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1.
Regen Ther ; 24: 167-173, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37448852

RESUMO

Background: A novel treatment has been developed to reconstruct large skin defects caused by the excision of giant congenital melanocytic nevi. It involves the reimplantation of high-hydrostatic pressurized nevus tissue as a cell-inactivated autologous scaffold for dermal regeneration, followed by the implantation of cultured epithelial autografts on the regenerated dermis. Because this treatment has shown promise in a first-in-human clinical trial which used a prototype pressure machine, a novel pressure device was specifically designed for clinical use. Methods: In a prospective investigator-initiated clinical trial involving three patients, we evaluated the safety and efficacy of the skin regeneration treatment using a pressure device. All three patients underwent surgical excision of the nevus tissue, primary reimplantation of the inactivated nevus tissue, and secondary implantation of cultured epithelial autografts. Results: Engraftment of inactivated nevus tissue and cultured epithelial autografts was successful in all three cases, with over 90% epithelialization at 8 weeks post-surgery. No serious adverse events or device malfunction were observed during the trial. Conclusion: The novel pressure device safely and effectively enabled dermal regeneration using the nevus tissue as an autologous scaffold. This innovative approach offers several advantages, including reduced invasiveness due to minimal sacrifice of normal skin for skin grafting and high curative potential resulting from full-thickness removal of the nevus tissue.

3.
JNCI Cancer Spectr ; 6(1)2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35118230

RESUMO

Background: Multiple common variants and also rare variants in monogenic risk genes such as BRCA2 and HOXB13 have been reported to be associated with risk of prostate cancer (PCa); however, the clinical setting in which germline genetic testing could be used for PCa diagnosis remains obscure. Herein, we tested the clinical utility of a 16 common variant-based polygenic risk score (PRS) that has been developed previously for Japanese men and also evaluated the frequency of PCa-associated rare variants in a prospective cohort of Japanese men undergoing prostate biopsy. Methods: A total of 1336 patients undergoing first prostate biopsy were included. PRS was calculated based on the genotype of 16 common variants, and sequencing of 8 prostate cancer-associated genes was performed by multiplex polymerase chain reaction based target sequencing. PRS was combined with clinical factors in logistic regression models to assess whether addition of PRS improves the prediction of biopsy positivity. Results: The top PRS decile was associated with an odds ratio of 4.10 (95% confidence interval = 2.46 to 6.86) with reference to the patients at average risk, and the estimated lifetime absolute risk approached 20%. Among the patients with prostate specific antigen 2-10 ng/mL who had prebiopsy magnetic resonance imaging, high PRS had an equivalent impact on biopsy positivity as a positive magnetic resonance imaging finding. Rare variants were detected in 19 (2.37%) and 7 (1.31%) patients with positive and negative biopsies, respectively, with BRCA2 variants being the most prevalent. There was no association between PRS and high-risk rare variants. Conclusions: Germline genetic testing could be clinically useful in both pre- and post-PSA screening settings.


Assuntos
Variação Genética , Mutação em Linhagem Germinativa , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Proteínas Mutadas de Ataxia Telangiectasia/genética , Biópsia por Agulha/estatística & dados numéricos , Intervalos de Confiança , Genes BRCA2 , Testes Genéticos , Genótipo , Proteínas de Homeodomínio/genética , Humanos , Japão , Modelos Logísticos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Fatores de Risco , Sequenciamento Completo do Genoma/métodos
4.
Esophagus ; 19(3): 444-451, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35050435

