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1.
Clin Orthop Relat Res ; 481(12): 2406-2416, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37184605

RESUMO

BACKGROUND: Reconstruction after periacetabular bone tumor resection involves important tradeoffs; large bone grafts or endoprostheses are reported to offer fair walking function in general but can be technically demanding and carry a high risk of severe complications. Conversely, hip transposition avoids implant-related risks, but stability and functional return may be less consistent. Fewer studies are available on hip transposition, which is also appealing in more resource-constrained environments, and little is known about the time course from surgery to functional return after hip transposition. QUESTIONS/PURPOSES: (1) What is the time course of recovery of walking function after hip transposition, especially in the first 6 months? (2) What factors are associated with a greater likelihood of early functional recovery? (3) Is early (2-month) functional recovery associated with a greater likelihood of walking ability and higher Musculoskeletal Tumor Society (MSTS) scores? METHODS: Between 2009 and 2019, six tertiary care centers in Japan treated 48 patients with internal hemipelvectomy for malignant tumors. During that time, the preferred reconstructive approach was hip transposition, and 92% (44 of 48) of our patients were treated with this procedure. Among them, 86% (38 of 44) had follow-up of at least 6 months, had no local recurrence during that time, and were included in our retrospective study. We chose 6 months as the minimum follow-up duration because the endpoints in this study pertained to early recovery rather than reconstructive durability. Hip transposition involved moving the proximal end of the femur (femoral head, resection end of the trochanteric area, and spacers such as prostheses) upward to the underside of the resected ilium or the lateral side of the sacrum if sacroiliac joint resection was performed. The end of the proximal femur was stabilized to the remaining ilium or sacrum using polyethylene tape, polyethylene terephthalate mesh, an iliotibial tract graft, or an external fixator, according to the surgeon's preference. The median age at surgery was 46 years (range 9 to 76 years), there were 23 women and 15 men, and the median follow-up duration was 17 months (range 6 to 110 months). The postoperative time course of functional recovery was assessed with a record review, the timing of functional milestones was identified (wheelchair, walker, bilateral crutches, single crutch or cane, and walking without an aid), and the MSTS score at the final follow-up was assessed. Additionally, demographic and surgical factors were reviewed, and their association with short-term functional recovery and the final functional outcome was analyzed. RESULTS: Patients started using a walker at median postoperative day (POD) 20 (IQR 14 to 36) and with bilateral crutches at median POD 35 (IQR 20 to 57). At POD 60, which was the approximate median date of discharge, 76% (29 of 38) of patients were able to walk using bilateral crutches (the early recovery group) and 24% (nine of 38) of patients were not able to do so (the delayed recovery group). No baseline factors were different between the two groups. The early recovery group had a higher median MSTS score than the delayed recovery group: 57% (range 17% to 90%) versus 45% (13% to 57%) (p = 0.047). Moreover, more patients acquired better function (a single crutch or cane or more) in the early recovery group, with a median of 5 months (95% CI 4 to 11) than did those in the delayed recovery group (median not reached) (p = 0.0006). The HR was 15.2 (95% CI 2.5 to 93). Forty-two percent (16 of 38) underwent additional surgery for wound management. CONCLUSION: It took patients a fair amount of time to recover walking function after hip transposition, and patients who could not walk on bilateral crutches at POD 60 seemed less likely to regain walking function and were likely to have lower MSTS scores thereafter. Wound-related complications were frequent. This method may be a realistic alternative for younger patients who have the strength for a long rehabilitation period or those who want to minimize prosthesis-related complications. Future studies with more patients are necessary to understand the risk factors associated with delayed recovery.Level of Evidence Level III, therapeutic study.


