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1.
J Orthop Sci ; 28(6): 1285-1290, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36372679

RESUMO

BACKGROUND: The present study was carried out to answer three questions: 1) How much forearm rotation can be expected after mobilization of congenital radioulnar synostosis (CRUS)? 2) Does preoperative radius head dislocation affect forearm rotation after mobilization? 3) What factors other than radius head dislocation affect postoperative forearm rotation? METHODS: We performed mobilization of CRUS with a free vascularized fascio-fat graft and a radius osteotomy (Kanaya's procedure) on 26 forearms of 25 patients. The age at the surgery ranged from 5.3 to 13.4 years. The follow-up duration ranged 24-111 months. We classified CRUS into 3 groups according to the dislocation of the radius head: posterior dislocation (N = 13), anterior dislocation (N = 9) and no dislocation (N = 4). Since major complaints of patients and parents were poor forearm rotation and lack of supination, they were evaluated separately. RESULTS: Mean preoperative forearm ankylosis angle was 34.8° (range; neutral to 90° pronation). Preoperative pronation ankylosis angle was higher in the posterior dislocation group (mean 55.3°) than the anterior dislocation (mean 11.6°) and no dislocation groups (mean 5.0°). There was no re-ankylosis after mobilization and the mean postoperative active range of motion (ROM) was 86.5°. The mean active ROM was 75.7° in the posterior dislocation group, 96.1° in anterior dislocation group and 100.0° in no dislocation group. The mean active supination was 6.9, 33.9 and 47.5° respectively. The posterior dislocation group showed less ROM and less supination than other groups. Preoperative pronation ankylosis angle showed negative correlation with postoperative ROM (ρ = - 0.59) and postoperative supination (ρ = - 0.73). CONCLUSION: The mean postoperative active ROM of this mobilization was 86.5°. Posterior dislocation group showed higher pronation ankylosis angle preoperatively, and less postoperative ROM and less supination than anterior and no dislocation groups. Preoperative pronation ankylosis angle showed negative correlation with postoperative ROM and supination.


Assuntos
Anquilose , Luxações Articulares , Sinostose , Humanos , Pré-Escolar , Criança , Adolescente , Antebraço/cirurgia , Rádio (Anatomia)/diagnóstico por imagem , Rádio (Anatomia)/cirurgia , Sinostose/diagnóstico por imagem , Sinostose/cirurgia , Ulna/diagnóstico por imagem , Ulna/cirurgia , Luxações Articulares/diagnóstico por imagem , Luxações Articulares/cirurgia , Pronação , Supinação
2.
Anticancer Res ; 41(7): 3287-3292, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230123

RESUMO

BACKGROUND: Osteosarcoma is the most frequent malignant bone neoplasm. The efficacy of combination therapy of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and a mammalian-target-of-rapamycin (mTOR) inhibitor was previously reported in several cancer types. In the present study, we evaluated the efficacy of a combination of palbociclib (CDK 4/6 inhibitor) and everolimus (mTOR inhibitor) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: osteosarcoma PDOX mouse models were randomized into five treatment groups of seven mice each: Group 1, untreated control; group 2, doxorubicin treatment; group 3, palbociclib treatment; group 4, everolimus treatment; group 5, palbociclib-everolimus combination treatment. Treatment duration was 2 weeks. RESULTS: The palbociclib-everolimus combination reduced the tumor-volume ratio in the osteosarcoma PDOX mouse model compared with the control and doxorubicin (p=0.018). Everolimus alone also inhibited osteosarcoma PDOX growth compared to the control (p=0.04), but less than the combination. Palbociclib alone and doxorubicin were ineffective. There were no significant body-weight losses in any group. Only the palbociclib-everolimus combination induced extensive tumor necrosis observed histopathologically. CONCLUSION: The present study demonstrated that the combination of CDK4/6 and mTOR inhibitors can be a translatable approach for doxorubicin-resistant osteosarcoma in the clinic.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Animais , Neoplasias Ósseas/metabolismo , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Everolimo/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Osteossarcoma/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Sci Rep ; 11(1): 8583, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33883561

