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BACKGROUND: Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma. METHODS: In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete. FINDINGS: Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT. INTERPRETATION: SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results. FUNDING: Galera Therapeutics.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Radiocirurgia , Humanos , Masculino , Feminino , Idoso , Adenocarcinoma/radioterapia , Adenocarcinoma/tratamento farmacológico , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/tratamento farmacológico , Radiocirurgia/efeitos adversos , Teorema de Bayes , Carcinoma Ductal Pancreático/radioterapia , Carcinoma Ductal Pancreático/tratamento farmacológico , Método Duplo-Cego , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
OBJECTIVE: To determine whether rituximab, a monoclonal antibody against the B-lymphocyte antigen CD20, is effective in the treatment of refractory noninfectious scleritis. DESIGN: Prospective, dose-ranging, randomized, double-masked phase I/II clinical trial. PARTICIPANTS: Twelve patients with noninfectious scleritis refractory to systemic corticosteroid and ≥1 other systemic immunosuppressive agent were enrolled from January 2007 to March 2010. INTERVENTION: Subjects were randomly assigned to 500 (n = 5) or 1000 mg (n = 7) dosing arms of rituximab intravenous infusions (500 or 1000 mg), given at study days 1 and 15. Initial responders with breakthrough inflammation after study week 24 were offered treatment with an additional cycle of 2 open-label rituximab 1000 mg infusions. MAIN OUTCOME MEASURES: Primary outcomes were reduction of inflammation, as measured with a validated scleritis disease grading scale (SGS) and reduction in corticosteroid dose by ≥50%. Patients were characterized as responders to study therapy if ≥1 of these endpoints showed improvement and neither showed evidence of worsening. Secondary outcomes were improvement in visual acuity, reduction in pain, and improvement in patient and physician-reported global health assessment. RESULTS: Of 12 enrolled patients, 9 met the SGS endpoint at or before week 24, and 4 additionally were able to reduce corticosteroid dose by ≥50%. With regard to secondary outcome measures, 11 and 9 patients showed improvement in patient and physician global health scores, respectively, and 7 patients had reduction in pain. Of 9 initial responders, 7 experienced breakthrough inflammation after 24 weeks and were treated with a second cycle of rituximab infusions. Four patients had significant objective or subjective worsening within 8 weeks of receiving rituximab; this event was averted in subsequent patients by treatment with peri-infusional oral corticosteroid. No other significant adverse events were noted. No differences in efficacy, toxicity, or likelihood of retreatment were noted between the dosing arms. CONCLUSIONS: Rituximab was effective treatment for 9 of 12 enrolled patients with refractory, noninfectious scleritis at 24 weeks, although 7 required reinfusion with rituximab to maintain inflammatory control. The treatment was well-tolerated, and peri-infusional inflammatory exacerbations were managed successfully with oral corticosteroids. Further long-term studies are warranted to determine the safety and efficacy of rituximab in treating noninfectious scleritis and other ocular inflammatory diseases.
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Anticorpos Monoclonais Murinos/administração & dosagem , Fatores Imunológicos/administração & dosagem , Esclerite/tratamento farmacológico , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Rituximab , Índice de Gravidade de Doença , Adulto JovemRESUMO
OBJECTIVES: We examine the associations of adherence to antiparkinson drugs (APDs) with health care utilization and economic outcomes among patients with Parkinson's disease (PD). METHODS: By using 2006-2007 Medicare administrative data, we examined 7583 beneficiaries with PD who filled two or more APD prescriptions during 19 months (June 1, 2006, to December 31, 2007) in the Part D program. Two adherence measures--duration of therapy (DOT) and medication possession ratio (MPR)--were assessed. Negative binomial and gamma generalized linear models were used to estimate the rate ratios (RRs) of all-cause health care utilization and expenditures, respectively, conditional upon adherence, adjusting for survival risk, sample selection, and health-seeking behavior. RESULTS: Approximately one-fourth of patients with PD had low adherence (MPR < 0.80, 28.7%) or had a short DOT (≤ 400 days, 23.9%). Increasing adherence to APD therapy was associated with decreased health care utilization and expenditures. For example, compared with patients with low adherence, those with high adherence (MPR = 0.90-1.00) had significantly lower rates of hospitalization (RR = 0.86), emergency room visits (RR = 0.91), skilled nursing facility episodes (RR = 0.67), home health agency episodes (RR = 0.83), physician visits (RR = 0.93), as well as lower total health care expenditures (-$2242), measured over 19 months. Similarly, lower total expenditure (-$6308) was observed in patients with a long DOT versus those with a short DOT. CONCLUSIONS: In this nationally representative sample, higher adherence to APDs and longer duration of use of APDs were associated with lower all-cause health care utilization and total health care expenditures. Our findings suggest the need for improving medication-taking behaviors among patients with PD to reduce the use of and expenditures for medical resources.
