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SFX-01 is a novel drug for clinical delivery of sulforaphane (SFN). SFN is a potent nuclear factor erythroid 2-related factor 2 activator that reduces inflammation and oxidation, improving outcomes after subarachnoid haemorrhage (SAH) in animal models. This was a multi-centre, double-blind, placebo-controlled, parallel-group randomised clinical trial to evaluate the safety, pharmacokinetics and efficacy of 28 days of SFX-01 300 mg BD in patients aged 18-80 with spontaneous SAH and high blood load on CT. Primary outcomes were (1) safety, (2) plasma and CSF SFN and metabolite levels and (3) vasospasm on transcranial doppler ultrasound. Secondary outcomes included CSF haptoglobin and malondialdehyde and clinical outcome on the modified Rankin Scale (mRS) and SAH outcome tool (SAHOT). A total of 105 patients were randomised (54 SFX-01, 51 placebo). There were no differences in adverse events other than nausea (9 SFX-01 (16.7%), 1 placebo (2.0%)). SFN, SFN-glutathione and SFN-N-acetyl-cysteine AUClast were 16.2, 277 and 415 h × ng/ml. Plasma SFN was higher in GSTT1 null individuals (t = 2.40, p = 0.023). CSF levels were low with many samples below the lower limit of quantification and predicted by the CSF/serum albumin ratio (R2 = 0.182, p = 0.039). There was no difference in CSF haptoglobin (1.981 95%CI 0.992-3.786, p = 0.052) or malondialdehyde (1.12 95%CI 0.7477-1.687, p = 0.572) or middle cerebral artery flow velocity (1.04 95%CI 0.903-1.211, p = 0.545) or functional outcome (mRS 1.647 95%CI 0.721-3.821, p = 0.237, SAHOT 1.082 95%CI 0.464-2.525, p = 0.855). SFX-01 is safe and effective for the delivery of SFN in acutely unwell patients. SFN penetrated CSF less than expected and did not reduce large vessel vasospasm or improve outcome. Trial registration: NCT02614742 clinicaltrials.gov.
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OBJECTIVE: Endobronchial ultrasound-guided transbronchial biopsy and needle aspiration (EBUS-TBB/EBUS-TBNA) are first line investigative modalities for lung and mediastinal pathology in adults. We aimed to characterize and assess the diagnostic yield of EBUS and virtual CT navigation guided biopsies in children. STUDY DESIGN: This single center, retrospective cohort study included patients who underwent radial or linear EBUS procedures (+/- CT navigation) for biopsy of mediastinal lymph nodes, tumors, and pulmonary nodules. Demographic, procedural, and outcome were collected. RESULTS: Sixty procedures were performed in 56 patients aged 2-22 years of age between January 2015 and May 2023. The most common indications for biopsy were pulmonary nodules (45%) and hilar/mediastinal lymphadenopathy (33%). For cases in which a final diagnosis was ascertained by any means, the diagnostic yield for linear EBUS (mediastinal pathology) was 76% and the diagnostic yield from radial EBUS (pulmonary nodules and lung masses) was 85%. The most common diagnoses were infection (45%), malignancy (17%), and sarcoidosis (11%). Among patients in whom infection was the final diagnosis, a total of 31 pathogens were identified. Eighteen were identified on bronchoalveolar lavage and an additional 14 pathogens identified on EBUS-TBB, representing an increase of 77% (p < .005). The sensitivity, specificity, negative and positive predictive values for malignancy detection were 73%, 100%, 94%, and 100%, respectively. CONCLUSION: EBUS-TBB/TBNA is a safe and effective way to diagnose lung and mediastinal pathology in children. Pediatric interventional pulmonology is a growing field offering minimally-invasive diagnostic opportunities for children in whom more invasive procedures were previously the only option.