RESUMO

BACKGROUND: The standard treatment for unresectable advanced/recurrent esophageal cancer in Japan is 5-fluorouracil plus platinum-containing drugs as first-line chemotherapy and taxanes as second-line chemotherapy. However, the standard regimen after patients become refractory to these treatments remains to be established. Therefore, we investigated the efficacy of trifluridine/tipiracil (FTD/TPI) in patients with esophageal cancer who are refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes. METHODS: This single-arm phase II trial was conducted in seven hospitals in Japan. Eligible patients were those with unresectable advanced/recurrent esophageal cancer that was refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes. The primary endpoint was the 3-month progression-free survival rate, and the secondary endpoints were the 6-month progression-free survival rate, progression-free survival, overall survival, response rate, disease control rate, and toxicity. RESULTS: Forty-two patients were enrolled between October 2015 and June 2016. All tumors were squamous cell carcinomas. The progression-free survival rates at 3 and 6 months were 15.4% (90% confidence interval 7.4-26.0%) and 7.7% (90% confidence interval 2.6-16.6%), respectively. The median progression-free survival and median overall survival were 1.3 (95% confidence interval 1.0-1.8) months and 4.5 (95% confidence interval 3.6-5.7) months, respectively. The response rate was 0%, and the disease control rate was 23.8% (95% confidence interval 13.5-38.5%). The major grade 3/4 toxicities were neutropenia (47.6%), leukocytopenia (35.7%), and anemia (21.4%). No treatment-related deaths occurred. Exploratory subgroup analyses showed better progression-free survival in the subgroup without distant metastasis at diagnosis. CONCLUSIONS: Trifluridine/tipiracil monotherapy is feasible and shows modest activity in patients with refractory esophageal squamous cell carcinoma.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Pirrolidinas , Trifluridina , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Fluoruracila/uso terapêutico , Humanos , Japão , Recidiva Local de Neoplasia/tratamento farmacológico , Compostos de Platina/uso terapêutico , Pirrolidinas/uso terapêutico , Taxoides/uso terapêutico , Trifluridina/uso terapêutico
5.
JID Innov ; 1(3): 100026, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34909725

RESUMO

TRIAL DESIGN: Human papillomavirus infection causes verruca vulgaris. CDK9 inhibitor FIT039 inhibits DNA virus proliferation in animal models. We conducted a multicenter, single-blind, placebo-controlled, randomized phase I/II clinical trial evaluating the safety and efficacy of FIT039 against verruca vulgaris. METHODS: Target lesions were treated with liquid nitrogen once, and a FIT039 patch or placebo patch was applied for 14 days. The primary endpoint was lesion disappearance. The secondary endpoints were safety and changes in dimension, cross-sectional area, and the number of petechial lesions. RESULTS: A total of 24 participants were randomly allocated to the FIT039 (n = 13, median age, 54 years) and placebo (n = 11, median age, 62 years) groups. Verruca vulgaris did not disappear. FIT039 decreased the dimension to 76% of the initial value on day 29, followed by an increase to 98% on day 57. Placebo showed a monotonic increase to 107% on day 57. Changes in the cross-sectional area and petechiae number were comparable between the groups. CONCLUSIONS: No drug-related adverse reactions occurred. FIT039 efficacy was not determined in this study.

6.
BMJ Open ; 11(6): e051343, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193504

RESUMO

INTRODUCTION: Alzheimer's disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD. METHODS AND ANALYSIS: This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted. ETHICS AND DISSEMINATION: The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process. TRIAL REGISTRATION NUMBER: jRCT2041200008, NCT04413344.


Assuntos
Doença de Alzheimer , Bromocriptina , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Bromocriptina/efeitos adversos , Método Duplo-Cego , Reposicionamento de Medicamentos , Humanos , Mutação , Presenilina-1/genética , Resultado do Tratamento
7.
Plast Reconstr Surg Glob Open ; 9(4): e3556, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33936917