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Antiparkinsonianos/uso terapêutico , Serviços de Saúde/estatística & dados numéricos , Medicare Part D/economia , Adesão à Medicação , Doença de Parkinson/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/economia , Estudos Transversais , Feminino , Gastos em Saúde/estatística & dados numéricos , Serviços de Saúde/economia , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/economia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Tempo , Estados UnidosRESUMO
PURPOSE: Cisplatin contributes to acute kidney injury (AKI) and chronic kidney disease (CKD) that occurs with greater frequency and severity in older patients. Age-associated cisplatin sensitivity in human fibroblasts involves increased mitochondrial superoxide produced by older donor cells. EXPERIMENTAL DESIGN: Young and old C57BL/6 J murine models of cisplatin-induced AKI and CKD were treated with the SOD mimetic avasopasem manganese to investigate the potential antioxidant and anti-inflammatory effects. Adverse event reporting from a phase 2 and a phase 3 randomized clinical trial (NCT02508389 and NCT03689712) conducted in patients treated with cisplatin and AVA was determined to have established the incidence and severity of AKI. RESULTS: Cisplatin-induced AKI and CKD occurred in all mice, however, was more pronounced in older mice. AVA reduced cisplatin-induced mortality, AKI, and CKD, in older animals. AVA also alleviated cisplatin-induced alterations in mitochondrial electron transport chain (ETC) complex activities and NADPH Oxidase 4 (NOX4) and inhibited the increased levels of the inflammation markers, TNFα, IL1, ICAM-1, and VCAM-1. Analysis of age-stratified subjects treated with cisplatin from clinical trials (NCT02508389, NCT03689712) also supported that the incidence of AKI increased with age and AVA reduced age-associated therapy-induced adverse events (AE), including hypomagnesemia, increased creatinine, and AKI. CONCLUSIONS: Older mice and humans are more susceptible to cisplatin-induced kidney injury, and treatment with AVA mitigates age-associated damage. Mitochondrial ETC and NOX4 activities represent sources of superoxide production contributing to cisplatin-induced kidney injury, and pro-inflammatory cytokine production and endothelial dysfunction may also be increased by superoxide formation.
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Injúria Renal Aguda , Compostos Organometálicos , Insuficiência Renal Crônica , Humanos , Camundongos , Animais , Idoso , Cisplatino/farmacologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Superóxidos , Camundongos Endogâmicos C57BL , Rim , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Anti-Inflamatórios/farmacologiaRESUMO
Soft tissue sarcomas (STSs) are mesenchymal malignant lesions that develop in soft tissues. Despite current treatments, including radiation therapy (RT) and surgery, STSs can be associated with poor patient outcomes and metastatic recurrences. Neoadjuvant radiation therapy (nRT), while effective, is often accompanied by severe postoperative wound healing complications due to damage to the surrounding normal tissues. Thus, there is a need to develop therapeutic approaches to reduce nRT toxicities. Avasopasem manganese (AVA) is a selective superoxide dismutase mimetic that protects against IR-induced oral mucositis and lung fibrosis. We tested the efficacy of AVA in enhancing RT in STSs and in promoting wound healing. Using colony formation assays and alkaline comet assays, we report that AVA selectively enhanced the STS (liposarcoma, fibrosarcoma, leiomyosarcoma, and MPNST) cellular response to radiation compared to normal dermal fibroblasts (NDFs). AVA is believed to selectively enhance radiation therapy by targeting differential hydrogen peroxide clearance in tumor cells compared to non-malignant cells. STS cells demonstrated increased catalase protein levels and activity compared to normal fibroblasts. Additionally, NDFs showed significantly higher levels of GPx1 activity compared to STSs. The depletion of glutathione using buthionine sulfoximine (BSO) sensitized the NDF cells to AVA, suggesting that GPx1 may, in part, facilitate the selective toxicity of AVA. Finally, AVA significantly accelerated wound closure in a murine model of wound healing post RT. Our data suggest that AVA may be a promising combination strategy for nRT therapy in STSs.
