RESUMO
BACKGROUND: Palliative care in outpatient setting has been shown to promote better symptom management and transition to hospice care among patients with advanced cancer. Nevertheless, specialized palliative care is rarely provided at cancer centers in Korea. Herein, we aimed to assess aggressiveness of end-of-life care for patients with metastatic colorectal cancer according to the use of outpatient palliative care (OPC) at a single cancer center in Korea. METHODS: We performed a retrospective medical record review for 132 patients with metastatic colorectal cancer who died between 2011 and 2014. Fifty patients used OPC (OPC group), while 82 patients did not (non-OPC group). Indicators of aggressiveness of end-of-life care including chemotherapy use, emergency department visits, hospitalization, and utilization of hospice care were analyzed according to the use of OPC. RESULTS: More patients in the OPC group were admitted to hospice than those in the non-OPC group (32% vs 17%, P = .047). The mean of inpatient days within 30 days of death was shorter for the OPC group than the non-OPC group (4.02 days vs 7.77 days, respectively, P = .032). There were no differences in the proportions of patients who received chemotherapy and visited the emergency department within 30 days from death. CONCLUSION: Among patients with metastatic colorectal cancer, OPC was associated with shorter inpatient days near death and greater hospice utilization. Further prospective studies are needed to evaluate the impact of OPC on end-of-life care in Korea.
Assuntos
Institutos de Câncer/estatística & dados numéricos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Cuidados Paliativos na Terminalidade da Vida/estatística & dados numéricos , Assistência Terminal/estatística & dados numéricos , Idoso , Assistência Ambulatorial , Antineoplásicos/administração & dosagem , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , República da Coreia , Estudos RetrospectivosRESUMO
Several in vivo studies have found that transplanting mesenchymal stem cells (MSCs) into degenerative intervertebral discs (IVDs) leads to regeneration of disc cells. Since the exact underlying mechanisms are not understood, we investigated the mechanisms of action of MSCs in regeneration of degenerative IVDs via paracrine actions. Human MSCs and degenerative disc cells from the same donor vertebrae were directly or indirectly cocultured. The multidifferentiation potential, cell proliferation, collagen synthesis, and mRNA expression levels were assessed. The proliferation rates of MSCs and degenerative disc cells were higher in the coculture system than in the monolayer cultures or in the conditioned medium of each cell type. During coculturing with nucleus pulposus (NP) cells, mRNA expression of the extracellular matrix (ECM) components aggrecan, versican (VCAN), SOX9, and type II and type VI collagen was significantly increased in MSCs, whereas mRNA expression for type V collagen was increased in MSCs cocultured with annulus fibrosus (AF) cells. In addition, the accumulation of total ECM collagen was greater in cocultured degenerative disc cells than in monocultured cells. During coculturing, MSCs downregulated the expression levels of various proinflammatory cytokine genes in degenerative NP [interleukin-1α ( IL-1α), IL-1ß, IL-6, and tumor necrosis factor-α ( TNF-α)] and AF cells ( IL-1α and IL-6), which are involved in the degradation of ECM molecules. In association with the trophic effect of MSCs on degenerative disc cells, upregulation of growth factor mRNA expression was shown in MSCs cocultured with degenerative NP cells [epidermal growth factor ( EGF), insulin-like growth factor-1 ( IGF-1), osteogenic protein-1 ( OP-1), growth and differentiation factor-7 ( GDF-7), and transforming growth factor-ß ( TGF-ß)] or degenerative AF cells ( IGF-1, OP-1, and GDF-7). In terms of MSC-based clinical approaches to IVD regeneration, implanting MSCs into a degenerative IVD may both stimulate MSC differentiation into an NP- or AF-like phenotype and stimulate the biological activation of degenerative disc cells for self-repair.