Assuntos
Artroplastia de Quadril , Neoplasias Ósseas , Masculino , Humanos , Feminino , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias Ósseas/patologia , Artroplastia de Quadril/efeitos adversos , Caminhada
2.
Br J Cancer ; 126(9): 1289-1300, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35017658

RESUMO

BACKGROUND: Dedifferentiated chondrosarcoma (DDCS) is an aggressive bone tumour with a poor prognosis and no effective treatment. Because changes in DNA methylation play critical roles in DDCS, we explored the roles that DNA methylation plays in oncogenesis to potentially identify an effective epigenetic treatment. METHODS: We identified genes downregulated in DDCS vs. conventional chondrosarcoma (CCS) due to DNA methylation using in silico analysis. The results were validated in DDCS clinical samples, and the molecular functions of the genes of interest were investigated in multiple chondrosarcoma cell lines (NDCS-1, SW1353, and OUMS-27). The therapeutic effect of decitabine, a DNA methyltransferase inhibitor, was evaluated in vitro and in vivo. RESULTS: PRKCZ was specifically downregulated by DNA methylation in DDCS. Overexpression of PRKCZ decreased the proliferation of NDCS-1 and SW1353 cells. PRKCZ directly bound to and activated ATM, which was followed by phosphorylation of CHK2 and subsequent apoptosis. Decitabine increased PRKCZ expression through de-methylating the promoter region of PRKCZ, which activated the ATM/CHK2 pathway and inhibited cell proliferation by inducing apoptosis. CONCLUSIONS: Increased DNA methylation and reduced expression of PRKCZ prevents apoptosis via inactivation of the ATM/CHK2 pathway in DDCS. Decitabine-induced expression of PRKCZ represents a promising therapy for DDCS.


Assuntos
Apoptose , Condrossarcoma , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Quinase do Ponto de Checagem 2/genética , Quinase do Ponto de Checagem 2/metabolismo , Condrossarcoma/tratamento farmacológico , Condrossarcoma/genética , Condrossarcoma/metabolismo , Metilação de DNA , Decitabina/metabolismo , Decitabina/farmacologia , Humanos , Proteína Quinase C
3.
J Orthop Sci ; 27(6): 1315-1322, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34531086

RESUMO

BACKGROUND: Mutant isocitrate dehydrogenase (IDH) in chondrosarcoma produces the oncometabolite 2-hydroxyglutarate (2-HG) and contributes to malignant progression, and is therefore a potential therapeutic target for chondrosarcoma. Robust historical control data are important in clinical trials of rare cancers such as chondrosarcoma in order to show a clear benefit of new drugs. However, it remains controversial whether IDH mutation status is associated with the clinical outcome of chondrosarcoma, and this hinders the development of mutant IDH inhibitors in clinical trials.background METHODS: We investigated the relationship between IDH gene status and clinicopathological data in 38 chondrosarcoma patients from whom frozen tumor samples were obtained at the time of biopsy or surgery. Targeted next-generation sequencing was also performed to compare genetic alterations between patients with and without IDH mutations. METHODS RESULTS: The results revealed 15 cases (40%) of heterozygous IDH1 mutations and five cases (13%) of IDH2 mutations. IDH-mutant chondrosarcoma was associated with worse overall survival than IDH-wild-type chondrosarcoma (IDH1/2 Mut vs. IDH Wt, P = 0.006; IDH1 Mut vs. IDH Wt, P = 0.030; IDH2 Mut vs. IDH Wt, P < 0.0001). IDH mutation was also a significant poor prognostic factor both in univariate (P = 0.026) and multivariate (P = 0.048) analyses. Targeted next-generation sequencing revealed that characteristic mutations in chondrosarcoma, including TP53 and COL2A1, were more common in the IDH-mutant group than in the IDH-wild-type group.results CONCLUSION: This study is the first to report in detail the characteristics and clinical courses of IDH-mutant chondrosarcoma patients in Japan. Our data suggested that IDH-mutant chondrosarcomas might have a worse prognosis than that of IDH-wild-type chondrosarcoma, possibly through the more aggressive characters after metastasis. This information will be useful for designing clinical trials of mutant IDH inhibitors for treatment of advanced chondrosarcoma.