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Avasopasem manganese (AVA or GC4419), a selective superoxide dismutase mimetic, is in a phase 3 clinical trial (NCT03689712) as a mitigator of radiation-induced mucositis in head and neck cancer based on its superoxide scavenging activity. We tested whether AVA synergized with radiation via the generation of hydrogen peroxide, the product of superoxide dismutation, to target tumor cells in preclinical xenograft models of non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, and pancreatic ductal adenocarcinoma. Treatment synergy with AVA and high dose per fraction radiation occurred when mice were given AVA once before tumor irradiation and further increased when AVA was given before and for 4 days after radiation, supporting a role for oxidative metabolism. This synergy was abrogated by conditional overexpression of catalase in the tumors. In addition, in vitro NSCLC and mammary adenocarcinoma models showed that AVA increased intracellular hydrogen peroxide concentrations and buthionine sulfoximine- and auranofin-induced inhibition of glutathione- and thioredoxin-dependent hydrogen peroxide metabolism selectively enhanced AVA-induced killing of cancer cells compared to normal cells. Gene expression in irradiated tumors treated with AVA suggested that increased inflammatory, TNFα, and apoptosis signaling also contributed to treatment synergy. These results support the hypothesis that AVA, although reducing radiotherapy damage to normal tissues, acts synergistically only with high dose per fraction radiation regimens analogous to stereotactic ablative body radiotherapy against tumors by a hydrogen peroxide-dependent mechanism. This tumoricidal synergy is now being tested in a phase I-II clinical trial in humans (NCT03340974).
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Compostos Organometálicos , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Peróxido de Hidrogênio , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Camundongos , Superóxido DismutaseRESUMO
Cisplatin is a chemotherapy agent commonly used to treat a wide variety of cancers. Despite the potential for both severe acute and chronic side effects, it remains a preferred therapeutic option for many malignancies due to its potent anti-tumor activity. Common cisplatin-associated side-effects include acute kidney injury (AKI) and chronic kidney disease (CKD). These renal injuries may cause delays and potentially cessation of cisplatin therapy and have long-term effects on renal function reserve. Thus, developing mechanism-based interventional strategies that minimize cisplatin-associated kidney injury without reducing efficacy would be of great benefit. In addition to its action of cross-linking DNA, cisplatin has been shown to affect mitochondrial metabolism, resulting in mitochondrially derived reactive oxygen species (ROS). Increased ROS formation in renal proximal convoluted tubule cells is associated with cisplatin-induced AKI and CKD. We review the mechanisms by which cisplatin may induce AKI and CKD and discuss the potential of mitochondrial superoxide dismutase mimetics to prevent platinum-associated nephrotoxicity.
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Physical dynamics of Harmful Algal Blooms in Massachusetts Bay in May 2005 and 2008 were examined by the simulated results. Reverse particle-tracking experiments suggest that the toxic phytoplankton mainly originated from the Bay of Fundy in 2005 and the western Maine coastal region and its local rivers in 2008. Mechanism studies suggest that the phytoplankton were advected by the Gulf of Maine Coastal Current (GMCC). In 2005, Nor'easters increased the cross-shelf surface elevation gradient over the northwestern shelf. This intensified the Eastern and Western MCC to form a strong along-shelf current from the Bay of Fundy to Massachusetts Bay. In 2008, both Eastern and Western MCC were established with a partial separation around Penobscot Bay before the outbreak of the bloom. The northeastward winds were too weak to cancel or reverse the cross-shelf sea surface gradient, so that the Western MCC carried the algae along the slope into Massachusetts Bay.