RESUMO

In order to identify more effective therapy for recalcitrant osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on tumor growth in a unique osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung metastasis of an osteosarcoma patient who failed doxorubicin therapy. We also determined the efficacy of this inhibitor combination on angiogenesis using an in vivo Gelfoam fluorescence angiogenesis mouse model implanted with osteosarcoma patient-derived cells (OS-PDCs). PDOX models were randomly divided into five groups of seven nude mice. Group 1, control; Group 2, doxorubicin (DOX); Group 3, everolimus (EVE, an mTOR and VEGF inhibitor); Group 4, pazopanib (PAZ, a VEGFR inhibitor); Group 5, EVE-PAZ combination. Tumor volume and body weight were monitored 2 times a week. The in vivo Gelfoam fluorescence angiogenesis assay was performed with implanted OS-PDCs. The nude mice with implanted Gelfoam and OSPDCs also were divided into the four therapeutic groups and vessel length was monitored once a week. The EVE-PAZ combination suppressed tumor growth in the osteosarcoma PDOX model and decreased the vessel length ratio in the in vivo Gelfoam fluorescent angiogenesis model, compared with all other groups (p < 0.05). There was no significant body-weight loss in any group. Only the EVE-PAZ combination caused tumor necrosis. The present study demonstrates that a combination of an mTOR-VEGF inhibitor and a VEGFR inhibitor was effective for a DOX-resistant lung-metastatic osteosarcoma PDOX mouse model, at least in part due to strong anti-angiogenesis efficacy of the combination.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Doxorrubicina/uso terapêutico , Everolimo/uso terapêutico , Indazóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Pirimidinas/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Animais , Neoplasias Ósseas/patologia , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Quimioterapia Combinada , Everolimo/administração & dosagem , Feminino , Humanos , Indazóis/administração & dosagem , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neovascularização Patológica/tratamento farmacológico , Osteossarcoma/patologia , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem
4.
Anticancer Res ; 41(2): 635-640, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517267

RESUMO

BACKGROUND: A mouse model of metastatic osteosarcoma is imperative to identify effective agents for metastatic osteosarcoma, which is a recalcitrant disease. In the present study, we established osteosarcoma patient-derived cells (OS-PDCs) and transfected them with green fluorescent protein (GFP). MATERIALS AND METHODS: The OS-PDCs were transfected with GFP-lentivirus. GFP-expressing OS-PDCs (2.0×105) were then injected into the tibia of nude mice to establish the patient-derived orthotopic cell (PDOC) model (n=3). Six weeks after injection, the primary tumor and each organ were resected and imaged. RESULTS: Primary orthotopic tumors were established in two out of three mice. The GFP-expressing OS-PDCs in the PDOC model were visualized. Multiple GFP-expressing lung metastases were detected in one of the two mice with primary tumor. CONCLUSION: The present study proves the concept that a GFP-expressing PDOC model can mimic clinical lung-metastatic osteosarcoma. This model can serve as a paradigm to screen for effective drugs for osteosarcoma lung metastasis.


Assuntos
Neoplasias Ósseas/patologia , Proteínas de Fluorescência Verde/metabolismo , Neoplasias Pulmonares/secundário , Osteossarcoma/secundário , Tíbia/patologia , Adolescente , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Rastreamento de Células , Feminino , Proteínas de Fluorescência Verde/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos Nus , Transplante de Neoplasias , Osteossarcoma/genética , Osteossarcoma/metabolismo , Tíbia/metabolismo , Transfecção , Células Tumorais Cultivadas
5.
J Hand Surg Glob Online ; 3(1): 41-46, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35415532

RESUMO

Purpose: To compare 2 types of newly devised 8-strand quadruple-looped suture (QLS) techniques with a 6-strand triple-looped suture (TLS) technique; and to assess the effects of different core suture lengths (CSLs) (the length between 2 locking sites of a suture strand) within each suture row on tensile strength. Methods: We repaired 24 flexor tendons from 12 rabbits using the TLS and QLS techniques, with equal CSL (QLS) or unequal CSL (unequal QLS) among each suture row. The QLS was composed of 4 looped sutures on the anterolateral and posterolateral aspects of the tendon. The cross-sectional area of the locking portion of each thread in the QLS was equal to that in the TLS. In the QLS technique, the CSL on each aspect of the tendon was 13 mm. In the unequal QLS technique, the CSL on each aspect of the tendon was 13 and 17 mm. The load at 1- and 2-mm gaps, the maximum load until the 3-mm gap, and the ultimate load were compared among the 3 techniques. Results: The QLS was significantly stronger than the unequal QLS and the TLS for loads at 1-mm and 2-mm gaps, maximum load until 3-mm gap, and ultimate load. There was no significant difference between the unequal QLS and TLS techniques. The QLS technique showed an approximately 30% increase in gap resistance and ultimate strength compared with the TLS technique. Conclusions: The QLS technique showed an estimated increase in tensile strength proportional to the number of suture strands compared with the TLS technique. Our study suggests that a consistent CSL in each suture row provides the highest strength in multistrand sutures consisting of the same configuration of suture rows. Clinical relevance: The QLS technique may reduce the risk for tendon rupture associated with early active mobilization after flexor tendon repair.

