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BACKGROUND: Degenerative cervical myelopathy (DCM) is a progressive chronic spinal cord injury estimated to affect 1 in 50 adults. Without standardised guidance, clinical research studies have selected outcomes at their discretion, often underrepresenting the disease and limiting comparability between studies. Utilising a standard minimum data set formed via multi-stakeholder consensus can address these issues. This combines processes to define a core outcome set (COS)-a list of key outcomes-and core data elements (CDEs), a list of key sampling characteristics required to interpret the outcomes. Further "how" these outcomes should be measured and/or reported is then defined in a core measurement set (CMS). This can include a recommendation of a standardised time point at which outcome data should be reported. This study defines a COS, CDE, and CMS for DCM research. METHODS AND FINDINGS: A minimum data set was developed using a series of modified Delphi processes. Phase 1 involved the setup of an international DCM stakeholder group. Phase 2 involved the development of a longlist of outcomes, data elements, and formation into domains. Phase 3 prioritised the outcomes and CDEs using a two-stage Delphi process. Phase 4 determined the final DCM minimal data set using a consensus meeting. Using the COS, Phase 5 finalised definitions of the measurement construct for each outcome. In Phase 6, a systematic review of the literature was performed, to scope and define the psychometric properties of measurement tools. Phase 7 used a modified Delphi process to inform the short-listing of candidate measurement tools. The final measurement set was then formed through a consensus meeting (Phase 8). To support implementation, the data set was then integrated into template clinical research forms (CRFs) for use in future clinical trials (Phase 9). In total, 28 outcomes and 6 domains (Pain, Neurological Function, Life Impact, Radiology, Economic Impact, and Adverse Events) were entered into the final COS. Thirty two outcomes and 4 domains (Individual, Disease, Investigation, and Intervention) were entered into the final CDE. Finally, 4 outcome instruments (mJOA, NDI, SF-36v2, and SAVES2) were identified for the CMS, with a recommendation for trials evaluating outcomes after surgery, to include baseline measurement and at 6 months from surgery. CONCLUSIONS: The AO Spine RECODE-DCM has produced a minimum data set for use in DCM clinical trials today. These are available at https://myelopathy.org/minimum-dataset/. While it is anticipated the CDE and COS have strong and durable relevance, it is acknowledged that new measurement tools, alongside an increasing transition to study patients not undergoing surgery, may necessitate updates and adaptation, particularly with respect to the CMS.
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Upper eyelid surgery is a common procedure performed by a variety of subspecialists including facial plastic surgeons, oculoplastic surgeons, general otolaryngologists, and plastic surgeons. Traditionally, a skin incision is marked in the preoperative setting to allow for an excision that eliminates upper eyelid hooding while preventing lagophthalmos. Many different methodologies have been proposed to maximize results and minimize complications. In this article, the authors propose a unique way to safely and effectively address dermatochalasis. The pinch technique allows for an accurate assessment of excess skin and provides a method that requires less operative time than traditional techniques. The use of both local anesthetic with epinephrine and hyaluronidase helps achieve the appropriate plane and attain better hemostasis. Importantly, the presented technique allows for reassessment and revision of the amount of skin excision before incision creation. It is a useful methodology for any surgeon performing upper lid blepharoplasty.
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Blefaroplastia , Doenças Palpebrais , Pálpebras/cirurgia , Face , Humanos , RejuvenescimentoRESUMO
BACKGROUND: Blinatumomab, a bispecific monoclonal antibody construct that enables CD3-positive T cells to recognize and eliminate CD19-positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B-cell precursor ALL on the basis of single-group trials that showed efficacy and manageable toxic effects. METHODS: In this multi-institutional phase 3 trial, we randomly assigned adults with heavily pretreated B-cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard-of-care chemotherapy. The primary end point was overall survival. RESULTS: Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group. CONCLUSIONS: Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B-cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167 .).
