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Ferroptosis is a distinct lipid peroxidation-dependent form of necrotic cell death. This process has been increasingly contemplated as a new target for cancer therapy because of an intrinsic or acquired ferroptosis vulnerability in difficult-to-treat cancers and tumour microenvironments. Here we review recent advances in our understanding of the molecular mechanisms that underlie ferroptosis and highlight available tools for the modulation of ferroptosis sensitivity in cancer cells and communication with immune cells within the tumour microenvironment. We further discuss how these new insights into ferroptosis-activating pathways can become new armouries in the fight against cancer.
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Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl ß-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3ß,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.
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Ferroptose , Hepatopatias , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Camundongos , Animais , Humanos , Dicloridrato de trans-1,4-Bis(2-clorobenzaminometil)ciclo-hexano , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismoRESUMO
Ferroptosis, marked by iron-dependent lipid peroxidation, may present an Achilles heel for the treatment of cancers. Ferroptosis suppressor protein-1 (FSP1), as the second ferroptosis mainstay, efficiently prevents lipid peroxidation via NAD(P)H-dependent reduction of quinones. Because its molecular mechanisms have remained obscure, we studied numerous FSP1 mutations present in cancer or identified by untargeted random mutagenesis. This mutational analysis elucidates the FAD/NAD(P)H-binding site and proton-transfer function of FSP1, which emerged to be evolutionarily conserved among different NADH quinone reductases. Using random mutagenesis screens, we uncover the mechanism of action of next-generation FSP1 inhibitors. Our studies identify the binding pocket of the first FSP1 inhibitor, iFSP1, and introduce the first species-independent FSP1 inhibitor, targeting the NAD(P)H-binding pocket. Conclusively, our study provides new insights into the molecular functions of FSP1 and enables the rational design of FSP1 inhibitors targeting cancer cells.
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Ferroptose , Ferroptose/genética , NAD , Mutação , Mutagênese , Sítios de Ligação , PrótonsRESUMO
BACKGROUND AND OBJECTIVES: Gentle tissue handling to avoid excessive motion of affected fragile vessels during surgical dissection is essential for both surgeon proficiency and patient safety during carotid endarterectomy (CEA). However, a void remains in the quantification of these aspects during surgery. The video-based measurement of tissue acceleration is presented as a novel metric for the objective assessment of surgical performance. This study aimed to evaluate whether such metrics correlate with both surgeons' skill proficiency and adverse events during CEA. METHODS: In a retrospective study including 117 patients who underwent CEA, acceleration of the carotid artery was measured during exposure through a video-based analysis. Tissue acceleration values and threshold violation error frequencies were analyzed and compared among the surgeon groups with different surgical experience (3 groups: novice , intermediate , and expert ). Multiple patient-related variables, surgeon groups, and video-based surgical performance parameters were compared between the patients with and without adverse events during CEA. RESULTS: Eleven patients (9.4%) experienced adverse events after CEA, and the rate of adverse events significantly correlated with the surgeon group. The mean maximum tissue acceleration and number of errors during surgical tasks significantly decreased from novice, to intermediate, to expert surgeons, and stepwise discriminant analysis showed that the combined use of surgical performance factors could accurately discriminate between surgeon groups. The multivariate logistic regression analysis revealed that the number of errors and vulnerable carotid plaques were associated with adverse events. CONCLUSION: Tissue acceleration profiles can be a novel metric for the objective assessment of surgical performance and the prediction of adverse events during surgery. Thus, this concept can be introduced into futuristic computer-aided surgeries for both surgical education and patient safety.