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Neoplasias Pulmonares , Linfadenopatia , Doenças do Mediastino , Neoplasias Torácicas , Adulto , Criança , Humanos , Broncoscopia/métodos , Estudos Retrospectivos , Mediastino/patologia , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Doenças do Mediastino/diagnóstico , Neoplasias Torácicas/patologia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Sensibilidade e Especificidade , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologiaRESUMO
OBJECTIVES: To evaluate the prevalence of hemosiderin-laden macrophages in children with bronchopulmonary dysplasia (BPD) and assess for an association between hemosiderin-laden macrophages and pulmonary arterial hypertension. STUDY DESIGN: Retrospective case-control study of infants and children with and without BPD who underwent bronchoscopy with bronchoalveolar lavage (BAL) the at Children's Hospital of Philadelphia between 2012 and 2021. RESULTS: BAL from 205 children with BPD and 106 controls without BPD matched for tracheostomy, infection, and age were reviewed for hemosiderin-laden macrophages. Seventy-one individuals (34.6%) with BPD had a BAL with 10% or more hemosiderin-laden macrophages compared with 3 (2.8%) controls (P < .0001; OR, 18.19; 95% CI, 5.57-59.41). Patients with pulmonary hypertension by echocardiogram (P = .04; OR, 3.69; 95% CI, 1.05-12.96) or an elevated mean pulmonary artery pressure during cardiac catheterization, rs (14) = 0.56, P = .04, were more likely to have elevated hemosiderin-laden macrophages on BAL samples less than 60 days from bronchoscopy. After adjusting for birth weight, gestational age, BPD grade, and age at the time of bronchoscopy using logistic regression, pulmonary hypertension was associated with a higher odds of hemosiderin-laden macrophages of 10% or more (P = .02; OR, 6.37; 95% CI, 1.28-31.87). No association was observed between hemosiderin-laden macrophages and sex, race, gestational age, birth weight, tracheostomy, or infectious studies. CONCLUSIONS: This retrospective study revealed increased hemosiderin-laden macrophages in BAL samples from patients with BPD and a significant association with pulmonary arterial hypertension. It is unclear whether elevated hemosiderin-laden macrophages within BPD contributes to the pathogenesis of lung and pulmonary vascular disease or is simply a biomarker of pulmonary arterial hypertension.
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Displasia Broncopulmonar , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Lactente , Recém-Nascido , Humanos , Criança , Displasia Broncopulmonar/complicações , Estudos Retrospectivos , Hemossiderina , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/complicações , Estudos de Casos e Controles , Líquido da Lavagem Broncoalveolar , Peso ao Nascer , Lavagem Broncoalveolar , Macrófagos , Hipertensão Pulmonar Primária Familiar/complicaçõesRESUMO
PURPOSE: Questions remain about whether moderately hypofractionated whole-breast irradiation is appropriate for patients with triple-negative breast cancer. METHODS AND MATERIALS: Using the prospective database of a multicenter, collaborative quality improvement consortium, we identified patients with node-negative, triple-negative breast cancer who received whole-breast irradiation with either moderate hypofractionation or conventional fractionation. Using inverse probability of treatment weighting (IPTW), we compared outcomes using the Kaplan-Meier product-limit estimation method with Cox regression models estimating the hazard ratio for time-to-event endpoints between groups. RESULTS: The sample included 538 patients treated at 18 centers in 1 state in the United States, of whom 307 received conventionally fractionated whole-breast irradiation and 231 received moderately hypofractionated whole-breast irradiation. The median follow-up time was 5.0 years (95% confidence interval [CI], 4.77-5.15 years). The 5-year IPTW estimates for freedom from local recurrence were 93.6% (95% CI, 87.8%-96.7%) in the moderate hypofractionation group and 94.4% (95% CI, 90.3%-96.8%) in the conventional fractionation group. The hazard ratio was 1.05 (95% CI, 0.51-2.17; P = .89). The 5-year IPTW estimates for recurrence-free survival were 87.8% (95% CI, 81.0%-92.4%) in the moderate hypofractionation group and 88.4% (95% CI 83.2%-92.1%) in the conventional fractionation group. The hazard ratio was 1.02 (95% CI, 0.62-1.67; P = .95). The 5-year IPTW estimates for overall survival were 96.6% (95% CI, 92.0%-98.5%) in the moderate hypofractionation group and 93.4% (95% CI, 88.7%-96.1%) in the conventional fractionation group. The hazard ratio was 0.65 (95% CI, 0.30-1.42; P = .28). CONCLUSIONS: Analysis of outcomes in this large observational cohort of patients with triple-negative, node-negative breast cancer treated with whole-breast irradiation revealed no differences by dose fractionation. This adds evidence to support the use of moderate hypofractionation in patients with triple-negative disease.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Estudos de Coortes , Fracionamento da Dose de Radiação , Feminino , Humanos , Hipofracionamento da Dose de Radiação , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/radioterapiaRESUMO