RESUMO

BACKGROUND: Although traditional wound dressings such as collagen scaffolds promote granulation tissue formation, the efficacy of these dressings in chronic wounds is limited because of high susceptibility to bacterial growth. Biomaterials that can be applied to chronic wounds should have an anti-bacterial function. We previously reported that administering a silk-elastin solution that forms moisturizing hydrogels to wound surfaces of diabetic mice reduced bacterial growth and promoted granulation tissue formation compared with control or carboxymethyl cellulose hydrogels. We hypothesized that silk-elastin promotes wound healing in human chronic wounds by suppressing bacterial growth. METHODS: An open-label, clinical case series was conducted with a prospective, single-arm design at Kyoto University Hospital in Kyoto, Japan. In this study, 6 patients with chronic skin ulcers of any origin (2 < ulcer area (cm2) < 25) on their lower extremities were included; patients with critical ischemia were excluded. Silk-elastin sponges were applied and covered with a polyurethane film without changing the dressing for 14 days. Inflammation triggered treatment discontinuation due to fear of infection. The primary study endpoint was adverse events, including inflammation and infection. RESULTS: Poor hydrogel formation, possibly due to continuous exudation, was observed. No serious adverse events were noted. Two patients discontinued treatment on day 6 and day 7, respectively, due to inflammation, but they were not infected. The other 4 patients completed the 14-day silk-elastin sponge treatment without infection. CONCLUSION: Silk-elastin sponge is safe for chronic skin ulcers, and its ability to promote wound healing should be determined by confirmatory clinical trials.

8.
PLoS One ; 15(2): e0229068, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32053676

RESUMO

Kyoto University Substance (KUS) 121, an ATPase inhibitor of valosin-containing protein, is a novel neuroprotectant. We tested the safety and effectiveness of KUS121 in patients with acute central retinal artery occlusion (CRAO). We conducted an investigator-initiated, first-in-humans, phase 1/2 clinical trial. Nine patients with non-arteritic CRAO symptoms lasting for 4-48 h were enrolled. These patients received daily intravitreal injections of KUS121 for 3 days: 25 µg (low-dose) in the first three patients and 50 µg (high-dose) in the next six patients. The primary endpoint was the safety of the drug. As a secondary endpoint, pharmacokinetics was evaluated. Other key secondary endpoints were changes in best-corrected visual acuity (BCVA), measured using the Early Treatment Diabetic Retinopathy Study chart, visual field scores, and retinal sensitivities between baseline and week 12; and decimal BCVA at week 12. Administration of KUS121 did not result in serious adverse events. All nine patients (100%) showed significant improvement of BCVA. Average readable letter counts, visual field scores, and retinal sensitivities also improved. Decimal BCVA at week 12 was better than 0.1 in four patients (44%) and equal to or better than 0.05 in seven patients (78%). This first-in-humans clinical trial provides support for the safety and efficacy of intravitreal KUS121 injection. To substantiate the safety and effectiveness for patients with acute CRAO, further larger scale clinical studies will be needed.


Assuntos
Fármacos Neuroprotetores/uso terapêutico , Oclusão da Artéria Retiniana/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Edema Macular/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Retina/efeitos dos fármacos , Oclusão da Veia Retiniana/tratamento farmacológico , Acuidade Visual/efeitos dos fármacos
9.
Trials ; 20(1): 489, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399147

RESUMO

BACKGROUND: Human papilloma viruses (HPVs) infect squamous epithelial cells and form verrucous lesions, or warts. Besides the psychosocial problems caused by the disfiguring warts, a subset of HPVs can be the primary etiologic agent for malignancies such as cervical cancer. However, there is no curative antiviral therapy for HPV infection. We recently found that the viral RNA transcription of DNA viruses requires cyclin dependent kinase 9 (CDK9) in the host cells, and that FIT039, a specific inhibitor of CDK9, suppressed the proliferation of DNA viruses such as herpes simplex virus 1 (HSV-1), HSV-2, human adenovirus, human cytomegalovirus, hepatitis virus B, and HPVs. Here, we describe a protocol to evaluate the safety and antiviral effect of FIT039 on common warts in human skin. METHODS AND DESIGN: A multi-institutional, single-blind, placebo-controlled randomized phase I/II clinical trial was designed to evaluate the safety and efficacy of FIT039 on common warts on the extremities. A total of 44 adults with a primary diagnosis of verruca vulgaris on the extremities without serious comorbidities will be randomized into either the intervention group with an FIT039-releasing transdermal patch or a control group for a duration of 14 days. Outcomes will be assessed at baseline and postintervention. Participants will be further assessed at 2 months follow-up. The primary endpoint for efficacy is the resolution of the warts. The safety endpoint is the incidence of adverse events and adverse drug reactions. The secondary endpoints are changes in the dimensions of the wart, the cross-sectional area of the wart, and the number of clots within the area of the wart. DISCUSSION: This study is the first to assess the efficacy of FIT039 and will contribute to the development of antiviral agents that can cure refractory common warts in immunocompromised patients. TRIAL REGISTRATION: UMIN Clinical Trials, UMIN000029695 . Registered on 1 November 2017.