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Endarterectomia das Carótidas , Humanos , Endarterectomia das Carótidas/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Artérias Carótidas , AceleraçãoRESUMO
Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers1-3. Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H+ as an electron donor, has been identified as the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of the cyst(e)ine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis4-6. To develop FSP1 inhibitors as next-generation therapeutic ferroptosis inducers, here we performed a small molecule library screen and identified the compound class of 3-phenylquinazolinones (represented by icFSP1) as potent FSP1 inhibitors. We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor5, does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition. icFSP1-induced FSP1 condensates show droplet-like properties consistent with phase separation, an emerging and widespread mechanism to modulate biological activity7. N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro. We further demonstrate that icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo. Hence, our results suggest that icFSP1 exhibits a unique mechanism of action and synergizes with ferroptosis-inducing agents to potentiate the ferroptotic cell death response, thus providing a rationale for targeting FSP1-dependent phase separation as an efficient anti-cancer therapy.
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Proteínas Reguladoras de Apoptose , Ferroptose , Proteínas Mitocondriais , Humanos , Aminoácidos/metabolismo , Cisteína/metabolismo , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , NAD/metabolismo , NADP/metabolismo , Neoplasias/tratamento farmacológico , Quinazolinas/farmacologia , Bibliotecas de Moléculas Pequenas , Ubiquinona/metabolismo , Vitamina K/metabolismo , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Mitocondriais/antagonistas & inibidores , Proteínas Mitocondriais/metabolismoRESUMO
PURPOSE: Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on disease-free survival (DFS). PATIENTS AND METHODS: This prospective, randomized, multicenter open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients who were disease-free after treatment with either 5 years of anastrozole alone or 2-3 years of tamoxifen followed by 2-3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole for an additional 5 years or stop anastrozole. The primary end point was DFS, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with University Hospital Medical Information Network, Japan (UMIN) clinical trials registry (UMIN000000818). RESULTS: We enrolled 1,697 patients from 117 facilities between November 2007 and November 2012. Follow-up information was available for 1,593 patients (n = 787 in the continue group, n = 806 in the stop group), who were defined as the full analysis set, including 144 patients previously treated with tamoxifen and 259 patients who underwent breast-conserving surgery without irradiation. The 5-year DFS rates were 91% (95% CI, 89 to 93) in the continue group and 86% (95% CI, 83 to 88) in the stop group (hazard ratio, 0.61; 95% CI, 0.46 to 0.82; P < .0010). Notably, extended anastrozole treatment reduced the incidence of local recurrence (continue group, n = 10; stop group, n = 27) and second primary cancers (continue group, n = 27; stop group, n = 52). There was no significant difference in overall or distant DFS. Menopausal or bone-related all-grade adverse events were more frequent among patients in the continue group than those in the stop group, but the incidence of grade ≥3 adverse events was <1% in both groups. CONCLUSION: Continuing adjuvant anastrozole for an additional 5 years after 5 years of initial treatment with anastrozole or tamoxifen followed by anastrozole was well tolerated and improved DFS. Although no difference in overall survival was observed as in other trials, extended anastrozole therapy could be one treatment choice in postmenopausal patients with hormone receptor-positive breast cancer.
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Neoplasias da Mama , Segunda Neoplasia Primária , Humanos , Feminino , Anastrozol/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Estudos Prospectivos , Segunda Neoplasia Primária/induzido quimicamente , Nitrilas/efeitos adversos , Triazóis/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Tamoxifeno/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Intervalo Livre de Doença , Adjuvantes Imunológicos/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Quimioterapia AdjuvanteRESUMO
The positive link between osteoporosis and hypercholesterolemia has been documented, and bone resorption inhibitors, such as nitrogen-containing bisphosphonates (N-BP) and selective estrogen receptor modulators (SERMs), are known to reduce serum cholesterol levels. However, the relationship between the baseline cholesterol level and incident fracture rate under the treatment using the bone resorption inhibitors has not been documented. We investigated the relation between vertebral fracture incident and the baseline cholesterol levels and cholesterol-lowering effect of N-BP and SERM in osteoporosis through a prospective randomized open-label study design. Patients with osteoporosis (n = 3986) were allocated into two groups based on the drug used for treatment: minodronic acid (MIN) (n = 1624) as an N-BP and raloxifene (RLX) as an SERM (n = 1623). Serum levels of cholesterol and incidence of vertebral fracture were monitored for 2 years. The vertebral fracture rates between the two groups were compared using the pre-specified stratification factors. The patients receiving MIN with baseline low-density lipoprotein (LDL)-cholesterol level of ≥ 140 mg/dL, high-density lipoprotein cholesterol level < 40 mg/dL, age group of ≥ 75 years, and T score of BMD ≥ -3 SD had significantly lower vertebral fracture rates than those receiving RLX (incidence rate ratios (IRR) 0.45 [95% confidence interval (CI) 0.30 0.75, p = 0.001], 0.25 [95% CI 0.09 0.65, p = 0.005], 0.71 [95% CI 0.56 0.91, p = 0.006], 0.47 [95% CI 0.30 0.75, p = 0.0012], respectively). The cholesterol-lowering effect was stronger in the RLX group than in the MIN group, regardless of prior statin use. These results indicated that MIN treatment was more effective in reducing fracture risk in patients with higher LDL cholesterol levels, although its cholesterol-lowering ability was lesser than the RLX treatment.Trial registration University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR), No. UMIN000005433; date: April 13, 2011.