BACKGROUND: Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a master transcriptional regulator of the protective cellular response to oxidative stress. Sulforaphane is a Nrf2 activator but is unstable at ambient temperature. SFX-01 is a novel composition comprised of synthetic sulforaphane stabilised within the pocket of an α-cyclodextrin complex. Here we tested the efficacy of SFX-01 in murine relapsing experimental autoimmune encephalomyelitis (EAE), a model of relapsing-remitting MS (RRMS). METHODS: Relapsing EAE was induced in female SJL mice using immunization against PLP139-151. In the therapeutic experiment, the aim was to model initiation of treatment after diagnosis in RRMS, so treatment was started at day 19, one day prior to the expected relapse onset. In the prophylactic experiment, mice were treated from the time of immunization and followed for three weeks. RESULTS: SFX-01 reduced residual disability in both experiments. Most of this effect was mediated by a decrease in maximum severity of relapses and improved recovery during follow-up. Histological examination of the spinal cord was consistent with the clinical findings, with improvement in demyelination and the number of apoptotic cells, but not inflammatory cell infiltration, compared to the vehicle group. CONCLUSIONS: SFX-01 is efficacious in EAE. In first-in-man and phase II clinical trials for other indications, SFX-01 was found to be well-tolerated. A trial comparing BG-12 and SFX-01 would address whether SFX-01 can offer RRMS patients a better option with respect to efficacy and tolerability.
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Anticarcinógenos/uso terapêutico , Encefalomielite Autoimune Experimental/complicações , Encefalomielite Autoimune Experimental/tratamento farmacológico , Isotiocianatos/uso terapêutico , Resultado do Tratamento , Animais , Avaliação da Deficiência , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Encefalomielite Autoimune Experimental/induzido quimicamente , Feminino , Adjuvante de Freund/toxicidade , Estimativa de Kaplan-Meier , Camundongos , Proteína Proteolipídica de Mielina/toxicidade , Fragmentos de Peptídeos/toxicidade , Sulfóxidos , Fatores de TempoRESUMO
The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target specificity, pharmacodynamic properties, efficacy and safety remain.
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Tratamento Farmacológico , Proteína 1 Associada a ECH Semelhante a Kelch/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Ativação Metabólica , Animais , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidoresRESUMO
Myricetin (MYR) is a natural compound that has been investigated as a chemopreventative agent. MYR has been shown to suppresses ultraviolet B (UVB)-induced cyclooxygenase-2 (COX-2) protein expression and reduce the incidence of UVB-induced skin tumors in mice. Despite MYR's promise as a therapeutic agent, minimal information is available to guide the progression of formulations designed for future drug development. Here, data is presented describing the solid-state and solution characterization of MYR. Investigation into the solid-state properties of MYR identified four different crystal forms, two hydrates (MYR I and MYR II) and two metastable forms (MYR IA and MYR IIA). From solubility studies, it was evident that all forms are very insoluble (<5 µg/ml) in pure water. MYR I was found to be the most stable form at 23, 35, and 56°C. Stability determination indicated that MYR undergoes rapid apparent first-order degradation under basic pH conditions, and that degradation was influenced by buffer species. Apparent first-order degradation was also seen when MYR was introduced to an oxidizing solution. Improved stability was achieved after introducing 0.1% antioxidants to the solution. MYR was found to have good stability following exposure to ultraviolet radiation (UVR), which is a consideration for topical applications. Finally, a partitioning study indicated that MYR possess a log P of 2.94 which, along with its solid-state properties, contributes to its poor aqueous solubility. Both the solid-state properties and solution stability of MYR are important to consider when developing future formulations.