Assuntos
Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Piridinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Verrugas/tratamento farmacológico , Adulto , Humanos , Piridinas/efeitos adversos , Projetos de Pesquisa , Método Simples-Cego
10.
Animals (Basel) ; 9(5)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052293

RESUMO

We previously showed that the agamid lizard Pogona vitticeps responded to an extremely low-frequency electromagnetic field (ELF-EMF; frequency: 6 and 8 Hz; peak magnetic field: 2.6 µT; peak electric field: 10 V/m) with tail-lifting behavior. In addition, the tail-lifting response to ELF-EMF disappeared when the parietal eyes of the lizards were covered by small round aluminum caps. This result suggests that the parietal eye contributes to light-dependent magnetoreception. In the present study, we set up an ELF-EMF group to evaluate the long-term effect of the ELF-EMF on lizards' behavior and examine our hypothesis that exposure to ELF-EMFs increases the magnetic field sensitivity in lizards. We therefore include the lunar phase (full moon/new moon) and K index as environmental factors related to the geomagnetic field in the analysis. The number of tail lifts per individual per day was the response variable while calendar month, daily mean temperature, daily mean humidity, daily mean atmospheric pressure, full moon, new moon, and K index were the explanatory variables. We analyzed an ELF-EMF group and a control group separately. In a multiple linear regression analysis, the independent determinants associated with the number of tail lifts were the full moon, the temperature, February, March, April, and May in the ELF-EMF group and March, April, May, and June in the control group. The P. vitticeps in the ELF-EMF group responded to the full moon whereas those in the control group did not. In addition, in the ELF-EMF group, the number of tail lifts was higher on days when the K index was higher (P = 0.07) in the first period whereas there was no such tendency in either period in the control group. There is the possibility that the exposure to ELF-EMFs may increase magnetic-field sensitivity in lizards.

12.
Clin Drug Investig ; 39(1): 55-61, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30284700

RESUMO

BACKGROUND: Cutaneous warts are caused by human papilloma virus (HPV) infection. FIT039, a specific inhibitor of CDK9, suppresses the proliferation of DNA viruses in vitro. PURPOSE: We evaluated the safety, plasma concentrations, and efficacy of FIT039 delivered by single application of an adhesive skin patch on normal back skin and cutaneous warts. PATIENTS AND METHODS: In this placebo-controlled, dose-escalation, open-label, two-cohort phase I/II clinical trial, after a single administration of a 1% FIT039 patch, 3% FIT039 patch, or placebo on back skin, patients with cutaneous warts were treated with cryotherapy followed by a 1% FIT039 patch for 24 h in the first cohort. In the second cohort, cutaneous warts were treated with cryotherapy followed by a 3% FIT039 patch for 24 h. Adverse events and adverse drug reactions, the concentrations of FIT039, and surface area of cutaneous warts were evaluated. RESULTS: Neither irritant reactions nor symptoms related to FIT039 occurred when the FIT039 patches were applied to patients' backs or on warts in ten patients. The concentrations of FIT039 were under 0.1 ng/ml at every time point. The median wart surface area at 1 week after application of the 1% FIT039 patch was similar to baseline, while that of the 3% FIT039 patch was smaller than baseline. CONCLUSION: The FIT039 patch showed no topical or systemic adverse reactions when applied on normal skin or cutaneous warts. The safety and good adherence of the FIT039 patch are encouraging and support further studies to evaluate the efficacy of FIT039 in patients with cutaneous warts.