6.
Anticancer Res ; 39(9): 4667-4671, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519565

RESUMO

BACKGROUND/AIM: Liver metastasis in colorectal-cancer is a recalcitrant disease. To develop precision individualized therapy of this disease, we developed a patient-derived orthotopic xenograft (PDOX) model of colorectal-cancer liver metastasis. In the present report, we evaluated the efficacy of oral recombinant methioninase (o-rMETase) in combination with 5-fluorouracil (5-FU) and oxaliplatinum (OXA) on the colorectal-cancer liver metastasis PDOX mouse model. MATERIALS AND METHODS: Colorectal-cancer liver metastasis PDOX models were randomized into three groups of seven mice. Group 1, untreated control with phosphate buffered saline (PBS); Group 2, treated with 5-FU + OXA; and Group 3, treated with 5-FU + OXA + o-rMETase. RESULTS: The colorectal-cancer liver metastasis PDOX model was resistant to 5-FU + OXA (p=0.83 at day 15 of treatment, Group 2). In contrast, the colorectal-cancer liver metastasis PDOX model was arrested by o-rMETase combined with 5-FU + OXA (p<0.01 at day 15, Group 3). No significant body-weight differences were observed among the groups. CONCLUSION: The combination therapy of 5-FU and OXA with o-rMETase can overcome the resistance of first line drugs for colorectal-cancer liver metastasis.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Liases de Carbono-Enxofre/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Modelos Animais de Doenças , Fluoruracila/administração & dosagem , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Oxaliplatina/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Anticancer Res ; 39(9): 4775-4779, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519578

RESUMO

BACKGROUND: Osteosarcoma is a recalcitrant disease treated with surgery and intensive chemotherapy as standard. The 5-year survival rate of patients with relapsed and lung metastatic osteosarcoma is as low as 20%. MATERIALS AND METHODS: A 16-year-old patient developed left distal femoral high-grade osteosarcoma and underwent cisplatinum-based neoadjuvant chemotherapy and surgery. From the resected tumor, a patient-derived orthotopic xenograft (PDOX) model was established in the femur of nude mice. PDOX models were randomized into the following groups: untreated control, or treatment with doxorubicin (3 mg/kg, i.p., weekly for 14 days), sunitinib (40 mg/kg, oral gavage, daily for 14 days), pazopanib (100 mg/kg, oral gavage, daily for 14 days), temozolomide(25 mg/kg, oral gavage, daily for 14 days), and eribulin (1.5 mg/kg, i.p., daily for 14 days). Tumor volume and body weight were monitored twice a week. RESULTS: The osteosarcoma PDOX was resistant to doxorubicin, sunitinib, and pazopanib. In contrast, eribulin and temozolomide arrested tumor growth. CONCLUSION: This study demonstrated the utility of the PDOX model in allowing effective from non-effective drugs to be distinguished in a model in which the tumor was growing on the organ corresponding to that of the patient.


Assuntos
Cisplatino/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Cetonas/farmacologia , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia , Adolescente , Animais , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Osteossarcoma/tratamento farmacológico , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Tissue Cell ; 58: 17-23, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31133242

RESUMO

Follicular dendritic cell sarcoma (FDCS) is a very rare and highly recalcitrant disease. A patient's doxorubicin-resistant FDCS was previously established orthotopically on the right high thigh into the biceps femoris of mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present manuscript was to identify an effective drug for this recalcitrant tumor. Here, we evaluated the efficacy of temozolomide (TMZ), trabectedin (TRAB) and pazopanib (PAZ) on the FDCS PDOX model. PDOX mouse models were randomized into five groups of eight to nine mice, respectively. Group 1, untreated control with PBS, i.p.; Group 2, treated with doxorubicin (DOX), 2.4 mg/kg, i.p., weekly for 3 weeks; Group 3, treated with PAZ, 50 mg/kg, oral gavage, daily for 3 weeks; Group 4, treated with TMZ, 25 mg/kg, oral gavage, daily for 3 weeks; Group 5, treated with TRAB, 0.15 mg/kg, i.v., weekly for 3 weeks. Body weight and tumor volume were assessed 2 times per week. TMZ arrested the FDCS PDOX model compared to the control group (p < 0.05). PAZ and TRAB did not have significant efficacy compared to the control group (p = 0.99, p = 0.69 respectively). The PDOX tumor was resistant to DOX (p= 0.99). as was the patient. The present study demonstrates that TMZ is effective for a PDOX model of FDCS established from a patient who failed DOX treatment, further demonstrating the power of PDOX to identify effective therapy including for tumors that failed first line therapy.