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Conservadores da Densidade Óssea , Fraturas Ósseas , Osteoporose Pós-Menopausa , Osteoporose , Fraturas da Coluna Vertebral , Humanos , Idoso , Feminino , Cloridrato de Raloxifeno/farmacologia , Cloridrato de Raloxifeno/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Fraturas da Coluna Vertebral/complicações , Estudos Prospectivos , Densidade Óssea , Osteoporose/complicações , Osteoporose/tratamento farmacológico , Fraturas Ósseas/etiologia , Colesterol , Osteoporose Pós-Menopausa/tratamento farmacológicoRESUMO
Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation1, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers2. Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K-a group of naphthoquinones that includes menaquinone and phylloquinone3-confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-44,5, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle6. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.
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Ferroptose , Vitamina K , Antídotos/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Carbono-Carbono Ligases/metabolismo , Coenzimas/metabolismo , Ferroptose/efeitos dos fármacos , Hidroquinonas/metabolismo , Hidroquinonas/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Oxirredução , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Vitamina K/metabolismo , Vitamina K/farmacologia , Varfarina/efeitos adversosRESUMO
Ferroptosis has recently attracted much interest because of its relevance to human diseases such as cancer and ischemia-reperfusion injury. We have reported that prolonged severe cold stress induces lipid peroxidation-dependent ferroptosis, but the upstream mechanism remains unknown. Here, using genome-wide CRISPR screening, we found that a mitochondrial Ca2+ uptake regulator, mitochondrial calcium uptake 1 (MICU1), is required for generating lipid peroxide and subsequent ferroptosis under cold stress. Furthermore, the gatekeeping activity of MICU1 through mitochondrial calcium uniporter (MCU) is suggested to be indispensable for cold stress-induced ferroptosis. MICU1 is required for mitochondrial Ca2+ increase, hyperpolarization of the mitochondrial membrane potential (MMP), and subsequent lipid peroxidation under cold stress. Collectively, these findings suggest that the MICU1-dependent mitochondrial Ca2+ homeostasis-MMP hyperpolarization axis is involved in cold stress-induced lipid peroxidation and ferroptosis.