Assuntos
Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Infecções por Papillomavirus/tratamento farmacológico , Piridinas/uso terapêutico , Verrugas/tratamento farmacológico , Adesivos , Administração Cutânea , Adulto , Idoso , Crioterapia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adesivo Transdérmico , Adulto Jovem
13.
Breast ; 38: 114-119, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29310035

RESUMO

INTRODUCTION: Adjuvant bisphosphonates lead to better prognosis in postmenopausal breast cancer. However, the association between clinical outcomes and immune modulation by them is still unclear. METHODS: In this prospective, open-label phase II study, postmenopausal women with estrogen receptor-positive and human epidermal growth factor receptor 2-negative early-stage breast cancer received neoadjuvant letrozole (LET) for one month, followed by treatment with a single dose of zoledronic acid. The patients underwent an additional 5 months of treatment with LET prior to surgery. The primary endpoint was the tumor objective response rate (ORR) determined by diameter via MRI. The association between the ORR and γδT cell frequencies was assessed as a secondary endpoint. RESULTS: Out of sixty patients, 55 patients were evaluable for response by MRI. The ORR for LET with zoledronic acid was 38.2% (21/55), which was comparable to that of historical controls (45%). A decrease in the frequency of the Vδ2 T cell subset was observed throughout treatment, and Vδ2 T cells were activated for 6 months. In planned subgroup analyses, patients with low frequencies of Vδ2 T cells prior to zoledronic acid infusion experienced a favorable tumor response compared to those with high frequencies (59.3% [16/27] vs 17.9% [5/28], p = .002). There were no serious adverse events with this treatment regimen. CONCLUSION: These results showed that neoadjuvant LET with zoledronic acid could not achieve overall effect for local tumor response. However, patients with a low frequency of γδ T cells would benefit from the treatment including zoledronic acid. (UMIN 000008701).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/farmacologia , Imidazóis/farmacologia , Linfócitos Intraepiteliais/efeitos dos fármacos , Nitrilas/farmacologia , Triazóis/farmacologia , Idoso , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Feminino , Humanos , Letrozol , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Pós-Menopausa , Estudos Prospectivos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Resultado do Tratamento , Ácido Zoledrônico
14.
Oncotarget ; 8(13): 22135-22144, 2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28212527

RESUMO

Photodynamic therapy (PDT) showed promising efficacy for local failure after chemoradiotherapy (CRT) for esophageal cancer. However, PDT required long sun shade period. This study aimed to evaluate the safety and efficacy of PDT using second generation photosensitizer, talaporfin sodium for local failure after CRT. This was the multi-institutional non-randomized phase II study. Patients with histologically proven local failure limited within the muscularis propria after 50Gy or more radiotherapy (RT) for esophageal cancer were eligible. We set the primary endpoint as local complete response (L-CR) per patients. And, secondary endpoints were confirmed L-CR, local progression free survival (L-PFS), progression free survival (PFS), overall survival (OS), L-CR per lesions (Lesion L-CR), and confirmed Lesion L-CR. The PDT procedure commenced with intravenous administration of a 40 mg/m2 dose of talaporfin sodium followed by diode laser irradiation at a 664 nm wavelength. 26 eligible patients were enrolled and all were treated with PDT. Twenty three patients with 25 lesions were assessed L-CR after PDT; the L-CR rate per patients was 88.5% (95% CI: 69.8%-97.6%). No skin phototoxicity was observed, and no grade 3 or worse non-hematological toxicities related to PDT were observed. PDT using talaporfin sodium and a diode laser is a safe and curative salvage treatment for local failure after CRT or RT for patients with esophageal cancer.