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Baías , Proliferação Nociva de Algas , Maine , Massachusetts , FitoplânctonRESUMO
BACKGROUND: To evaluate visual and safety outcomes for 25-gauge (25G) and 27-gauge (27G) micro-incision vitrectomy platforms (MIVS) for the treatment of epiretinal membrane and full-thickness macular holes. METHODS: Retrospective analysis of all patients who underwent internal limiting membrane (ILM) peel surgery from January 2017 through December 2018. 207 cases met the eligibility criteria for inclusion. Primary endpoint was post-operative Best-Corrected Distance Visual Acuity (BCVA) at 6 months. RESULTS: For all patients combined, mean logMAR BCVA improved from 0.57 (± 0.40) to 0.37 (± 0.36) post-operatively (p < 0.001). For 25G ERMs, logMAR BCVA improved from 0.51 (± 0.28) to 0.30 (± 0.25) post-operatively (p < 0.001). For 27G ERMs, logMAR BCVA improved from 0.33 (± 0.28) to 0.28 (± 0.27) post- operatively (p = 0.15). For 25G FTMHs, logMAR BCVA improved from 0.87 (± 0.48) to 0.51 (± 0.44) post-operatively (p < 0.001). For 27G FTMHs, logMAR BCVA changed from 0.89 (± 0.47) to 0.96 (± 0.60). CONCLUSION: Final visual outcomes improved for both 25G and 27G ERM groups and the 25G FTMH group. Both 25G and 27G were safe and well tolerated MIVS platforms for the treatment of ERM and FTMH.
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Lung cancer, together with head and neck cancer, accounts for more than one-fourth of cancer deaths worldwide. New, non-toxic therapeutic approaches are needed. High-dose IV vitamin C (aka, pharmacological ascorbate; P-AscH-) represents a promising adjuvant to radiochemotherapy that exerts its anti-cancer effects via metal-catalyzed oxidation to form H2O2. Mn(III)-porphyrins possessing superoxide dismutase (SOD) mimetic activity have been shown to increase the rate of oxidation of AscH-, enhancing the anti-tumor effects of AscH- in several cancer types. The current study demonstrates that the Mn(II)-containing pentaazamacrocyclic selective SOD mimetic GC4419 may serve as an AscH-/O2â¢- oxidoreductase as evidenced by the increased rate of oxygen consumption, steady-state concentrations of ascorbate radical, and H2O2 production in complete cell culture media. GC4419, but not CuZnSOD, was shown to significantly enhance the toxicity of AscH- in H1299, SCC25, SQ20B, and Cal27 cancer cell lines. This enhanced cancer cell killing was dependent upon the catalytic activity of the SOD mimetic and the generation of H2O2, as determined using conditional overexpression of catalase in H1299T cells. GC4419 combined with AscH- was also capable of enhancing radiation-induced cancer cell killing. Currently, AscH- and GC4419 are each being tested separately in clinical trials in combination with radiation therapy. Data presented here support the hypothesis that the combination of GC4419 and AscH- may provide an effective means by which to further enhance radiation therapy responses.