Assuntos
Neoplasias Ósseas , Condrossarcoma , Humanos , Isocitrato Desidrogenase/genética , Prognóstico , Condrossarcoma/genética , Condrossarcoma/patologia , Mutação , Inibidores Enzimáticos/farmacologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia
4.
Cancer Sci ; 112(6): 2314-2324, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33792119

RESUMO

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin's lymphoma, which is characterized by overexpression of cyclin D1. Although novel drugs, such as ibrutinib, show promising clinical outcomes, relapsed MCL often acquires drug resistance. Therefore, alternative approaches for refractory and relapsed MCL are needed. Here, we examined whether a novel inhibitor of enhancer of zeste homologs 1 and 2 (EZH1/2), OR-S1 (a close analog of the clinical-stage compound valemetostat), had an antitumor effect on MCL cells. In an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model, OR-S1 treatment by oral administration significantly inhibited MCL tumor growth, whereas ibrutinib did not. In vitro growth assays showed that compared with an established EZH2-specific inhibitor GSK126, OR-S1 had a marked antitumor effect on MCL cell lines. Furthermore, comprehensive gene expression analysis was performed using OR-S1-sensitive or insensitive MCL cell lines and showed that OR-S1 treatment modulated B-cell activation, differentiation, and cell cycle. In addition, we identified Cyclin Dependent Kinase Inhibitor 1C (CDKN1C, also known as p57, KIP2), which contributes to cell cycle arrest, as a direct target of EZH1/2 and showed that its expression influenced MCL cell proliferation. These results suggest that EZH1/2 may be a potential novel target for the treatment of aggressive ibrutinib-resistant MCL via CDKN1C-mediated cell cycle arrest.


Assuntos
Adenina/análogos & derivados , Antineoplásicos/farmacologia , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Linfoma de Célula do Manto/tratamento farmacológico , Piperidinas/farmacologia , Complexo Repressor Polycomb 2/antagonistas & inibidores , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Camundongos , Piperidinas/uso terapêutico , Sindecana-1/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Hered Cancer Clin Pract ; 19(1): 34, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34419117

RESUMO

BACKGROUND: Muir-Torre syndrome (MTS), which accounts for a small subset (1-3 %) of Lynch syndrome (LS), is an autosomal dominant genetic disorder characterized by sebaceous gland or keratoacanthoma associated with visceral malignancies. Most families with MTS have pathogenic germline variants (PGV) in MSH2. Sarcomas are not common on the LS tumor spectrum, and sarcomas associated with MTS are extremely rare. CASE PRESENTATION: Here we report a myxofibrosarcoma of the abdominal wall in a 73-year-old man with a sebaceoma that occurred synchronically, leading to a diagnosis of MTS. The loss of MLH1 and PMS2 protein expression was detected in immunohistochemistry, and high-frequency microsatellite instability (MSI-H) was also confirmed. A germline genetic analysis revealed that he harbored the MLH1 PGV. CONCLUSIONS: This is the first case of MSI-H myxofibrosarcoma with MTS in an MLH1 PGV carrier. Although rare, we should recognize that sarcomas can be part of the spectrum of LS and MTS.

6.
Sensors (Basel) ; 21(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071392

RESUMO

A laser-induced breakdown spectroscopy (LIBS) system using a microchip laser for plasma generation is proposed for in-situ analysis of trace minerals in human hair. The LIBS system is more compact and less expensive than conventional LIBS systems, which use flashlamp-excited Q-switched Nd:YAG lasers. Focusing optics were optimized using a Galilean beam expander to compensate for the low emitted pulse energy of the microchip laser. Additionally, hundreds of generated LIBS spectra were accumulated to improve the signal-to-noise ratio of the measurement system, and argon gas was injected at the irradiation point to enhance plasma intensity. LIBS spectra of human hair in the UV to near IR regions were investigated. Relative mass concentrations of Ca, Mg, and Zn were analyzed in hairs obtained from five subjects using the intensity of C as a reference. The results coincide well with those measured via inductively coupled argon plasma mass spectrometry. The lowest detectable concentrations of the measured LIBS spectra were 9.0 ppm for Mg, 27 ppm for Zn, and 710 ppm for Ca. From these results, we find that the proposed LIBS system based on a microchip laser is feasible for the analysis of trace minerals in human hair.