Assuntos
Sarcoma de Células Dendríticas Foliculares/tratamento farmacológico , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Temozolomida/farmacologia , Animais , Sarcoma de Células Dendríticas Foliculares/metabolismo , Sarcoma de Células Dendríticas Foliculares/patologia , Feminino , Humanos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Orthop Surg (Hong Kong) ; 27(1): 2309499018816428, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30798768

RESUMO

PURPOSE: The aim of this study was to investigate the histopathological changes in the humeral head in cuff tear arthropathy (CTA) compared with those in glenohumeral osteoarthritis (OA) and humeral neck fracture, which served as non-cuff tear controls. METHODS: Twenty-three humeral heads extracted at the time of shoulder prosthesis arthroplasty between June 2014 and July 2015 were evaluated in the present study. The diagnoses included four-part humeral neck fracture ( n = 4; average age, 85.0 years), glenohumeral OA ( n = 4; average age, 71.0 years), and CTA ( n = 15; average age, 73.0 years). The humeral heads were evaluated pathologically by hematoxylin and eosin and Safranin-O staining, and the thickness of the articular cartilage was measured. RESULTS: Fibrillation, thinning, and tearing of the cartilage were observed in the superior area of the humeral heads in CTA and glenohumeral OA. In CTA cases, clusters of chondrocytes in the cartilage were observed. Moreover, the thickness of the cartilage layer in the middle of the humeral head was 1.54 ± 0.07, 0.32 ± 0.46, and 2.19 ± 0.50 mm in humeral neck fracture, glenohumeral OA, and CTA, respectively. The cartilage layer in CTA was thicker than that in glenohumeral OA (CTA vs. OA: p < 0.05). CONCLUSION: OA changes in the superior area of the humeral heads and thickening of the cartilage layer from the middle to the inferior of the humeral heads were confirmed histopathologically, suggesting that simultaneous mechanical and nutritional factors might be contributing to CTA pathogenesis. The current study provided the better understanding of cartilage damage and thickening in CTA. This will help guide treatment options in the setting of CTA.


Assuntos
Cabeça do Úmero/patologia , Artropatia de Ruptura do Manguito Rotador/complicações , Artropatia de Ruptura do Manguito Rotador/patologia , Idoso , Idoso de 80 Anos ou mais , Artroplastia do Ombro , Cartilagem Articular/patologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Osteoartrite/patologia , Osteoartrite/cirurgia , Artropatia de Ruptura do Manguito Rotador/cirurgia , Fraturas do Ombro/patologia , Fraturas do Ombro/cirurgia , Articulação do Ombro/patologia , Articulação do Ombro/cirurgia , Prótese de Ombro
10.
Anticancer Res ; 39(1): 81-85, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30591443

RESUMO

BACKGROUND/AIM: Undifferentiated pleomorphic sarcoma (UPS) is a common soft tissue sarcoma and highly recalcitrant. We have previously developed patient-derived orthotopic xenograft (PDOX) mouse models of UPS and other major sarcoma types. Unlike PDOX models of other cancer types, it has been difficult to demonstrate metastasis in the sarcoma PDOX models. MATERIALS AND METHODS: To visualize metastasis at high resolution in the UPS PDOX model, established tumor fragments were implanted in transgenic nude mice expressing red fluorescent protein (RFP) for one passage. The tumors acquired RFP-expressing stroma from transgenic host. UPS tumor with RFP stromal cells were harvested and implanted orthotopically in non-transgenic nude mice. After six weeks of UPS tumor growth in the PDOX model, the primary tumor was imaged non-invasively and lung, liver, and spleen were resected and imaged ex-vivo in order to visualize the presence of RFP, with a FluorVivo® imaging system and FV1000® confocal laser microscope, respectively. RESULTS: The primary tumor was imaged non-invasively. Confocal microscopy visualized the presence of RFP in the lung and liver indicating metastases in these organs. This is the first report of metastasis in a sarcoma PDOX model. CONCLUSION: This study should prove very useful to screen for anti-metastatic drugs for the PDOX donor patients and to understand the metastatic process in sarcoma.