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Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Biespecíficos/efeitos adversos , Antineoplásicos/efeitos adversos , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Sepse/induzido quimicamente , Transplante de Células-Tronco , Análise de Sobrevida , Transplante Homólogo , Adulto JovemRESUMO
In the phase 3 TOWER study, blinatumomab significantly improved overall survival in adults with relapsed or refractory (R/R) Philadelphia chromosome-negative (Ph-) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) relative to standard-of-care chemotherapy. A secondary objective of this study was to assess the impact of blinatumomab on health-related quality of life (HRQL) as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). This analysis included the 342 of 405 randomized patients for whom baseline and ≥1 postbaseline result were available in any EORTC multi-item scale or single-item measure. In general, patients receiving blinatumomab (n = 247) reported better posttreatment HRQL across all QLQ-C30 subscales, based on descriptive mean change from baseline, than did those receiving chemotherapy (n = 95). The hazard ratios for time to deterioration (TTD) of ≥10 points from baseline in HRQL or death ranged from 0.42 to 0.81 in favor of blinatumomab, with the upper bounds of the 95% confidence interval <1.0 across all measures, except insomnia, social functioning, and financial difficulties; sensitivity analysis of TTD in HRQL without the event of death were consistent with these findings. When treatment effect over time was tested using a restricted maximum likelihood-based mixed model for repeated measures analysis, P < .05 was reached for blinatumomab vs chemotherapy for all subscale measures except financial difficulties. The clinically meaningful benefits in overall survival and HRQL support the clinical value of blinatumomab in patients with R/R Ph- BCP-ALL when compared with chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT02013167.
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Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Qualidade de Vida , Adulto , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Estudos Prospectivos , Análise de SobrevidaRESUMO
Phosphatidylinositol-4,5-bisphosphate (PIP2) is an important signaling lipid in eukaryotic cell plasma membranes, playing an essential role in diverse cellular processes. The headgroup of PIP2 is highly negatively charged, and this lipid displays a high critical micellar concentration compared to housekeeping phospholipid analogs. Given the crucial role of PIP2, it is imperative to study its localization, interaction with proteins, and membrane-shaping properties. Biomimetic membranes have served extensively to elucidate structural and functional aspects of cell membranes including protein-lipid and lipid-lipid interactions, as well as membrane mechanics. Incorporation of PIP2 into biomimetic membranes, however, has at times resulted in discrepant findings described in the literature. With the goal to elucidate the mechanical consequences of PIP2 incorporation, we studied the desorption of PIP2 from biomimetic giant unilamellar vesicles by means of a fluorescent marker. A decrease in fluorescence intensity with the age of the vesicles suggested that PIP2 lipids were being desorbed from the outer leaflet of the membrane. To evaluate whether this desorption was asymmetric, the vesicles were systematically diluted. This resulted in an increase in the number of internally tubulated vesicles within minutes after dilution, suggesting that the desorption was asymmetric and also generated membrane curvature. By means of a saturated chain homolog of PIP2, we showed that the fast desorption of PIP2 is facilitated by presence of an arachidonic lipid tail and is possibly due to its oxidation. Through measurements of the pulling force of membrane tethers, we quantified the effect of this asymmetric desorption on the spontaneous membrane curvature. Furthermore, we found that the spontaneous curvature could be modulated by externally increasing the concentration of PIP2 micelles. Given that the local concentration of PIP2 in biological membranes is variable, spontaneous curvature generated by PIP2 may affect the formation of highly curved structures that can serve as initiators for signaling events.