Assuntos
Lasers de Estado Sólido , Oligoelementos , Humanos , Luz , Análise Espectral , Oligoelementos/análise
7.
Int J Mol Sci ; 22(21)2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34769486

RESUMO

We previously reported that conjugates of antimicrobial peptide fragment analogues and poly (lactic-co-glycolic) acid (PLGA) enhance antimicrobial activity and that the conjugated micelle structure is an effective tool for antimicrobial drug delivery. In recent years, the delivery of antimicrobial peptides to targets for antimicrobial activity has attracted attention. In this study, we targeted Candida albicans, a causative organism of catheter-related bloodstream infections, which is refractory to antimicrobial agents and is currently a problem in medical practice. We evaluated the antifungal activity of CKR12 (a mutant fragment of the human cathelicidin peptide, LL-37)-PLGA-miconazole (MCZ) micelles using nanotechnology with MCZ delivery. The prepared CKR12-PLGA-MCZ micelles were characterised by measuring dynamic light scattering, zeta potential, dilution stability, and drug release. CKR12-PLGA-MCZ micelles showed higher antifungal activity than CKR12-PLGA micelles and MCZ solution. Furthermore, scanning and transmission electron microscopy suggested that CKR12-PLGA-MCZ micelles disrupted both cell wall and cell membrane of C. albicans. Our results revealed a synergistic effect of antifungal activity using a combination of antimicrobial peptide fragment analogues and MCZ, and that MCZ is a promising tool for the delivery to target microorganisms.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Miconazol/farmacologia , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Antifúngicos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Candidíase/metabolismo , Candidíase/microbiologia , Micelas , Miconazol/química , Catelicidinas
8.
Cancer Immunol Immunother ; 69(5): 745-758, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32047957

RESUMO

BACKGROUND: Osteosarcoma (OS) is the most common malignant bone tumor and the prognosis of advanced cases is still poor. Recently, there have been several reports suggesting the relationship between innate immunity and OS, but the detailed mechanism is unknown. We demonstrate the relationship between OS and Toll-like receptor 4 (TLR4) which is one of the most important factors in innate immunity. METHODS: We established a syngenic mouse tumor model using C3H/HeN, C3H/HeJ mouse and a highly metastatic OS cell line, LM8. TLR4 activation with lipopolysaccharide (LPS) was performed on both mice and its influence on the progression of OS was evaluated. We also performed CD8 + cells depletion to examine the influence on TLR4 activation effects. RESULTS: Tumor volume of C3H/HeN mice was significantly smaller and overall survival of C3H/HeN mice was significantly longer than C3H/HeJ mice. We found more CD8+ cells infiltrating in lung metastases of C3H/HeN mice and depletion of CD8+ cells canceled the antitumor effects of LPS. CONCLUSION: TLR4 activation by LPS increased CD8+ cells infiltrating into lung metastases and suppressed OS progression in the mouse model. TLR4 activation may suppress the progression of OS via stimulating CD8+ cells and can be expected as a novel treatment for OS.


Assuntos
Neoplasias Ósseas/imunologia , Neoplasias Pulmonares/imunologia , Osteossarcoma/imunologia , Linfócitos T Citotóxicos/imunologia , Receptor 4 Toll-Like/metabolismo , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Linhagem Celular Tumoral/transplante , Quimioterapia Adjuvante , Criança , Pré-Escolar , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Lipídeo A/administração & dosagem , Lipídeo A/análogos & derivados , Lipopolissacarídeos/administração & dosagem , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Depleção Linfocítica , Masculino , Camundongos , Pessoa de Meia-Idade , Osteossarcoma/mortalidade , Osteossarcoma/secundário , Osteossarcoma/terapia , Prognóstico , Intervalo Livre de Progressão , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/metabolismo , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/imunologia , Carga Tumoral/imunologia , Adulto Jovem
9.
Ann Surg Oncol ; 27(7): 2427-2435, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31970570