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Proteínas de Transporte de Cátions , Ferroptose , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Resposta ao Choque Frio , Humanos , Potencial da Membrana Mitocondrial , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismoRESUMO
BACKGROUND: Surgical manipulation of a tumor can lead to shedding of tumor cells that can enter the circulation and lead to metastasis. The present study evaluated the clinical relevance of circulating tumor cells (CTCs) that were identified immediately after non-small cell lung cancer resection in patients without preoperative CTCs, and whether postoperative CTC detection was associated with recurrence. METHODS: Immediate preoperative testing for CTCs was performed for 147 patients with pulmonary nodules. This study included 81 lung cancer patients (55.1%) with negative preoperative results for CTCs and who completed postoperative testing for CTCs. The clinical relevance of postoperative CTC detection was evaluated based on the clinicopathological characteristics and recurrence patterns. RESULTS: Among the eligible patients, the postoperative CTC results were none detected in 58 patients (71.6%, "Group N"), only a single CTC detected in 6 patients (7.4%, "Group S"), and CTC clusters detected in 17 patients (21.0%, "Group C"). The presence of postoperative CTCs was associated with tumor vessel invasion, lymph duct invasion, and pleural invasion. Distant metastasis was very common in cases with postoperatively detected CTC clusters. The 2-year recurrence-free survival rates were 94.6% for Group N, 62.5% for Group S, and 52.9% for Group C (P<0.01). Multivariate analysis revealed that recurrence was independently related to the postoperative detection of single CTCs and CTC clusters. CONCLUSIONS: In cases without preoperative CTCs, we postoperatively detected CTCs and the postoperative CTC results were an independent predictor of recurrence.
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AIMS: We conducted a head-to-head randomized trial of minodronate, a bisphosphonate, and raloxifene, a selective estrogen receptor modulator, to obtain clinical evidence and information about their efficacy and safety. METHODS: The Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04) trial is a multi-center, open-labeled, blinded endpoints, head-to-head randomized trial of minodronate and raloxifene. Ambulatory elderly women with osteoporosis (age, >60 years) were randomly allocated to the raloxifene or minodronate group by central registration. The co-primary endpoints included any one of osteoporotic fractures (vertebral, humeral, femoral, and radial fractures), vertebral fractures, and major osteoporotic fractures (clinical vertebral, humeral, femoral, and radial fractures). The biological effects of each drug, patients' quality of life, and drug safety were assessed based on the secondary outcomes. This study was registered at the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) under trial identification number UMIN000005433. RESULTS: A total of 3896 patients were randomized to the minodronate and raloxifene groups, and drug efficacy assessments were performed for 3247 patients (1623 and 1624 patients, respectively). Among these patients, 1176 and 1187 patients received allocated treatment for 2 years. The incidence rate ratios for osteoporotic, vertebral, and major osteoporotic fractures in the minodronate group were 0.94 (95% CI: 0.78-1.13, p = .494), 0.86 (95% CI: 0.70-1.05, p = .147), and 1.22 (95% CI: 0.86-1.74, p = .274), respectively. Compared to the raloxifene group, the minodronate group showed significantly increased bone mineral density of the lumbar spine for each visit (6 months: p = .007, 12 months: p = .0003, 24 months: p<.0001). Also, serious adverse reactions were observed for four and six patients in the minodronate and raloxifene groups, respectively. CONCLUSIONS: Overall, there were no statistical differences in the incidence rates of osteoporotic, vertebral, or major osteoporotic fractures between the two groups. Serious adverse reactions were rare in both groups.
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Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/epidemiologia , Cloridrato de Raloxifeno/uso terapêutico , Idoso , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/efeitos adversos , Feminino , Humanos , Imidazóis/efeitos adversos , Incidência , Japão/epidemiologia , Fraturas por Osteoporose/prevenção & controle , Qualidade de Vida , Cloridrato de Raloxifeno/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Iron is essential for many types of biological processes. However, excessive iron can be cytotoxic and can lead to many diseases. Since ferroptosis, which is an iron-dependent regulated form of necrosis, was recently discovered, iron and iron-catalysed oxidative stress have attracted much interest because of their sophisticated mechanism of cellular signalling leading to cell death and associated with various diseases. SCOPE OF REVIEW: In this review, we first focus on how iron catalyses reactive oxygen species (ROS). Next, we discuss the roles of iron in cell death and senescence and, in particular, the downstream signalling pathways of ROS. Finally, we discuss the potential regulation mechanism of iron as a therapeutic target for various iron-related diseases. MAJOR CONCLUSIONS: Both labile iron released from organelles upon various stresses and iron incorporated in enzymes produce ROS, including lipid ROS. ROS produced by iron activates various signalling pathways, including mitogen-activated protein kinase (MAPK) signalling pathways such as the apoptosis signal-regulating kinase 1 (ASK1)-p38/JNK pathway. These ROS-activated signalling pathways regulate senescence or cell death and are linked to cancer, ischaemia-reperfusion injury during transplantation and ageing-related neurodegenerative diseases. GENERAL SIGNIFICANCE: Iron overload damages cells and causes harmful effects on the body through oxidative stress. Thus, understanding the spatiotemporal availability of iron and the role of iron in generating ROS will provide clues for the suppression of ROS and cytotoxic redox-active iron. Moreover, elucidating the molecular mechanisms and signalling pathways of iron-dependent cytotoxicity will enable us to find novel therapeutic targets for various diseases.