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Flavonoides/química , Soluções Farmacêuticas/química , Química Farmacêutica/métodos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Solubilidade , Raios Ultravioleta , Água/químicaRESUMO
CONTEXT: Sulforaphane (SFN) is a natural compound that has been investigated as a chemopreventive agent. SFN has been shown to inhibit the activator-protein-1 (AP-1) transcription factor and may be effective for inhibition of ultraviolet (UV) induced skin carcinogenesis. This study was designed to investigate the stability of SFN as a function of pH, temperature and in various solvents and formulations. MATERIALS AND METHODS: Stability was analyzed using high-performance liquid chromatography. A potential lead formulation was identified and evaluated in vivo. RESULTS: SFN was determined to undergo apparent first-order degradation kinetics for the conditions explored. It was observed that SFN undergoes base catalyzed degradation. Buffer species and solvent type impacts stability as well. SFN was found to be very sensitive to temperature with degradation rate changing by a factor of nearly 3.1 for every 10 °C change in temperature (at pH 4.0). SFN completely degraded after 30 days in a conventional pharmaceutical cream formulation. Improved stability was observed in organic formulation components. Stability studies were conducted on two nonaqueous topical formulations: a polyethylene glycol (PEG) ointment base and an organic oleaginous base. CONCLUSION: Topically applied SFN in the PEG base formulation significantly reduced AP-1 activation after UV stimulation in the skin of a transgenic mouse model, indicating that SFN in this formulation retains efficacy in vivo.
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Anticarcinógenos/administração & dosagem , Isotiocianatos/administração & dosagem , Solventes/química , Fator de Transcrição AP-1/antagonistas & inibidores , Administração Cutânea , Animais , Anticarcinógenos/química , Anticarcinógenos/farmacologia , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Feminino , Concentração de Íons de Hidrogênio , Isotiocianatos/química , Isotiocianatos/farmacologia , Cinética , Camundongos , Camundongos Transgênicos , Polietilenoglicóis/química , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Sulfóxidos , Temperatura , Fatores de Tempo , Raios Ultravioleta/efeitos adversosRESUMO
BACKGROUND: We report the first application of Gamma Knife radiosurgery (GKR) for recurrent glossopharyngeal neuralgia (GN) after microvascular decompression (MVD). The patient is a 51-year-old male with left-sided GN. He underwent MVD and did well for almost 4 years. Later on, the patient started to experience recurrent intolerable throat pain, frequently 10/10 in intensity. Based on the application of radiosurgery for trigeminal neuralgia, GKR was offered to the patient. METHODS: After careful identification of the nerve with the assistance of a neuroradiologist, we targeted the nerve root complex, which is the cisternal portion of the nerve, using the Coherent Oscillatory State Acquisition for the Manipulation of Image Contrast (COSMIC) pulse sequence with contiguous 1-mm slices obtained by an 1.5 Tesla MRI. The radiosurgery was planned utilizing the Leksell Gamma Plan version 8.1. A single shot with a 4-mm collimator was used to deliver 80 Gy to the 100% isodose line. RESULTS: Four weeks after the treatment, the patient began to notice significant pain relief. At the 12-month follow-up, the patient's pain, which was intolerable prior to radiosurgery, was mild and occasional. CONCLUSION: GKR, which is now widely used for refractory trigeminal neuralgia, can be considered for refractory or recurrent GN. With a multidisciplinary approach and advanced neuroimaging, GKR is feasible for GN after MVD, despite the shortness of the intracranial cisternal nerve portion. Further studies are necessary to establish the role of GKR for refractory GN after MVD; however, given its rarity and the lack of experience with GKR for this condition, retrospective studies with dozens of patients are almost impossible at this time.