RESUMO

BACKGROUND: Sarcopenia influences overall survival (OS) and tumor progression in non-small cell lung cancer (NSCLC) patients. However, the impact of postoperative complications and the outcome of limited surgery have not been highlighted. Therefore, the aim of this study is to elucidate the prognostic impact of sarcopenia on surgical outcomes. PATIENTS AND METHODS: This study included NSCLC patients who had undergone lung cancer resection between 2007 and 2017. Sarcopenia was confirmed based on computed tomography of the cross-sectional area of the psoas muscle at the third lumbar vertebra level. We used propensity score-matched analysis to elucidate the impact of sarcopenia on postoperative complications and limited surgery. RESULTS: A total of 391 patients were enrolled, including 198 sarcopenic patients. Multivariate analysis showed that sarcopenia was an independent unfavorable prognostic factor associated with OS and recurrence-free survival [hazard ratio (HR), 3.33, P < 0.001; HR, 2.76, P < 0.001, respectively]. Regarding the incidence of postoperative complications, there was no difference between sarcopenic and nonsarcopenic patients (69/198 versus 55/193, P = 0.19). After propensity score matching, among patients without sarcopenia, the 5-year OS was lower in those with limited surgery than in those with standard surgery (70.7% vs. 96.4%, P = 0.011). In contrast, among sarcopenic patients, there was no difference in the 5-year OS between patients with limited surgery and those with standard surgery (53.2% vs. 60.7%, P = 0.66). CONCLUSIONS: Sarcopenia is a prognostic predictor for poor OS and may contribute to the selection of limited surgery for sarcopenic patients. Preoperative assessment of sarcopenia may provide clinically important information.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Sarcopenia , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/cirurgia , Complicações Pós-Operatórias/etiologia , Prognóstico , Estudos Retrospectivos , Sarcopenia/complicações , Sarcopenia/diagnóstico por imagem , Resultado do Tratamento
10.
Ann Surg Oncol ; 27(2): 481-489, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31407181

RESUMO

BACKGROUND: Pericardial fat (PF) has not been considered a prognostic biomarker for overall survival (OS) in lung cancer. This study was designed to elucidate the impact of PF on prognosis of resected non-small cell lung cancer patients. METHODS: We retrospectively reviewed a total of 349 patients who underwent lung resection and received high-resolution computed tomography in our institute. PF volume was calculated. PF extended vertically from the diaphragm to the bifurcation of the right main pulmonary artery. Propensity score matched analysis was used to compare OS between the high- and low-PF groups. RESULTS: PF volume increased according to body mass index (p < 0.001). Receiver operating characteristics (ROC) curve analysis for 3-year OS showed the possibility of better predictivity of PF than body-mass index (area under the curve, 0.66 vs. 0.61, p = 0.010). Cutoff level of PF volume was determined based on the ROC with 122 cm3. Five-year OS was poorer in the low-PF group (63.5% vs. 73.4%; p = 0.002). After propensity score matching, each group consisted of 89 cases. Five-year OS was poorer in the low-PF group (66.5% vs. 82.7%; p = 0.008). A Cox proportional hazards model showed low-PF volume was associated with poorer OS (hazard ratio, 2.14; p = 0.009). The number of respiratory-related deaths was higher in the low-PF group (10/89 vs. 2/89, p = 0.032). CONCLUSIONS: Low-PF volume may be associated with poor OS with an increase in the number of respiratory-related deaths. Patients with low-PF volume require careful follow-up after surgery.


Assuntos
Adenocarcinoma de Pulmão/patologia , Tecido Adiposo/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Pericárdio/patologia , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/cirurgia , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/cirurgia , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
11.
Cancer Sci ; 110(1): 194-208, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30343511

RESUMO

Multiple myeloma (MM) is an incurable hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs as a result of a remaining population of drug-resistant myeloma stem cells. Side population (SP) cells show cancer stem cell-like characteristics in MM; thus, targeting these cells is a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non-SP cells, suggesting that EZH1 as well as EZH2 contributes to the stemness maintenance of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR-S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including a unique patient-derived xenograft model. Moreover, long-term continuous dosing of OR-S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM, and overactivation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH1/2 in the maintenance of myeloma stem cells and provide a preclinical rationale for therapeutic application of OR-S1, leading to significant advances in the treatment of MM.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Mieloma Múltiplo/prevenção & controle , Células-Tronco Neoplásicas/efeitos dos fármacos , Complexo Repressor Polycomb 2/antagonistas & inibidores , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Células da Side Population/efeitos dos fármacos , Células da Side Population/metabolismo , Via de Sinalização Wnt/genética
12.
Curr Treat Options Oncol ; 20(7): 54, 2019 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-31129726