Assuntos
Histiocitoma Fibroso Maligno/diagnóstico , Proteínas Luminescentes/genética , Sarcoma/diagnóstico , Animais , Diferenciação Celular/genética , Histiocitoma Fibroso Maligno/patologia , Humanos , Camundongos , Metástase Neoplásica , Sarcoma/genética , Sarcoma/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína Vermelha Fluorescente
11.
J Cell Biochem ; 120(1): 283-289, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30145815

RESUMO

Human osteosarcoma 143B cells were previously stably transfected with an αv integrin green flourescent protein (GFP) vector. 143B cells expressing αv integrin-GFP were transplanted orthotopically in the tibia of transgenic nude mice ubiquitously expressing red fluorescent protein (RFP). The primary tumors acquired RFP-expressing stroma and were passaged orthotopically in the tibia in noncolored nude mice, which maintained the RFP stroma. The interaction of αv integrin-GFP expression in 143B cells with RFP-expressing host stromal cells was observed by confocal microscopy using the Olympus FV1000. Collagen fibers were imaged simultaneously in reflectance mode. The RFP-expressing stroma included cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) which persisted even 3 weeks after passage to nontransgenic nude mice. CAFs expressing RFP were aligned between collagen fibers and cancer cells expressing αv integrin-GFP. Six weeks after transplantation, pulmonary metastases expressing αv integrin-GFP could be identified. TAMs expressing RFP accompanied metastasized osteosarcoma cells expressing αv integrin-GFP in the lung. The current study demonstrates the importance of αv integrin interaction with stromal elements in osteosarcoma.


Assuntos
Neoplasias Ósseas/metabolismo , Colágeno/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Integrina alfaV/metabolismo , Proteínas Luminescentes/metabolismo , Neoplasias Pulmonares/metabolismo , Osteossarcoma/metabolismo , Células Estromais/metabolismo , Microambiente Tumoral , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Fibroblastos/metabolismo , Proteínas de Fluorescência Verde/genética , Humanos , Integrina alfaV/genética , Neoplasias Pulmonares/secundário , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Nus , Camundongos Transgênicos , Microscopia Confocal , Osteossarcoma/patologia , Transfecção , Transplante Heterólogo , Proteína Vermelha Fluorescente
12.
Biochem Biophys Res Commun ; 505(3): 733-739, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30292411

RESUMO

Myxofibrosarcoma (MFS) is the most common sarcomas in elderly patients and is either chemo-resistant or recurs with metastasis after chemotherapy. This recalcitrant cancer in need of improved treatment. We have established a patient-derived orthotopic xenograft (PDOX) of MFS. The MFS PDOX model was established in the biceps femoris of nude mice and randomized into 7 groups of 7 mice each: control; doxorubicin (DOX); pazopanib (PAZ); temozolomide (TEM); Irinotecan (IRN); IRN combined with TEM; IRN combined with cisplatinum (CDDP) and Salmonella typhimurium A1-R (S. typhimurium A1-R). Treatment was evaluated by relative tumor volume and relative body weight. The MFS PDOX models were DOX, PAZ, and TEM resistant. IRN combined with TEM and IRN combined with CDDP were most effective on the MFS PDOX. S. typhimurium A1-R arrested the MFS PDOX tumor. There was no significant body weight loss in any group. The present study suggests that the combination of IRN with either TEM or CDDP, and S. typhimurium have clinical potential for MFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Fibrossarcoma/tratamento farmacológico , Infecções por Salmonella/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Fibrossarcoma/microbiologia , Humanos , Indazóis , Irinotecano/administração & dosagem , Masculino , Camundongos Nus , Pirimidinas/administração & dosagem , Distribuição Aleatória , Infecções por Salmonella/microbiologia , Salmonella typhimurium/fisiologia , Sulfonamidas/administração & dosagem , Temozolomida/administração & dosagem , Carga Tumoral/efeitos dos fármacos
13.
Tissue Cell ; 53: 30-36, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30060824

RESUMO

Pleomorphic liposarcoma (PLPS) is a heterogeneous resistant group of tumors. Complete surgical resection is the only known way to treat PLPS. PLPS is reristant to both radiation and chemotherapy. Therefore, precise individualized therapy is needed to improve outcome of advanced PLPS patients. In this study, a patient-derived orthotopic xenograft (PDOX) model of a PDGFRA-amplified PLPS was established in the biceps femoris of nude mice by surgical orthotopic implantation (SOI) in order to match the patient. The PLPS PDOX was treated with pazopanib (PAZ) which targets PDGFRA, as well as with temozolomide (TEM) and first-line therapy doxorubicin (DOX). The PLPS PDOX was resistant to DOX and responded very well to PAZ as well as TEM. The tumor volume on treatment day-14 relative to day-1 was as follows: DOX (4.50 ±â€¯2.6, p = 0.8087); PAZ (1.29 ±â€¯0.9, p = 0.0008 compared to the control, p = 0.0167 compared to DOX); TEM (1.07 ±â€¯0.8, p = 0.0079 compared to the control, p = 0.0079 compared to DOX). There was no significant difference in body weight between any treated group or control. The PAZ- and TEM-treated tumors showed extensive necrosis compared to the DOX-treated and untreated PDOX tumors. The present study showed that PDGFRA amplification could be effectively targeted by PAZ. The PLPS PDOX model also identified the efficacy of TEM which does not target PDGFRA, indicating that the PDOX model can identify effective targeted therapy as well as standard therapy and at the same time, identify ineffective drugs, even if they are first-line.