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Importance: Traditionally cyclophotocoagulation has been reserved as a treatment of last resort for eyes with advanced stage glaucoma, but increasingly it is offered to eyes with less severe disease. Endoscopic approaches in particular are utilized in increasing numbers of patients despite only a small number of publications on its results. Objective: The purpose of this study was to compare the efficacy and safety of endoscopic and transcleral cyclophotocoagulation (ECP and TCP) procedures in eyes with refractory glaucomas. Design, Setting, and Participants: A chart review was performed on consecutive patients who underwent ECP and TCP at a tertiary ophthalmology care center between January 2000 and December 2010. Cases with fewer than 3 months of follow-up or that had concurrent pressure reducing procedures were excluded. The main outcome measures examined were intraocular pressure (IOP), number of glaucoma medications, best corrected visual acuity (BCVA), additional glaucoma procedure required, and complications. Main Outcomes and Measures: Forty-two eyes (42 patients) that underwent ECP and forty-four eyes (44 patients) that underwent TCP were identified. The TCP group had a statistically higher mean age (71.2 ± 16.7 vs. 58.1 ± 22.9 years, respectively), larger proportion of neovascular glaucoma (40.9% vs. 16.7%), worse initial BCVA (logMAR 2.86 vs. 1.81), and higher preoperative IOP (45.3 vs. 26.6 mmHg) than the ECP group. At 12 months follow-up, the mean IOP difference between groups was not statistically significant, although the change in IOP from baseline to 12 months was greater for the TCP group (p = 0.006). The rates of progression to no light perception (NLP) and phthisis bulbi were significantly higher amongst TCP eyes than ECP eyes (27.2% vs. 4.8%, p = 0.017, and 20.5% vs. 0%, p = 0.003, respectively). Of these eyes that progressed, a majority had neovascular glaucoma (NVG). Corneal decompensation was the most frequent complication following ECP (11.9%). Conclusions and Relevance: In patients with preoperative BCVA of 20/400 or better, overall complication rates (cystoid macular edema, exudative retinal detachment, inflammation, cornea decompensation) were higher after ECP than with TCP. In refractory glaucomas in a real world setting (not a trial), TCP was more frequently used in ischemic eyes. TCP was associated with a higher rate of progression to phthisis bulbi and loss of light perception than ECP. However, ECP was associated with a clinically significant rate of corneal decompensation. These outcomes likely were related to the severity of underlying ocular diseases found in these eyes.
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INTRODUCTION: Many ocular diseases require intravitreal injections of pharmacological agents. Optimizing patients' experiences during injections is important to ensure compliance and maintenance of quality of life. The objective of this study was to identify strategies to help alleviate discomfort during intravitreal injections. METHODS: A cross-sectional study surveying 128 patients during clinic visits between 2014 and 2015 in two outpatient Retina Clinics (one academic and one private). Patients receiving an intravitreal injection(s) for any retinal disorder were given a questionnaire with 10-yes/no responses for various potential strategies. Responses were stratified by sex, age (<30 years, 30-60 years, and >60 years) and total number of prior injections (0-9 injections, 10-20 injections and >20 injections). RESULTS: A total of 128 patients were surveyed: 59 males, 41 females and 28 with no sex specified. Our results identified four favorable strategies as those receiving more than 50% "yes" votes. These included the presence of technician/staff during the procedure, the use of a neck pillow, a verbal warning before the injection and performing injections in both eyes on the same day. Other specific strategies were identified for females, younger patients and those with greatest experience. These included: females preferred having their hand held during injections (P = 0.001) and using a stress ball (P = 0.000) when compared to males. Stratifying by age, patients 30-60 years old preferred having their hand held (P = 0.008) and background music (P = 0.007). Stratifying by prior injections, patients with >20 prior injections preferred having their hand held (P = 0.001), using a stress ball (P = 0.021) and, if necessary, having bilateral injections performed the same day to improve comfort (P = 0.037). CONCLUSIONS: Having an extra staff member present during the injection, having a neck pillow, having a verbal warning prior to injection and having both eyes injected on the same day were indicated as favorable strategies by over half of those surveyed. Further, specific strategies were identified for females, younger patients (30-60 years old) and those with greatest experience (>20 injections).
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We present a case of sequential bilateral idiopathic solitary granuloma of the uveal tract in a 51 year-old woman, who underwent enucleation in one eye due to complications of this condition, but was then successfully treated in the contralateral eye with anti-tumor necrosis-alpha therapy followed shortly by intraocular steroids and a steroid-releasing implant. Her visual acuity at its worst was 20/200 due to vitreous haze and cystoid macular edema, but then stabilized after successful treatment with a final visual acuity of 20/25 in her only seeing eye at 1 year follow-up. This represents the first known biopsy-proven case of bilateral idiopathic solitary granuloma, which additionally, has responded favorably to treatment.