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Doenças do Nervo Glossofaríngeo/cirurgia , Cirurgia de Descompressão Microvascular , Radiocirurgia/instrumentação , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: This study was carried out to report our experience using intensity-modulated radiotherapy (IMRT) with daily image-guided radiotherapy (IGRT) for tumors involving the base of skull. METHODS: In all, 100 patients were prospectively treated with IMRT to a median dose of 64 Gy (range, 45-70 Gy). Daily helical megavoltage computed tomography (MVCT) scans were obtained as part of an IGRT registration protocol for patient alignment. RESULTS: The 2-year local-regional control was 91%. A total of 3295 daily MVCT scans were obtained. The mean shift to account for interfraction motion was 1.18 ± 1.75 mm, 1.81 ± 1.34 mm, and 1.33 ± 1.19 mm for the medial-lateral (ML), superior-inferior (SI), and anterior-posterior (AP) directions, respectively. Pretreatment shifts of >3 mm occurred in 10%, 26%, and 18%, in the ML, SI, and AP directions, respectively. CONCLUSIONS: The feasibility and efficacy of daily IGRT as a complement to IMRT for skull base were demonstrated.
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Radiografia Intervencionista , Radioterapia de Intensidade Modulada , Neoplasias da Base do Crânio/diagnóstico por imagem , Neoplasias da Base do Crânio/radioterapia , Tomografia Computadorizada Espiral , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Humanos , Pessoa de Meia-Idade , Posicionamento do Paciente , Estudos Prospectivos , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Neoplasias da Base do Crânio/mortalidadeRESUMO
A summary is provided of presentations and discussions at the NASA Radiation Biomarker Workshop held September 27-28, 2007 at NASA Ames Research Center in Mountain View, CA. Invited speakers were distinguished scientists representing key sectors of the radiation research community. Speakers addressed recent developments in the biomarker and biotechnology fields that may provide new opportunities for health-related assessment of radiation-exposed individuals, including those exposed during long-duration space travel. Topics discussed included the space radiation environment, biomarkers of radiation sensitivity and individual susceptibility, molecular signatures of low-dose responses, multivariate analysis of gene expression, biomarkers in biodefense, biomarkers in radiation oncology, biomarkers and triage after large-scale radiological incidents, integrated and multiple biomarker approaches, advances in whole-genome tiling arrays, advances in mass spectrometry proteomics, radiation biodosimetry for estimation of cancer risk in a rat skin model, and confounding factors. A summary of conclusions is provided at the end of the report.
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Bioensaio/métodos , Biomarcadores/análise , Educação , Expressão Gênica/efeitos da radiação , Radiobiologia/métodos , Radiometria/métodos , Animais , Humanos , Doses de RadiaçãoRESUMO
OBJECTIVE: This review provides an update on the management of painful bone metastases, with an emphasis on radionuclide therapy, and introduces oligometastases and quantitative imaging evaluations for clinical trials. METHODS: The current use of radionuclides, alone and in combination with chemotherapy and radiation therapy for painful bone metastases, is discussed, including toxicity, cost and overall outcomes. RESULTS: Radionuclide therapy is shown to be a useful and cost-effective means of alleviating bone pain in metastatic disease and may be more effective when combined with chemotherapy, bisphosphonates and radiation therapy. Early use of radionuclides in pain therapy may limit cancer progression by inhibiting oligometastases development. Thus, radionuclides can significantly decrease patient morbidity, prolong patient survival, and may decrease the occurrence of new bone metastases. CONCLUSION: Palliative pain therapy is critical for effectively managing bone metastases, with treatment options including analgesics, external beam radiotherapy, chemotherapy and radionuclides. Radionuclide therapy is underutilized. Recent studies using radionuclides with chemotherapy and bisphosponates, or using newer radionuclides or combinations of radionuclides and treatment paradigms (e.g., higher activities, repetitive or cyclic administration, chemo sensitization, chemo supplementation), are encouraging. A comprehensive, inter-disciplinary clinical approach is needed. Clinical collaborations will optimize radionuclide therapy for pain palliation and increase awareness of its benefits.