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Morte Celular , Senescência Celular , Homeostase , Ferro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Apoptose , Humanos , Estresse Oxidativo , Transdução de SinaisRESUMO
BACKGROUND: The 'gentle' handling of tissue (i.e., 'respect for tissue') is a fundamental aspect of surgical performance and learning. To date, there have been no methodological assessments that quantitatively measure 'gentleness.' Therefore, the aims of this study were (1) to propose a novel metric for gentle surgical maneuvers, (2) to validate the feasibility of this methodology, and (3) to explore safer surgical techniques through this methodology. METHODS: Using surgical video-based motion software, the motion of the carotid artery around plaque was analyzed and quantified during a carotid endarterectomy. Kinematic parameters (minimum and maximum acceleration, and maximum and mean velocity) were compared among the surgical tasks and techniques, as well as between novice and expert surgeons. RESULTS: The surgical tasks of dissecting the common carotid artery, passing the proximal vessel loops, and ligating vessels showed the highest absolute values of kinematic parameters. Dissections perpendicular to the line of the internal carotid artery tended to show higher kinematic parameters than those in the parallel direction, with blunt dissections typically higher than sharp dissections. The kinematic parameters of novice surgeons were significantly higher than those of experts, and receiver operating curve analysis showed a strong discriminative power. CONCLUSION: This study shows that tissue motion parameters could be a novel and feasible surrogate marker for the objective assessment on the 'gentleness' of surgical performance. Future studies should be performed to further elucidate the relationship on the direct correlation between tissue kinematic data and clinical outcomes or surgical adverse events.
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Endarterectomia das Carótidas , Idoso , Idoso de 80 Anos ou mais , Fenômenos Biomecânicos , Competência Clínica , Humanos , Pessoa de Meia-Idade , Movimento (Física) , Projetos Piloto , Gravação em VídeoRESUMO
Currently, the only available evidence for the efficacy of once-weekly 17.5 mg risedronate in preventing vertebral fractures was obtained in a 48-week study in Japan. We performed a 156-week prospective, longitudinal, observational study to determine the efficacy of the 17.5 mg risedronate in preventing vertebral fractures. We included Japanese patients with established osteoporosis who were older than 50 years and had radiographically confirmed vertebral fractures. The primary endpoint was the incidence of vertebral fractures every 24 weeks, with the final interval spanning 36 weeks. We also calculated the change in bone mineral density of the lumbar spine (L2-4 BMD) and urinary N-telopeptide of type I collagen (u-NTX), and assessed the incidence of adverse drug reactions and the drug adherence rate. Data from 241 patients were available for analysis of vertebral fracture prevention. The incidence rate of vertebral fractures decreased in a time-dependent manner (P = 0.0006; Poisson regression analysis). The risk ratio (fracture incidence per 100 person-years in the final 36 weeks versus that in the first 24 weeks) was 0.21 (95 % confidence interval 0.08-0.55). Compared to baseline values, L2-4 BMD increased by 6.41 % at 156 weeks, while u-NTX decreased by 36 % at 24 weeks and was maintained thereafter (P < 0.0001). The incidence rate of adverse drug reactions was 9.18 %. Drug adherence rates assessed every 4 weeks were over 90 %. Our results indicate that 156 weeks of treatment with once-weekly 17.5 mg risedronate effectively reduced the risk of vertebral fracture in Japanese patients with established osteoporosis older than 50 years.