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OBJECTIVES: To examine 1) the effect of prior antiparkinson drug (APD) nonadherence on subsequent APD regimen modifications; and 2) the influence of modifications on healthcare utilization and costs by patients with Parkinson's disease (PD). METHODS: This retrospective cohort study included 7052 PD patients with ≥2 APD prescriptions who initiated a modification of APD regimens in 2007. Modification was assessed as changing from one APD to another and/or adding a new APD to an existing regimen. Nonadherence was measured using Medication Possession Ratio <0.8. Discrete-time survival analyses were used to estimate the effect of prior nonadherent behavior on initiating APD modifications. Generalized linear models were used to estimate the effect of initiating medication modifications on subsequent 3-month medical use and costs. RESULTS: Initiation of APD modifications in any given month was higher among patients who were nonadherent to APDs in the preceding month (adjusted hazard ratio [HR] = 1.23), compared to their adherent counterparts. Modifications significantly predicted higher risk of all-cause and PD-related hospitalizations (adjusted relative risk [RR] = 1.22 and 1.83, respectively), home health agency utilization (RR = 1.18 and 1.52), and use of physician services (RR = 1.14 and 1.41), as well as higher total all-cause healthcare expenditures (mean = $1064) in any given 3-month interval. CONCLUSIONS: Prior nonadherence to APDs might influence initiation of APD modification. APD modifications were associated with increased health care utilization and expenditures, with the caveats that indications of modifications and disease severity may still play roles. Prescribers should consider patients' medication adherence when changing APD regimens to lower the costs of medical services.
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Antiparkinsonianos/uso terapêutico , Gastos em Saúde , Adesão à Medicação , Doença de Parkinson/tratamento farmacológico , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Doença de Parkinson/economia , Doença de Parkinson/psicologiaRESUMO
PURPOSE: To report visual acuity, contrast sensitivity and color vision prior to, 1 year after, 2 years after and 3 years after iodine-125 brachytherapy for choroidal and ciliary body melanoma (CCM). DESIGN: Prospective interventional case series. PARTICIPANTS: Thirty-seven patients (37 eyes) with CCM. METHODS: Patients had best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, Pelli-Robson contrast sensitivity and Hardy-Rand-Rittler color vision measurement; comprehensive ophthalmology examination; optical coherence tomography; and ultrasonography at baseline prior to, 1 year after, 2 years after and 3 years after I-125 brachytherapy. MAIN OUTCOME MEASURES: Visual acuity, contrast sensitivity and color vision prior to, 1 year after, 2 years after and 3 years after brachytherapy. RESULTS: Nineteen (19) men and 18 women with mean age of 58 years (SD 13, range 30-78) prior to, 1 year after, 2 years after and 3 years after brachytherapy had mean best-corrected visual acuity of 77 letters (20/32), 65 letters (20/50), 56 letters (20/80) and 47 letters (20/125); contrast sensitivity of 30, 26, 22 and 19 letters; color vision of 26, 20, 17 and 14 test figures, respectively. Decrease in visual acuity, contrast sensitivity and color vision was statistically significant from baseline at 1 year, 2 years, and 3 years after brachytherapy. Decreased acuity at 3 years was associated with mid-choroid and macula melanoma location, ≥ 4.1 mm melanoma height, radiation maculopathy and radiation optic neuropathy. CONCLUSION: 1, 2 and 3 years after brachytherapy, eyes with CCM had significantly decreased visual acuity, contrast sensitivity and color vision.
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PURPOSE: Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. This study tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA. EXPERIMENTAL DESIGN: We evaluated the prognostic significance of EcSOD in a human tissue microarray (TMA) of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase (NOS) inhibitor to determine the mechanism of action of EcSOD in PDA. RESULTS: Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Overexpression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity. CONCLUSIONS: These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide, which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease.