Assuntos
Anel Fibroso/citologia , Células-Tronco Mesenquimais/metabolismo , Núcleo Pulposo/citologia , Comunicação Parácrina/fisiologia , Adulto , Anel Fibroso/metabolismo , Proteína Morfogenética Óssea 7/genética , Proteína Morfogenética Óssea 7/metabolismo , Diferenciação Celular , Proliferação de Células , Técnicas de Cocultura , Matriz Extracelular/metabolismo , Feminino , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/terapia , Masculino , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Pessoa de Meia-Idade , Núcleo Pulposo/metabolismo , Projetos Piloto , Regeneração/fisiologia , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismoRESUMO
Human bone marrow mesenchymal stem cells (hBMSCs) were isolated from bone marrow of the vertebral body. The hBMSCs were cultured under either hypoxic (1% O2) or normoxic (21% O2; control) conditions and the characteristics as mesenchymal stem cells were compared. Results revealed that hypoxia reduced proliferative potential and colony-forming efficiency of hBMSCs, and significantly enhanced osteogenic and chondrogenic differentiation. The hBMSCs enhanced the regenerative potential of bone in vivo. In vitro synthesis of soluble and insoluble collagen was significantly increased in the hypoxic condition. In vivo collagen tissue regeneration was also enhanced under the hypoxic condition, with concomitant increased expressions of various subtypes of collagen and lysyl-oxidase family mRNA. MicroRNA assays revealed that miR-155-5p, which negatively regulates HIF-1α, was significantly highly expressed. These observations demonstrate that hBMSCs obtained from human vertebrae exhibit altered characteristics under hypoxic conditions, and each factor contributing to hBMSC-mediated tissue healing should be evaluated with the goal of allowing their clinical application.
Assuntos
Células da Medula Óssea/citologia , Células-Tronco Mesenquimais/citologia , Regeneração/fisiologia , Adipócitos/citologia , Adulto , Diferenciação Celular , Hipóxia Celular , Proliferação de Células , Células Cultivadas , Condrócitos/citologia , Condrogênese , Colágeno/química , Feminino , Citometria de Fluxo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Osteogênese , Oxigênio/química , Coluna Vertebral/citologia , Células-Tronco , CicatrizaçãoRESUMO
The effects of fibroblast growth factor-2 (FGF-2) on collagen tissue regeneration by human bone marrow stem cells (hBMSCs) were investigated. hBMSCs were isolated from human vertebral body bone marrow during vertebral surgery and a population of hBMSCs with the characteristics of mesenchymal stem cells was observed. The FGF-2 treatment (5 ng/mL) affected on the colony-forming efficiency, proliferation, and in vitro differentiation of hBMSCs. Insoluble/soluble collagen and hydroxyproline synthesis was significantly enhanced in hBMSCs expanded with FGF-2 and the treatment of FGF-2 caused a reduction in the mRNA expression of collagen type I, but an increase of collagen types II and III along with lysyl oxidase family genes. Collagen formation was also examined using an in vivo assay model by transplanting hBMSCs into immunocompromised mice (n=4) and the histologic and immunohistochemical results revealed that significantly more collagen with a well-organized structure was formed by FGF-2-treated hBMSCs at 8 weeks posttransplantation (P<0.05). The DNA microarray assay demonstrated that genes related to extracellular matrix formation were significantly upregulated. To elucidate the underlying mechanism, chemical inhibitors against extracellular-signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) were treated and following downstream expression was observed. Collectively, FGF-2 facilitated the collagen-producing potency of hBMSCs both in vitro and in vivo, rendering them more suitable for use in collagen regeneration in the clinical field.