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Povo Asiático , Osteoporose/tratamento farmacológico , Ácido Risedrônico/administração & dosagem , Ácido Risedrônico/uso terapêutico , Fraturas da Coluna Vertebral/epidemiologia , Idoso , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/uso terapêutico , Colágeno Tipo I/urina , Esquema de Medicação , Feminino , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/prevenção & controle , Humanos , Incidência , Japão , Estudos Longitudinais , Vértebras Lombares/efeitos dos fármacos , Masculino , Osteoporose/complicações , Osteoporose/fisiopatologia , Osteoporose/urina , Cooperação do Paciente , Peptídeos/urina , Prevalência , Estudos Prospectivos , Ácido Risedrônico/efeitos adversos , Fatores de Risco , Fraturas da Coluna Vertebral/complicações , Fraturas da Coluna Vertebral/fisiopatologia , Fraturas da Coluna Vertebral/urinaRESUMO
PURPOSE: To assess the joint symptoms and the impact on patients' health-related quality of life (HRQOL) due to 5 years of anastrozole from the baseline data in the N-SAS BC 05 trial, a randomized clinical trial was designed to assess the efficacy of 5 additional years of anastrozole among women with breast cancer. METHODS: Joint symptoms and HRQOL were evaluated using an original questionnaire for joint symptoms, the Short Form 36-item Health Survey (SF-36), the EuroQol EQ-5D-3L, and a subscale of the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES). RESULTS: Baseline joint symptom and HRQOL data were collected from 330 patients between November 2007 and March 2010. Joint pain and joint stiffness were reported by 61.6 and 59.1 % of patients, respectively, although these symptoms did not affect the activities of daily living in 96.0 and 97.9 % of patients, respectively. Joint pain was reported in the knee by 61.0 % of patients and in the hand by 36.0 % of patients. Joint stiffness mainly affected the hand (67.9 %), especially the proximal interphalangeal joint, and typically occurred upon waking up or in the morning. Most SF-36 domains had good average scores, although slight decreases in physical functioning and role-physical were observed (compared to the national standard scores). The mean EQ-5D utility score was 0.86, and the total FACT-ES subscale score was 62.2/76. CONCLUSIONS: After 5 years of anastrozole, many of the patients reported joint pain and stiffness in mainly the hand and knee with mild symptoms and good HRQOL.
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Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Artropatias/induzido quimicamente , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Anastrozol , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Qualidade de Vida , Inquéritos e Questionários , Resultado do TratamentoRESUMO
BACKGROUND: Patients with developmental dysplasia of the hip (DDH) have a greater risk of acetabular labral tearing and joint instability, which predispose them to developing osteoarthritis. The arthroscopic management of DDH, however, remains controversial. HYPOTHESIS: Specific clinical characteristics and radiographic parameters correlate with and predict a worsened clinical outcome after hip arthroscopic surgery for DDH. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: Of patients with DDH who underwent an arthroscopic procedure between March 2009 and June 2011, there were 28 hips in 28 patients (6 male and 22 female) that met the inclusion criteria. The mean patient age was 28.4 years. Clinical and radiographic follow-up evaluations up to a minimum of 2 years after surgery were performed for all patients. Failure of the procedure was defined as conversion to subsequent surgery or having a Tönnis osteoarthritis grade of 2 and modified Harris Hip Score (mHHS) that remained <85, and success was defined as patients who did not need subsequent surgery and had an mHHS >85. Univariate analysis and Cox hazard proportional analysis were