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Carcinoma Ductal Pancreático/patologia , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/patologia , Superóxido Dismutase/biossíntese , Animais , Western Blotting , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Fenótipo , Espécies Reativas de Oxigênio , Reação em Cadeia da Polimerase em Tempo Real , Programa de SEER , Superóxido Dismutase/metabolismo , Análise Serial de TecidosRESUMO
IMPORTANCE: Orbital inflammation is a potentially blinding and disfiguring disease process that is often treated with systemic corticosteroids and immunosuppression; better treatments are needed. OBJECTIVE: To determine whether rituximab, a monoclonal antibody against the B-lymphocyte antigen CD20, is effective in the treatment of refractory orbital inflammation. DESIGN, SETTING, AND PARTICIPANTS: A dose-ranging, randomized, double-masked phase 1/2 clinical trial was conducted at a tertiary referral ophthalmology clinic. Ten individuals with orbital inflammation refractory to systemic corticosteroids and at least 1 other immunosuppressive agent were enrolled from January 2007 to March 2010. INTERVENTIONS: Rituximab infusions were administered on study days 1 and 15 at doses of either 500 mg or 1000 mg. Initial responders with recurrent inflammation after week 24 were permitted reinfusion with an additional cycle of 2 open-label 1000-mg rituximab infusions. MAIN OUTCOMES AND MEASURES: The primary outcomes were reduction of inflammation measured with a validated orbital disease grading scale and corticosteroid dose reduction by at least 50%. The secondary outcomes were visual acuity, reduction in pain, and participant- and physician-reported global health assessment. RESULTS: Of 10 enrolled patients, 7 demonstrated improvement on the orbital disease grading scale at the 24-week end point with rituximab therapy. Of these 7 individuals, 4 were receiving corticosteroids at study inception and all achieved successful dose reduction. For the secondary outcome measures in the 10 participants, 7 patients and 8 patients improved in self-rated and physician global health scores, respectively, and 7 patients had reduction in pain by 25% or more at 24 weeks. Four patients who were positive responders at the week 24 end point experienced breakthrough inflammation after week 24 and received reinfusions between 24 and 48 weeks. Vision remained stable in all participants. Three of 10 patients had short-term objective or subjective worsening 2 to 8 weeks after receiving rituximab infusions, which was averted in subsequent patients with oral corticosteroids administered during the infusion and did not affect the eventual positive treatment outcome. No significant differences with regard to efficacy, toxicity, or likelihood of retreatment were noted between the dosing arms. CONCLUSIONS AND RELEVANCE: Rituximab was safe and effective in 7 of 10 patients with noninfectious orbital disease, although 4 required reinfusion with rituximab to maintain control of orbital inflammation. Substantial toxicity was not noted. Rituximab should be considered in the treatment of refractory orbital inflammation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00415506.
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Anticorpos Monoclonais Murinos/administração & dosagem , Pseudotumor Orbitário/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD20 , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Fatores Imunológicos/administração & dosagem , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Pseudotumor Orbitário/patologia , Recidiva , Estudos Retrospectivos , Rituximab , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Acuidade VisualRESUMO
A 68-year-old Caucasian man with a remote history of daily colloidal silver ingestion presented for ophthalmic examination in which he was noted to have a distinct slate gray skin discoloration. Funduscopy revealed confluent perimacular drusenoid deposits bilaterally, most of which localized at the level of or anterior to the inner segment ellipsoid band by optical coherence tomography (OCT) imaging. Enhanced depth imaging OCT demonstrated marked choroidal thinning. Fluorescein angiogram displayed a dark or silent choroid. Confirmatory serum silver levels were found to be markedly elevated. This report describes a unique geographic maculopathy with large drusenoid deposits anterior to the ellipsoid layer and severe choroidal thinning in association with ocular argyrosis.
Assuntos
Argiria/diagnóstico , Doenças da Coroide/diagnóstico , Drusas Retinianas/diagnóstico , Tomografia de Coerência Óptica , Idoso , Argiria/sangue , Doenças da Coroide/sangue , Angiofluoresceinografia , Humanos , Masculino , Drusas Retinianas/sangue , Escotoma/sangue , Escotoma/diagnóstico , Compostos de Prata/sangue , Compostos de Prata/toxicidadeRESUMO
Diabetic macular edema (DME) remains one of the leading causes of moderate to severe vision loss. Although laser photocoagulation was the standard of care for several years, few patients achieved significant improvements in visual acuity. As a result, several pharmacotherapies and surgeries have been investigated. The fluocinolone acetonide devices are one of the latest therapies considered for the treatment of DME. Despite bringing significant improvements in visual acuity, fluocinolone devices are associated with cataract formation, increased intraocular pressure (IOP), and surgery to lower IOP. Due to the risk of complications, fluocinolone acetonide devices should be considered only in cases refractive to first-line therapies. In this review, we evaluate current and emerging therapies for DME, with special emphasis on fluocinolone acetonide intravitreal devices.