RESUMO

OPINION STATEMENT: The proper diagnosis and treatment planning for subcutaneous soft tissue sarcoma is very important. Soft tissue tumors can occur anywhere in the body, but if they occur subcutaneously, patients can easily notice a subcutaneous soft tissue mass. Therefore, it is possible to determine through recording, the growth speed of the mass, which is often difficult to obtain with deep-situated soft tissue masses. Palpation can also provide information about the firmness and mobility of the mass. Thus, history taking and physical examinations are informative for subcutaneous soft tissue tumors, compared to tumors that occur deeply. Because subcutaneous soft tissue tumors are easily recognized, they are often resected, without sufficient imaging analyses or thorough treatment planning. An operation performed based on such an inadequate preoperative plan is called a "whoops surgery." In the case of "whoops surgeries," subsequent radical surgery is required to remove additional areas, including hematomas that result from the initial surgery, that require a wider range of resection and soft tissue reconstruction. Therefore, as with deep-seated soft tissue tumors, it is important to conduct careful imaging examinations and make appropriate preoperative plans for subcutaneous soft tissue tumors. Subcutaneous soft tissue sarcomas often show an invasive pattern, and such tumors require a more careful assessment to prevent local recurrence after surgery. During surgery, it is necessary to remove the entire infiltration area along the fascia. Sometimes, an adequately wide excision is necessary, which is considered the minimum necessary procedure to eradicate the lesion. As noted above, clinicians who see patients with subcutaneous soft tissue tumors are encouraged to have sufficient knowledge and experience regarding the diagnosis and treatment. This article is intended for all doctors who deal with subcutaneous soft tissue tumors and focuses on essential points regarding their diagnosis and management.


Assuntos
Sarcoma/diagnóstico , Sarcoma/cirurgia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/cirurgia , Gerenciamento Clínico , Humanos , Margens de Excisão , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/cirurgia , Fatores de Risco , Carga Tumoral
13.
J Am Chem Soc ; 140(15): 4991-4994, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29613794

RESUMO

The selective large-scale syntheses of noble metal nanocrystals with complex shapes using wet-chemical approaches remain exciting challenges. Here we report the chirality-controllable syntheses of double-helical Au nanowires (NWs) using chiral soft-templates composed of two organogelators with their own active functions; one organogelator serves to introduce helicity into the template and the other acts as a capping agent to control the Au shape. One-dimensional twisted-nanoribbon templates are prepared simply by mixing the two organogelators in water containing a small amount of toluene, followed by the addition of LiCl; template chirality is controlled through the selection of the handedness of the helicity-inducing organogelator. Double-helical Au NWs synthesized on these chiral templates have the same helical structure as the template because the Au NWs grow along both edges of the twisted nanoribbons with right- or left-handed helicities. Dispersions of the right- and left-handed double-helical Au NWs exhibit opposite CD signals.

14.
Cancer Sci ; 109(8): 2342-2348, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29845708

RESUMO

Polycomb group (PcG) proteins regulate the expression of target genes by modulating histone modifications and are representative epigenetic regulators that maintain the stemness of embryonic and hematopoietic stem cells. Histone methyltransferases enhancer of zeste homolog 1 and 2 (EZH1/2), which are subunits of polycomb repressive complexes (PRC), are recurrently mutated or highly expressed in many hematological malignancies. EZH2 has a dual function in tumorigenesis as an oncogene and tumor suppressor gene, and targeting PRC2, in particular EZH1/2, for anticancer therapy has been extensively developed in the clinical setting. Here, we review the oncogenic function of EZH1/2 and introduce new therapeutic drugs targeting these enzymes.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Neoplasias Hematológicas/genética , Oncogenes/genética , Complexo Repressor Polycomb 2/genética , Animais , Carcinogênese/genética , Humanos , Proteínas do Grupo Polycomb/genética
15.
Circ J ; 80(10): 2155-64, 2016 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-27628221