performed on the 2 subpopulations. RESULTS: There were 9 patients in the failure group (including 3 hips with T nnis grade 2) and 19 patients in the success group. In 22 of 28 patients, the mean mHHS significantly improved from 61.6 ± 18.8 (range, 12.0-85.0) preoperatively to 94.3 ± 7.0 (range, 73.7-100.0) at final follow-up, and the mean Non-Arthritic Hip Score (NAHS) improved from 56.2 ± 13.9 (range, 35.0-81.3) preoperatively to 92.7 ± 9.5 (range, 65.0-100.0) at final follow-up (P < .001, Wilcoxon signed-rank test). Univariate analysis showed that a broken Shenton line was significantly more prevalent in the failure group compared with the success group (8/9 [89%] vs 3/19 [16%] patients, respectively; P < .001). High-grade cartilage delamination (Multicenter Arthroscopy of the Hip Outcomes Research Network [MAHORN] grades 3-5) was significantly higher in the failure group than in the success group (8/9 [89%] vs 3/19 [16%] patients, respectively; P < .001). The median femoral neck-shaft (FNS) angle in the failure group was significantly higher than that in the success group (139° vs 134°, respectively; P = .01). Further, Cox hazard proportional analysis of the failure group showed that the predictors for a poor clinical outcome were the presence of a broken Shenton line, FNS angle >140°, center-edge (CE) angle <19°, body mass index (BMI) >23 kg/m(2), acetabular cartilage damage (MAHORN grades 3-5), and cartilage damage of the femoral head (International Cartilage Repair Society grades 2-4). The most important predictors for a poor clinical outcome at the time of surgery were a broken Shenton line and an FNS angle >140°. CONCLUSION: Patients with a broken Shenton line, FNS angle >140°, CE angle <19°, or BMI >23 kg/m(2) at the time of surgery are not good candidates for the arthroscopic management of DDH.
Assuntos
Artroscopia/métodos , Luxação Congênita de Quadril/cirurgia , Complicações Pós-Operatórias/etiologia , Acetábulo/cirurgia , Adulto , Cartilagem Articular/cirurgia , Estudos de Casos e Controles , Feminino , Cabeça do Fêmur/cirurgia , Colo do Fêmur/cirurgia , Seguimentos , Luxação Congênita de Quadril/diagnóstico por imagem , Humanos , Instabilidade Articular/etiologia , Instabilidade Articular/cirurgia , Masculino , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/etiologia , Complicações Pós-Operatórias/diagnóstico por imagem , Radiografia , Resultado do TratamentoRESUMO
We examined response to bone mineral density (BMD) gains in the MOVER study following treatment with intravenous (IV) ibandronate 1 mg/month, and investigated the characteristics of a non-responder group. At 1 year, responder rates for patients with BMD increases >0 % were similar with IV ibandronate 0.5 or 1 mg/month and oral risedronate 2.5 mg/day. However, after 3 years, responder rates with BMD increases ≥3 % were highest with ibandronate 1 mg at all bone sites (>80 % at the lumbar spine [L2-L4] and >50 % at all femur sites, which was significantly higher than with risedronate). Non-responders were defined by BMD increases ≤3 % at L2-L4 or ≤0 % at total hip, and ≤50 % reduction in creatinine-corrected urinary collagen type 1 cross-linked C-telopeptide (uCTX) from baseline to 1 year. There were a small number of non-responders in the ibandronate 1 mg group: 3.3 % (10/299) with ≤0 % total hip BMD increase and ≤50 % uCTX reduction from baseline. These non-responders had lower 25-hydroxyvitamin D (25[OH]D) levels than responders, but no differences in kidney function, L2-L4 BMD or bone turnover marker baseline values. Throughout the study, non-responders failed to show any increases in BMD. Our analysis demonstrates significantly higher responder rates with IV ibandronate 1 mg/month than with risedronate at 3 years. A small number of non-responders in the ibandronate group had lower 25(OH)D baseline levels than responders, suggesting that 25(OH)D levels could be a useful indicator of BMD response to therapy.