Assuntos
Células da Medula Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Colágeno/biossíntese , Fator 2 de Crescimento de Fibroblastos/farmacologia , Células-Tronco Mesenquimais/metabolismo , Regeneração/efeitos dos fármacos , Coluna Vertebral/metabolismo , Adulto , Animais , Células da Medula Óssea/citologia , Células Cultivadas , Feminino , Xenoenxertos , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Proteína-Lisina 6-Oxidase/biossíntese , Coluna Vertebral/citologiaRESUMO
PURPOSE: Cetuximab-containing chemotherapy is known to be effective for KRAS wild-type metastatic colorectal cancer; however, it is not clear whether cetuximab-based preoperative chemoradiation confers an additional benefit compared with chemoradiation without cetuximab in patients with locally advanced rectal cancer. METHODS AND MATERIALS: We analyzed EGFR, KRAS, BRAF, and PIK3CA mutation status with direct sequencing and epidermal growth factor receptor (EGFR) and Phosphatase and tensin homolog (PTEN) expression status with immunohistochemistry in tumor samples of 82 patients with locally advanced rectal cancer who were enrolled in the IRIX trial (preoperative chemoradiation with irinotecan and capecitabine; n=44) or the ERBIRIX trial (preoperative chemoradiation with irinotecan and capecitabine plus cetuximab; n=38). Both trials were similarly designed except for the administration of cetuximab; radiation therapy was administered at a dose of 50.4 Gy/28 fractions and irinotecan and capecitabine were given at doses of 40 mg/m2 weekly and 1650 mg/m2/day, respectively, for 5 days per week. In the ERBIRIX trial, cetuximab was additionally given with a loading dose of 400 mg/m2 on 1 week before radiation, and 250 mg/m2 weekly thereafter. RESULTS: Baseline characteristics before chemoradiation were similar between the 2 trial cohorts. A KRAS mutation in codon 12, 13, and 61 was noted in 15 (34%) patients in the IRIX cohort and 5 (13%) in the ERBIRIX cohort (P=.028). Among 62 KRAS wild-type cancer patients, major pathologic response rate, disease-free survival and pathologic stage did not differ significantly between the 2 cohorts. No mutations were detected in BRAF exon 11 and 15, PIK3CA exon 9 and 20, or EGFR exon 18-24 in any of the 82 patients, and PTEN and EGFR expression were not predictive of clinical outcome. CONCLUSIONS: In patients with KRAS wild-type locally advanced rectal cancer, the addition of cetuximab to the chemoradiation with irinotecan plus capecitabine regimen was not associated with improved clinical outcome compared with chemoradiation without cetuximab.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Quimiorradioterapia/métodos , Genes ras/genética , Mutação/genética , Neoplasias Retais/genética , Neoplasias Retais/terapia , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Capecitabina , Cetuximab , Classe I de Fosfatidilinositol 3-Quinases , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Esquema de Medicação , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Cuidados Pré-Operatórios , Proteínas Proto-Oncogênicas B-raf/genética , Dosagem Radioterapêutica , Neoplasias Retais/metabolismo , Neoplasias Retais/patologia , Resultado do TratamentoRESUMO
Previously, we identified p85, a subunit of PI3K, as one of the molecules that interacts with the N-terminal region of Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76). We also demonstrated that tyrosine phosphorylation either at the 113 and/or 128 position is sufficient for the association of SLP-76 with the Src homology 2 domain near the N terminus of p85. The present study further examines the role of the association of these two molecules on the activation of PI3K signaling cascade. Experiments were done to determine the role of SLP-76, either wild-type, tyrosine mutants, or membrane-targeted forms of various SLP-76 constructs, on the membrane localization and phosphorylation of Akt, which is an event downstream of PI3K activation. Reconstitution studies with these various SLP-76 constructs in a Jurkat variant cell line that lacks SLP-76 or linker for activation of T cells (LAT) show that the activation of PI3K pathway following TCR ligation requires both SLP-76 and LAT adaptor proteins. The results suggest that SLP-76 associates with p85 after T cell activation and that LAT recruits this complex to the membrane, leading to Akt activation.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Ativação Linfocitária/imunologia , Proteínas de Membrana/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Fosfoproteínas/fisiologia , Subunidades Proteicas/fisiologia , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Membrana Celular/enzimologia , Membrana Celular/imunologia , Membrana Celular/metabolismo , Ativação Enzimática/imunologia , Humanos , Células Jurkat , Proteínas de Membrana/metabolismo , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas/metabolismo , Fosforilação/imunologia , Subunidades Proteicas/metabolismo , Transporte Proteico/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/fisiologia , Subpopulações de Linfócitos T/enzimologiaRESUMO
To investigate additional functions of the T cell adaptor, Src homology 2 (SH2) domain-containing leukocyte protein of 76 kD (SLP-76), we performed a yeast two-hybrid assay using the N-terminal region of SLP-76 fused with the kinase domain of Syk. By screening a human leukemia cDNA library, we identified the p85 subunit of phosphoinositide 3-kinase (PI3K) as one of the interacting molecules. Unlike the SH2 domain of Vav or Nck, tyrosine phosphorylation of SLP-76 at position 113 or 128 was sufficient for it to associate with the N-terminal SH2 of p85. Collectively, these data suggest that SLP-76 may play a role in PI3K signaling pathways.