RESUMO

BACKGROUND: There is no robust evidence of pharmacological interventions to improve mortality in heart failure (HF) patients with preserved left ventricular ejection fraction (LVEF) (HFpEF). In this subanalysis study of the SUPPORT Trial, we addressed the influence of LVEF on the effects of olmesartan in HF. METHODS AND RESULTS: Among 1,147 patients enrolled in the SUPPORT Trial, we examined 429 patients with reduced LVEF (HFrEF, LVEF <50%) and 709 with HFpEF (LVEF ≥50%). During a median follow-up of 4.4 years, 21.9% and 12.5% patients died in the HFrEF and HFpEF groups, respectively. In HFrEF patients, the addition of olmesartan to the combination of angiotensin-converting enzyme inhibitor (ACEI) and ß-blocker (BB) was associated with increased incidence of death (hazard ratio (HR) 2.26, P=0.002) and worsening renal function (HR 2.01, P=0.01), whereas its addition to ACEI or BB alone was not. In contrast, in HFpEF patients, the addition of olmesartan to BB alone was significantly associated with reduced mortality (HR 0.32, P=0.03), whereas with ACEIs alone or in combination with BB and ACEI was not. The linear mixed-effect model showed that in HFpEF, the urinary albumin/creatinine ratio was unaltered when BB were combined with olmesartan, but significantly increased when not combined with olmesartan (P=0.01). CONCLUSIONS: LVEF substantially influences the effects of additive use of olmesartan, with beneficial effects noted when combined with BB in hypertensive HFpEF patients. (Circ J 2016; 80: 2155-2164).


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Insuficiência Cardíaca , Hipertensão , Imidazóis/administração & dosagem , Volume Sistólico/efeitos dos fármacos , Tetrazóis/administração & dosagem , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/complicações , Hipertensão/dietoterapia , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida
16.
Eur Heart J ; 36(15): 915-23, 2015 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-25637937

RESUMO

We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, ß-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96-1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19-2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and ß-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11-1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01-2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24-2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and ß-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/complicações , Hipertensão/tratamento farmacológico , Imidazóis/uso terapêutico , Tetrazóis/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Doença Crônica , Quimioterapia Combinada , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Estimativa de Kaplan-Meier , Masculino , Adesão à Medicação , Estudos Prospectivos , Resultado do Tratamento
19.
J UOEH ; 37(2): 121-5, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26073501

RESUMO

We herein report a very rare case of adenoid cystic carcinoma of the peripheral lungs. A 77-year-old female visited a family physician for aortitis syndrome, diabetes mellitus and hyperlipidemia. A follow-up chest computed tomography scan for aortitis syndrome revealed a nodule in the middle lobe of the right lung. Although a transbronchial lung biopsy was attempted, a definitive diagnosis could not be made. Because the possibility of lung malignancy could not be ruled out, thoracoscopic wedge resection of the middle lobe was performed. The intraoperative pathological diagnosis revealed carcinoma of the lungs and we performed middle lobectomy under complete video-assisted thoracoscopic surgery. A histopathological examination demonstrated an adenoid cystic carcinoma with a characteristic cribriform structure.


Assuntos
Carcinoma Adenoide Cístico , Neoplasias Pulmonares/patologia , Idoso , Biópsia , Carcinoma Adenoide Cístico/cirurgia , Feminino , Humanos , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Tomografia Computadorizada por Raios X
20.
Oncology ; 86(2): 109-16, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24457449

RESUMO

Epithelioid tumors with aggressive behavior have been reported; however, the epithelioid type of malignant pleural mesothelioma (MPM) has a less aggressive behavior. Few studies have evaluated the prognostic value of epithelial-mesenchymal transition (EMT) markers in MPM. We hypothesized that mesenchymal characteristics might predominate in the tumors. Tumor specimens were collected from 33 consecutive patients. We analyzed the EMT expression levels in tumor samples by an immunohistochemical analysis. Positive expression of E-cadherin, γ-catenin, vimentin, fibronectin, Twist and YB-1 was observed in 25, 14, 21, 1, 19 and 18 patients, respectively. No significant association between these markers and the clinicopathological characteristics was found. γ-Catenin demonstrated a trend towards decreased expression in sarcomatoid tumors compared to epithelioid tumors. On the other hand, a trend was noted towards higher expression of vimentin, Twist and YB-1 in sarcomatoid tumors. The survival curves demonstrated that the patients with negative γ-catenin and positive Twist staining had a tendency to have a worse prognosis. Although the individual proteins might not significantly affect the progression of MPM, the combination of γ-catenin and Twist staining can predict the prognosis of patients with MPM.


Assuntos
Biomarcadores Tumorais/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Pleurais/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , gama Catenina/metabolismo , Idoso , Antígenos CD , Caderinas/metabolismo , Feminino , Fibronectinas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/mortalidade , Mesotelioma/patologia , Mesotelioma Maligno , Análise Multivariada , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/patologia , Prognóstico , Vimentina/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo
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