Assuntos
Doxorrubicina/farmacologia , Amplificação de Genes , Lipossarcoma , Proteínas de Neoplasias , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Idoso , Animais , Humanos , Indazóis , Lipossarcoma/tratamento farmacológico , Lipossarcoma/genética , Lipossarcoma/metabolismo , Lipossarcoma/patologia , Masculino , Camundongos , Camundongos Nus , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
BMC Cancer ; 18(1): 840, 2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-30126369

RESUMO

BACKGROUND: Pleomorphic liposarcoma (PLPS) is a rare, heterogeneous and an aggressive variant of liposarcoma. Therefore, individualized therapy is urgently needed. Our recent reports suggest that trabectedin (TRAB) is effective against several patient-derived orthotopic xenograft (PDOX) mouse models. Here, we compared the efficacy of first-line therapy, doxorubicin (DOX), and TRAB in a platelet-derived growth factor receptor-α (PDGFRA)-amplified PLPS. METHODS: We used a fresh sample of PLPS tumor derived from a 68-year-old male patient diagnosed with a recurrent PLPS. Subcutaneous implantation of tumor tissue was performed in a nude mouse. After three weeks of implantation, tumor tissues were isolated and cut into small pieces. To match the patient a PDGFRA-amplified PLPS PDOX was created in the biceps femoris of nude mice. Mice were randomized into three groups: Group 1 (G1), control (untreated); Group 2 (G2), DOX-treated; Group 3 (G3), TRAB-treated. Measurement was done twice a week for tumor width, length, and mouse body weight. RESULTS: The PLPS PDOX showed resistance towards DOX. However, TRAB could arrest the PLPS (p < 0.05 compared to control; p < 0.05 compared to DOX) without any significant changes in body-weight. CONCLUSIONS: The data presented here suggest that for the individual patient the PLPS PDOX model could specifically distinguish both effective and ineffective drugs. This is especially crucial for PLPS because effective first-line therapy is harder to establish if it is not individualized.


Assuntos
Dioxóis/administração & dosagem , Doxorrubicina/administração & dosagem , Lipossarcoma/tratamento farmacológico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Tetra-Hidroisoquinolinas/administração & dosagem , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doxorrubicina/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Lipossarcoma/genética , Lipossarcoma/patologia , Masculino , Camundongos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Trabectedina , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Cell Biochem ; 119(9): 7827-7833, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29932244

RESUMO

Pleomorphic liposarcoma (PLPS) is a recalcitrant soft-tissue sarcoma (STS) subtype in need of transformative therapy. We have previously established a patient-derived orthotopic xenograft (PDOX) model, of PLPS with PDGFRA amplification, using surgical orthotopic implantation. In the current study, the PLPS PDOX model was randomized into 3 groups of 7 mice each: untreated control; doxorubicin (DOX)-treated; and treated with Salmonella typhimurium A1-R (S. typhimurium A1-R) expressing green fluorescent protein (GFP). Tumor volume and body weight were monitored during the treatment period. The PLPS PDOX was resistant to DOX. In contrast, the PLPS PDOX was highly sensitive to S. typhimurium A1-R. There was no significant body-weight loss among these 3 groups. Fluorescence imaging demonstrated that S. typhimurium A1-R-GFP was very effective to target the PLPS PDOX tumor. The current study demonstrates that a PLPS PDOX, resistant to first-line therapy DOX, was highly sensitive to tumor targeting S. typhimurium A1-R.


