to progression) and response to treatment. RESULTS: No significant differences regarding the patients' survival and response rates were seen when all German and foreign patients were compared. A subgroup analysis of German and foreign patients with head and neck cancer revealed a significantly longer progression-free survival for the German patients. Differences in response to treatment could not be found in this subgroup analysis. CONCLUSIONS: In summary, no major differences in survival and response rates of German and foreign cancer patients were revealed in this study. Nevertheless, the differences in progression-free survival, which could be found in the subgroup analysis of patients with head and neck cancer, should lead to further research, especially evaluating the role of infectious diseases like human papillomavirus (HPV) and Epstein-Barr virus (EBV) on carcinogenesis and disease progression.
Assuntos
Neoplasias dos Genitais Femininos/etnologia , Neoplasias dos Genitais Femininos/mortalidade , Neoplasias de Cabeça e Pescoço/etnologia , Neoplasias de Cabeça e Pescoço/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Neoplasias dos Genitais Femininos/terapia , Alemanha/etnologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , População Branca , Adulto JovemRESUMO
Regardless of the recent advances in cytotoxic therapies, 30% of children diagnosed with medulloblastoma. succumb to the disease. Therefore, novel therapeutic approaches are warranted. Here we demonstrate that Pazopanib a clinically approved multi-kinase angiogenesis inhibitor (MKI) inhibits proliferation and apoptosis in medulloblastoma cell lines. Moreover, Pazopanib profoundly attenuates medulloblastoma cell migration, a prerequisite for tumor invasion and metastasis. In keeping with the observed anti-neoplastic activity of Pazopanib, we also delineate reduced phosphorylation of the STAT3 protein, a key regulator of medulloblastoma proliferation and cell survival. Finally, we document profound in vivo activity of Pazopanib in an orthotopic mouse model of the most aggressive c-myc amplified human medulloblastoma variant. Pazopanib reduced the growth rate of intracranial growing medulloblastoma and significantly prolonged the survival. Furthermore, to put these results into a broader perspective we analysed Pazopanib side by side with the MKI Sorafenib. Both compounds share a similar target profile but display different pharmacodynamics and pharmacokinetics with distinct cytotoxic activity in different tumor entities. Thus, we identified Pazopanib as a new promising candidate for a rational clinical assessment for targeted paediatric medulloblastoma therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Cerebelares/tratamento farmacológico , Meduloblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Cerebelares/enzimologia , Neoplasias Cerebelares/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Indazóis , Masculino , Meduloblastoma/enzimologia , Meduloblastoma/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Sorafenibe , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The WNT/beta-catenin pathway is involved in numerous human cancers. Mutations of the CTNNB1 (beta-catenin) gene have also been detected in a subset of pediatric Wilms tumors, but the target genes of the deregulated WNT/beta-catenin pathway in these tumors have yet to be identified. To compare gene expression profiles of Wilms tumors with and without mutations of CTNNB1, we used 11.5-k cDNA microarrays. Most of the tumors (86%) had received preoperative chemotherapy as mandated by the European SIOP protocol. The comparison between Wilms tumors with and without CTNNB1 mutations revealed several target genes specifically deregulated in CTNNB1-mutated Wilms tumors. Among these, PITX2, APCDD1, and two members of the endothelin axis (EDN3 and EDNRA) are directly activated downstream targets of the WNT/beta-catenin pathway that may enhance proliferation of these tumor cells. In addition, several upstream inhibitors of WNT/beta-catenin signaling like WIF1 and PRDC were also strongly up-regulated in the CTNNB1-mutated Wilms tumors. This overexpression may be a negative feedback mechanism in tumors with uncontrolled WNT signaling. Moreover, we identified deregulated genes in both the retinoic acid and the RAS pathways, such as ATX/ENPP2 and RIS1, suggesting an association between these two pathways with that of WNT. In addition, the strong representation of muscle-related genes in the expression profile of CTNNB1-mutated Wilms tumors corresponded to histologically detectable areas of myomatous cells in these tumors that displayed intense and preferential nuclear beta-catenin antibody staining. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.