Assuntos
Densidade Óssea/efeitos dos fármacos , Difosfonatos/administração & dosagem , Vértebras Lombares/metabolismo , Osteoporose/tratamento farmacológico , Ácido Risedrônico/administração & dosagem , Administração Intravenosa , Administração Oral , Idoso , Colágeno Tipo I/urina , Creatinina/urina , Método Duplo-Cego , Feminino , Fêmur/metabolismo , Humanos , Ácido Ibandrônico , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Osteoporose/sangue , Osteoporose/urina , Peptídeos/urina , Fraturas da Coluna Vertebral/sangue , Fraturas da Coluna Vertebral/etiologia , Fraturas da Coluna Vertebral/prevenção & controle , Fraturas da Coluna Vertebral/urina , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
BACKGROUND: Various procedures, such as arthroscopic debridement, osteochondral transplantation, and bone plug fixation, have been described for the treatment of osteochondritis dissecans (OCD) of the humeral capitellum. However, the use of hydroxyapatite/poly-L-lactate acid (HA/PLLA) thread pins to fix the osteochondral fragment in an OCD lesion is a recent development. HYPOTHESIS: Adolescent throwing athletes would return to preinjury levels of function after arthroscopic osteochondral fragment fixation using HA/PLLA thread pins. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Enrolled in this prospective cohort study were 18 adolescent baseball players (mean age, 14.2 years; range 12-16, years) with elbow OCD who underwent arthroscopic fragment fixation with HA/PLLA thread pins between 2006 and 2009. All patients were affected on their dominant side. Plain radiographs taken before surgery showed an open physis in 13 patients (72%) and a closed physis in 5 patients (28%). During surgery, the condition of the OCD lesion was evaluated by use of the International Cartilage Research Society (ICRS) classification system; there were 5 grade II, 11 grade III, and 2 grade IV cases. Outcomes were assessed after 3 years (mean, 39 months; range, 36-50 months). Elbow function was measured using the Timmerman and Andrews score and the Mayo Elbow Performance Index. Return to sports activity was assessed as higher than preinjury, same level, lower level, or no return to sports. RESULTS: The mean Timmerman and Andrews score improved significantly from 126.6±6.5 to 197.5±1.5, and the mean Mayo Elbow Performance Index improved significantly from 68.0±2.1 to 98.06±0.9 (P=.0001 for both). Mean elbow extension improved significantly from -10°±10.4° to -0.8°±5.2° (P=.006), and mean flexion improved significantly from 123.1°±17.9° to 138.6°±6.1° (P=.001). Three patients had a loss of extension greater than 5°. Five patients returned to a higher level of sports activity, 10 patients returned to the same level, and 2 patients returned to a lower level. A remaining patient did not return to baseball. In one patient, the lesion did not heal, resulting in fragmentation at 1 year after surgery. This patient consequently underwent revision arthroscopy to remove the lesion, and he eventually returned to sports at the same level of activity. CONCLUSION: Arthroscopic fragment fixation using HA/PLLA thread pins provides a beneficial clinical outcome to adolescent baseball players with humeral capitellar OCD.
Assuntos
Artroscopia/métodos , Beisebol/lesões , Articulação do Cotovelo/cirurgia , Osteocondrite Dissecante/cirurgia , Adolescente , Pinos Ortopédicos , Criança , Estudos de Coortes , Desbridamento/métodos , Durapatita/química , Humanos , Úmero/cirurgia , Ácido Láctico/química , Masculino , Procedimentos Ortopédicos/métodos , Poliésteres , Polímeros/química , Estudos Prospectivos , Amplitude de Movimento ArticularRESUMO
In addition to the underlying shallow acetabular deformity, a patient with hip dysplasia has a greater risk of development of a labral tear, a cam lesion, and capsular laxity. This combination of abnormalities exacerbates joint instability, ultimately leading to osteoarthritis. Unsurprisingly, only repairing the acetabular labrum remains controversial, and the outcome is unpredictable. In this technical note, with video, we demonstrate an entirely endoscopic approach for simultaneously repairing the most common mechanical abnormalities found in moderate hip dysplasia: labral repair, cam osteochondroplasty, capsular plication, and shelf acetabuloplasty using an autologous iliac bone graft.