Assuntos
Doxorrubicina/administração & dosagem , Lipossarcoma/tratamento farmacológico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Salmonella typhimurium/fisiologia , Sarcoma/tratamento farmacológico , Idoso , Animais , Peso Corporal , Terapia Combinada , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Amplificação de Genes , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Lipossarcoma/genética , Masculino , Camundongos , Distribuição Aleatória , Salmonella typhimurium/genética , Sarcoma/genética , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Methods Mol Biol ; 1760: 205-214, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29572806

RESUMO

Cell and tissue culture can be performed on different substrates such as on plastic, in Matrigel™, and on Gelfoam®, a sponge matrix. Each of these substrates consists of a very different surface, ranging from hard and inflexible, a gel, and a sponge-matrix, respectively. Folkman and Moscona found that cell shape was tightly coupled to proper gene expression. The flexibility of a substrate is important for cells to maintain their optimal shape. Human osteosarcoma cells, stably expressing a fusion protein of av integrin, and green fluorescent protein (GFP), grew as a simple monolayer without any structure formation on the surface of a plastic dish. When the osteosarcoma cells were cultured within Matrigel, the cancer cells formed colonies but no other structures. When the cancer cells were seeded on Gelfoam®, the cells formed 3-dimensional tissue-like structures. These results indicate that Gelfoam® histoculture, unlike Matrigel™ culture, is true 3-dimensional.


Assuntos
Técnicas de Cultura de Células , Colágeno , Laminina , Proteoglicanas , Células Tumorais Cultivadas , Biomarcadores Tumorais , Linhagem Celular Tumoral , Combinação de Medicamentos , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Microscopia de Fluorescência
17.
J Hand Surg Eur Vol ; 43(7): 739-743, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29402171

RESUMO

We reconstructed three-dimensional images of radius and ulna in 38 forearms of 25 patients with congenital proximal radioulnar synostosis from their computed tomographic studies. We also analysed correlations between the deformities of radius and ulna and degrees of fixed pronation of these forearms. The average ulnar deviation, flexion and internal rotation deformities of the radius were 6°, 3° and 18°, respectively. The average radial deviation, extension and internal rotation deformities of the ulna were 3°, 4° and 30°, respectively. The flexion deformity of the radius and the internal rotation deformity of the radius and ulna were correlated significantly with degree of fixed pronation. We conclude that the patients with congenital proximal radioulnar synostosis have remarkable flexion deformity of the radius and internal rotation deformity of the radius and ulna, which might impede forearm rotation after corrective surgery in the proximal part of the forearm.


Assuntos
Imageamento Tridimensional , Rádio (Anatomia)/anormalidades , Rádio (Anatomia)/diagnóstico por imagem , Sinostose/diagnóstico por imagem , Ulna/anormalidades , Ulna/diagnóstico por imagem , Adolescente , Anquilose/fisiopatologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pronação/fisiologia , Rádio (Anatomia)/fisiopatologia , Rotação , Sinostose/fisiopatologia , Tomografia Computadorizada por Raios X , Ulna/fisiopatologia
18.
Anticancer Res ; 38(1): 159-164, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29277768

RESUMO

BACKGROUND: We previously developed a color-coded imaging model that can quantify the length of nascent blood vessels using Gelfoam® implanted in nestin-driven green fluorescent protein (ND-GFP) nude mice. In this model, nascent blood vessels selectively express GFP. We also previously showed that osteosarcoma cells promote angiogenesis in this assay. We have also previously demonstrated the tumor-targeting bacteria Salmonella typhimurium A1-R (S. typhimurium A1-R) can inhibit or regress all tested tumor types in mouse models. The aim of the present study was to determine if S. typhimurium A1-R could inhibit osteosarcoma angiogenesis in the in vivo Gelfoam® color-coded imaging assay. MATERIALS AND METHODS: Gelfoam® was implanted subcutaneously in ND-GFP nude mice. Skin flaps were made 7 days after implantation and 143B-RFP human osteosarcoma cells expressing red fluorescent protein (RFP) were injected into the implanted Gelfoam. After establishment of tumors in the Gelfoam®, control-group mice were treated with phosphate buffered saline via tail-vein injection (iv) and the experimental group was treated with S. typhimurium A1-R iv Skin flaps were made at day 7, 14, 21, and 28 after implantation of the Gelfoam® to allow imaging of vascularization in the Gelfoam® using a variable-magnification small-animal imaging system and confocal fluorescence microscopy. RESULTS: Nascent blood vessels expressing ND-GFP extended into the Gelfoam® over time in both groups. However, the extent of nascent blood-vessel growth was significantly inhibited by S. typhimurium A1-R treatment by day 28. CONCLUSION: The present results indicate S. typhimurium A1-R has potential for anti-angiogenic targeted therapy of osteosarcoma.