Assuntos
Neoplasias Esofágicas/terapia , Lasers Semicondutores/uso terapêutico , Recidiva Local de Neoplasia/terapia , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêutico , Terapia de Salvação , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia/efeitos adversos , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Radioterapia/efeitos adversos , Taxa de Sobrevida
15.
Int Orthop ; 40(8): 1747-1754, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26715504

RESUMO

PURPOSE: We evaluated the safety and clinical outcomes of a single local administration of gelatin hydrogel impregnated with recombinant human fibroblast growth factor (rhFGF)-2 for the treatment of the precollapse stage of osteonecrosis of the femoral head (ONFH). METHODS: Patients with ONFH (precollapse stage ≤2) received a single local administration of 800 µg of rhFGF-2-impregnated gelatin hydrogel and were followed up for one year. The surgery was performed using a minimally invasive technique involving a 1-cm skin incision, and walking was allowed from day one postoperatively. The primary outcomes included occurrence of adverse events and complications. The secondary outcomes included changes in the Harris hip scores, visual analog scale for pain scores, University of California, Los Angeles (UCLA) activity scores, and radiological images. RESULTS: We included ten patients, of which five experienced 14 adverse events, including one complication from spinal anesthesia. However, patients completely recovered from all adverse events. The mean clinical scores significantly improved by one year postoperatively compared with the pre-operative scores (before vs. after: visual analog score for pain, 21.2 vs. 5.3 mm; UCLA activity score, 5.5 vs. 6.6; Harris hip score, 81.0 vs. 96.9 points). There was only one case of femoral head collapse; however, this occurred in a hip with extensive necrosis. Stage progression and collapse did not occur in the other nine cases. Computed tomography confirmed bone regeneration in the femoral heads. CONCLUSIONS: Clinical application of rhFGF-2-impregnated gelatin hydrogel for patients with precollapse ONFH was feasible and safe.


Assuntos
Necrose da Cabeça do Fêmur/cirurgia , Cabeça do Fêmur/cirurgia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Projetos Piloto , Proteínas Recombinantes/metabolismo , Regeneração/fisiologia , Adulto , Preparações de Ação Retardada , Feminino , Fator 2 de Crescimento de Fibroblastos/química , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Proteínas Recombinantes/química , Regeneração/genética , Tomografia Computadorizada por Raios X
16.
BMC Med ; 12: 219, 2014 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-25406953

RESUMO

BACKGROUND: To date, no therapeutic option has been established for sudden deafness refractory to systemic corticosteroids. This study aimed to examine the efficacy and safety of topical insulin-like growth factor-1 (IGF-1) therapy in comparison to intratympanic corticosteroid therapy. METHODS: We randomly assigned patients with sudden deafness refractory to systemic corticosteroids to receive either gelatin hydrogels impregnated with IGF-1 in the middle ear (62 patients) or four intratympanic injections with dexamethasone (Dex; 58 patients). The primary outcome was the proportion of patients showing hearing improvement (10 decibels or greater in pure-tone average hearing thresholds) 8 weeks after treatment. The secondary outcomes included the change in pure-tone average hearing thresholds over time and the incidence of adverse events. RESULTS: In the IGF-1 group, 66.7% (95% confidence interval [CI], 52.9-78.6%) of the patients showed hearing improvement compared to 53.6% (95% CI, 39.7-67.0%) of the patients in the Dex group (P = 0.109). The difference in changes in pure-tone average hearing thresholds over time between the two treatments was statistically significant (P = 0.003). No serious adverse events were observed in either treatment group. Tympanic membrane perforation did not persist in any patient in the IGF-1 group, but did persist in 15.5% (95% CI, 7.3-27.4%) of the patients in the Dex group (P = 0.001). CONCLUSIONS: The positive effect of topical IGF-1 application on hearing levels and its favorable safety profile suggest utility for topical IGF-1 therapy in patients with sudden deafness. TRIAL REGISTRATION: UMIN Clinical Trials Registry Number UMIN000004366, October 30th, 2010.