Assuntos
Neoplasias Ósseas/terapia , Neovascularização Patológica/terapia , Osteossarcoma/terapia , Salmonella typhimurium , Animais , Neoplasias Ósseas/irrigação sanguínea , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos Nus , Camundongos Transgênicos , Osteossarcoma/irrigação sanguínea , Osteossarcoma/patologia
19.
J Hand Surg Asian Pac Vol ; 22(4): 490-496, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29117840

RESUMO

BACKGROUND: Radius osteotomy is one of the standard surgical procedures for the treatment of Kienböck's disease. Unfortunately, radius osteotomy can result in an incongruous distal radio-ulnar joint (DRUj) postoperatively, because the procedure is performed proximal to the DRUj. METHODS: A very distal radius wedge osteotomy was performed as a 15-degree lateral closing wedge osteotomy with the apex of the wedge distal to that of conventional lateral closing wedge osteotomy; this procedure was developed to avoid postoperative incongruous DRUj. We performed this procedure on 6 patients (stage III-A: 1, stage III-B: 5) with a mean age of 49 years. Clinical and radiographic evaluations were performed at a mean follow-up of 32 months. RESULTS: Wrist pain disappeared in all patients. Mean grip strength improved from 35% to 87% of the contralateral side (p = 0.0255). Mean range of motion, measured as flexion-extension arc, improved from 93 to 128 degrees. Nakamura's score was good in all patient. Mean lunate covering ratio increased from 61% to 90% (p = 0.0151) and mean sigmoid notch inclination angle, a radiographic parameter of DRUj congruency, was not significantly different between pre-operative and final follow-up evaluation. No clinical or radiographic DRUj osteoarthritis findings were observed. CONCLUSIONS: Our procedure of very distal radius wedge osteotomy provided satisfactory clinical results without an incongruous DRUj. This technique might prevent the occurrence of postoperative DRUj osteoarthritis.


Assuntos
Osteonecrose/cirurgia , Osteotomia/métodos , Procedimentos de Cirurgia Plástica/métodos , Rádio (Anatomia)/cirurgia , Articulação do Punho/cirurgia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteonecrose/diagnóstico , Osteonecrose/fisiopatologia , Período Pós-Operatório , Rádio (Anatomia)/diagnóstico por imagem , Amplitude de Movimento Articular , Resultado do Tratamento , Articulação do Punho/diagnóstico por imagem , Articulação do Punho/fisiopatologia
20.
BMC Musculoskelet Disord ; 18(1): 210, 2017 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-28532476

RESUMO

BACKGROUND: There has been increased interest in one-step cell-free procedures to avoid the problems related to cell manipulation and its inherent disadvantages. We have studied the chondrogenic induction ability of a PAMPS/PDMAAm double-network (DN) gel and found it to induce chondrogenesis in animal osteochondral defect models. The purpose of this study was to investigate whether the healing process and the degree of cartilage regeneration induced by the cell-free method using DN gel are influenced by the size of osteochondral defects. METHODS: A total of 63 mature female Japanese white rabbits were used in this study, randomly divided into 3 groups of 21 rabbits each. A 2.5-mm diameter osteochondral defect was created in the femoral trochlea of the patellofemoral joint of bilateral knees in Group I, a 4.3-mm osteochondral defect in Group II, and a 5.8-mm osteochondral defect in Group III. In the right knee of each animal, a DN gel plug was implanted so that a vacant space of 2-mm depth was left above the plug. In the left knee, we did not conduct any treatment to obtain control data. Animals were sacrificed at 2, 4, and 12 weeks after surgery, and gross and histological evaluations were made. RESULTS: The present study demonstrated that all sizes of the DN gel implanted defects as well as the 2.5mm untreated defects showed cartilage regeneration at 4 and 12 weeks. The 4.3-mm and 5.8-mm untreated defects did not show cartilage regeneration during the 12-week period. The quantitative score reported by O'Driscoll et al. was significantly higher in the 4.3-mm and 5.8-mm DN gel-implanted defects than the untreated defects at 4 and 12 weeks (p < 0.05). The 2.5-mm and 4.3-mm DN gel implanted defects maintained relatively high macroscopic and histological scores for the 12-week implantation period, while the histological score of the 5.8-mm DN gel implanted defect had decreased somewhat but statistically significantly at 12 weeks (p = 0.0057). CONCLUSIONS: The DN gel induced cartilage regeneration in defects between 2.5 and 5.8 mm, offering a promising device to establish a cell-free cartilage regeneration therapy and applicable to various sizes of osteochondral defects.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Condrogênese/efeitos dos fármacos , Hidrogel de Polietilenoglicol-Dimetacrilato/administração & dosagem , Articulação Patelofemoral/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Animais , Regeneração Óssea/fisiologia , Cartilagem Articular/patologia , Cartilagem Articular/fisiologia , Condrogênese/fisiologia , Feminino , Osteocondrose/tratamento farmacológico , Osteocondrose/patologia , Articulação Patelofemoral/patologia , Articulação Patelofemoral/fisiologia , Coelhos , Regeneração/fisiologia
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