Assuntos
Glucocorticoides/administração & dosagem , Perda Auditiva Súbita/tratamento farmacológico , Fator de Crescimento Insulin-Like I/administração & dosagem , Administração Cutânea , Dexametasona/administração & dosagem , Feminino , Perda Auditiva Súbita/fisiopatologia , Testes Auditivos , Humanos , Injeções Intra-Articulares , Japão , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Membrana Timpânica
17.
J Transl Med ; 12: 310, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25421542

RESUMO

BACKGROUND: Although the efficacy of zoledronic acid in postmenopausal women with breast cancer has been suggested, the underlying mechanism has not been fully clarified. Therefore, which patients may benefit from zoledronic acid and the optimal frequency of zoledronic acid administration are unclear. This study evaluates the effects of zoledronic acid on the tumor response in postmenopausal women with breast cancer and explores the relationship between its efficacy and γδ T cells. METHODS/DESIGN: This study is an open-label, multi-institutional, single-arm, phase II clinical trial. Zoledronic acid will be administered once during preoperative hormonal therapy with letrozole for 24 weeks in postmenopausal women with Estrogen Receptor (ER)-positive , Human Epidermal Growth Factor Receptor 2 (HER2)-negative, clinical T1 or T2 N0M0 breast cancer. The primary endpoint is the objective response rate measured by MRI at 12 and 24 weeks. The secondary endpoints are the associations between the frequency of Vγ2Vδ2 T cells before the administration of zoledronic acid and the objective response, the association between the frequency of Vγ2Vδ2 T cells and the Preoperative Endocrine Prognostic Index score, and the association between the frequency of Vγ2Vδ2 T cells and Ki67 (MIB-1 index). DISCUSSION: This study is designed to determine the add-on effect of zoledronic acid during preoperative hormonal therapy and to investigate the changes of the frequency of Vγ2Vδ2 T cells after the administration of zoledronic acid to explore the potential mechanism of zoledronic acid in breast cancer patients. TRIAL REGISTRATION: This trial was registered at the UMIN Clinical Trials Registry as UMIN000008701.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/farmacologia , Imidazóis/farmacologia , Nitrilas/uso terapêutico , Pós-Menopausa , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Triazóis/uso terapêutico , Neoplasias da Mama/cirurgia , Protocolos Clínicos , Feminino , Humanos , Letrozol , Cuidados Pré-Operatórios , Ácido Zoledrônico
18.
Endocr J ; 61(7): 735-42, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24739333

RESUMO

The majority of patients with systemic sclerosis (SSc) have gastrointestinal (GI) tract involvement, but therapies using prokinetic agents are usually unsatisfactory. Ghrelin stimulates gastric motility in healthy human volunteers. In this study, we investigated whether ghrelin could improve gastric emptying in patients with gastrointestinal symptoms due to SSc. The study was performed in a randomized, double-blind, placebo-controlled crossover fashion on two occasions. Ten SSc patients with GI tract involvement received an infusion of either ghrelin (5.0 µg/kg) or saline, and gastric emptying rate was evaluated by ¹³C-acetic acid breath test. Gastric emptying was significantly accelerated by ghrelin infusion in patients with SSc (ghrelin vs. saline: 43.3 ± 11.4 min vs. 53.4 ± 5.4 min, P=0.03). No serious adverse effects were observed. Our results suggest that ghrelin might represent a new therapeutic approach for GI tract involvement in patients with SSc.


Assuntos
Drogas em Investigação/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Trato Gastrointestinal/efeitos dos fármacos , Gastroparesia/prevenção & controle , Grelina/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Bebidas , Estudos Cross-Over , Método Duplo-Cego , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacocinética , Feminino , Esvaziamento Gástrico/efeitos dos fármacos , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/farmacocinética , Trato Gastrointestinal/fisiopatologia , Gastroparesia/etiologia , Grelina/administração & dosagem , Grelina/efeitos adversos , Grelina/farmacocinética , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Resposta de Saciedade/efeitos dos fármacos , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/fisiopatologia , Índice de Gravidade de Doença
19.
Psychiatry Clin Neurosci ; 68(6): 404-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24612477

RESUMO

AIM: Some previous studies have shown a positive relation between geomagnetic disturbances and an increased incidence of suicide. If such a relation exists, stronger geomagnetic fields may affect the number of suicides, because stronger geomagnetic fields generally cause larger geomagnetic field disturbances. Therefore, we here investigated the relation between local geomagnetic field magnetic flux density and the standardized morbidity ratios (SMR) for suicide by each prefecture in Japan. METHODS: Monthly suicide data for each prefecture in the period January 1999 to December 2008 was obtained, and it was found that a total of 216 171 male individuals and 85 154 female individuals committed suicide during this period. A multiple linear regression analysis was carried out with a backward elimination procedure. The SMR for suicide by each prefecture was taken as the response variable and the explanatory variables were each prefecture's local geomagnetic field magnetic flux density (nT), north latitude (°), monthly mean unemployment rate (%), monthly mean air pressure (hPa), monthly mean air temperature (°C), monthly mean humidity (%), and monthly total day length (hours). Analyses were carried out separately for each sex. RESULTS: In the multiple linear regression analysis for male subjects, the local geomagnetic field magnetic flux density (nT), monthly mean unemployment rate (%), and monthly mean humidity (%) were associated with the incidence of suicide, but in the multiple linear regression analysis of female subjects, only north latitude was associated with that. CONCLUSION: In this study, we generated a hypothesis that stronger geomagnetic fields affect the number of cases of male suicide.


Assuntos
Campos Magnéticos , Suicídio/estatística & dados numéricos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Geografia , Humanos , Lactente , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Desemprego/estatística & dados numéricos , Tempo (Meteorologia) , Adulto Jovem
20.
Tissue Eng Part B Rev ; 20(4): 233-42, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24593258

RESUMO

Idiopathic osteonecrosis of femoral head (ION) is a painful disorder that progresses to collapse of the femoral head and destruction of the hip joint. Although its precise pathology remains unknown, the loss of blood supply causing the loss of living bone-forming cells is a hallmark of the pathophysiology of osteonecrosis. Transplantation of multipotent mesenchymal stromal cells (MSCs) is a promising tool for regenerating the musculoskeletal system. The aim of the present study was to assess the safety and efficacy of transplantation of cultured autologous bone marrow-derived MSCs mixed with ß-tricalcium phosphate (ß-TCP) in combination with vascularized bone grafts for the treatment of advanced stage ION in a clinical trial. Ten patients with stage 3 ION were enrolled in this study. Autologous bone marrow-derived MSCs were cultured with autologous serum, and cells (0.5-1.0×10(8)) were transplanted after mixing with ß-TCP granules in combination with vascularized iliac bone grafts. Patients were assessed 24 months after treatment. The primary and secondary endpoints were progression of the radiological stage and changes in bone volume at the femoral head, and clinical score, respectively. Nine of ten patients completed the protocol, seven of whom remained at stage 3, and the remaining two cases progressed to stage 4. The average bone volume increased from 56.5±8.5 cm(3) to 57.7±10.6 cm(3). The average clinical score according to the Japan Orthopaedic Association improved from 65.6±25.5 points to 87.9±19.0 points. One severe adverse event was observed, which was not related to the clinical trial. Although the efficacy of cell transplantation was still to be determined, all procedures were successfully performed and some young patients with extensive necrotic lesions with pain demonstrated good bone regeneration with amelioration of symptoms. Further improvements in our method using MSCs and the proper selection of patients will open a new approach for the treatment of this refractory disease.


Assuntos
Materiais Biocompatíveis/administração & dosagem , Transplante Ósseo , Fosfatos de Cálcio/administração & dosagem , Necrose da Cabeça do Fêmur/cirurgia , Transplante de Células-Tronco Mesenquimais , Adulto , Fatores Etários , Animais , Autoenxertos , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade
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