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Membrana Celular/metabolismo , Fosfatidilinositol 4,5-Difosfato/metabolismo , Animais , Humanos , Micelas , SuínosRESUMO
Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation (alloHSCT) have a poor prognosis, and alternative therapies are needed for this patient population. Blinatumomab, a bispecific T cell engager immunotherapy, was evaluated in an open-label, single-arm, phase II study of adults with R/R Philadelphia chromosome-negative B cell precursor ALL and resulted in a rate of complete remission (CR) or CR with partial hematologic recovery of peripheral blood counts (CRh) of 43% within 2 treatment cycles. We conducted an exploratory analysis to determine the efficacy and safety of blinatumomab in 64 patients who had relapsed following alloHSCT before enrollment in the phase II study. Forty-five percent of the patients (29 of 64) achieved a CR/CRh within the first 2 cycles of treatment, 22 of whom had a minimal residual disease (MRD) response (including 19 with a complete MRD response). After 1 year and 3 years of follow-up, the median relapse-free survival was 7.4 months for patients who achieved CR/CRh in the first 2 cycles, and the median overall survival was 8.5 months; overall survival rate (Kaplan-Meier estimate) was 36% at 1 year and 18% at 3 years. Grade 3 and 4 adverse events were reported in 20 patients (31%) and 28 patients (44%), respectively, with grade 3 and 4 neurologic events in 8 and 2 patients, respectively, and grade 3 cytokine release syndrome in 2 patients. Eight patients had fatal adverse events, including 5 due to infections. Seven patients had grade ≤ 3 graft-versus-host disease during the study, none of which resulted in the discontinuation of blinatumomab or hospitalization. Our data suggest that blinatumomab is an effective salvage therapy in this patient population.
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Anticorpos Biespecíficos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Recidiva , Indução de Remissão , Taxa de SobrevidaRESUMO
Neurologic events (NEs) have been reported during treatment with blinatumomab, a bispecific T cell engager (BiTE®) construct. We evaluated the occurrence, severity, and management of NEs; the relationship between NEs and blinatumomab dose; and the potential clinical risk factors in an open-label, single-arm, phase 2 study (N = 189). Patients had Philadelphia chromosome-negative, relapsed/refractory acute lymphoblastic leukemia (ALL) and ≥ 10% bone marrow blasts. The relationship between blinatumomab exposure and NE incidence and severity was assessed. Clinical risk factors for NEs were assessed in a post hoc multivariate analysis. Overall, 98 patients (52%) experienced NEs: most frequently, dizziness, tremor, confusional state, and encephalopathy. NEs occurred predominantly during cycle 1 (median onset, 9 days) and were usually grades 1 or 2. Grade ≥ 3 NEs (13-17% incidence), serious NEs (16-19% incidence), and recurring NEs were managed with infusion interruptions or dexamethasone treatment. The incidence of NEs increased with increasing blinatumomab exposure at a given dose, but exposure appeared unrelated to NE severity. NEs were more frequent in patients ≥ 65 years than < 65 years (72 vs 49%). In a multivariate analysis, race other than white (hazard ratio [HR], 2.11; P = 0.009), > 2 prior salvage therapies (HR, 2.48; P = 0.006), and prior NEs (HR, 1.65; P = 0.020) were risk factors for time to first on-study NE. Although the mechanism underlying NEs associated with blinatumomab treatment in patients with relapsed/refractory ALL remains unclear, NEs tended to occur early during treatment and were often resolved by interrupting treatment and with dexamethasone. Additional research is warranted to investigate the risk factors for NEs.
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Anticorpos Biespecíficos , Crise Blástica , Dexametasona/administração & dosagem , Doenças do Sistema Nervoso , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Adulto , Fatores Etários , Idoso , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Crise Blástica/tratamento farmacológico , Crise Blástica/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Recidiva , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Multi-agent chemotherapy is the standard treatment for most B cell malignancies. Since chemotherapy can be associated with significant toxicity and since relapses resistant to chemotherapy often develop, new therapies are needed. Blinatumomab (AMG 103 or MT103) is a late-stage candidate in clinical development, which belongs to a novel class of antibody constructs termed bi-specific T cell engager antibodies. This antibody construct has dual specificity for CD19 and CD3 and can re-direct polyclonal cytotoxic T lymphocytes toward the tumor. This review focuses on the pre-clinical and clinical development of blinatumomab as a powerful new tool in the treatment of B cell malignancies.
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Anticorpos Biespecíficos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia/métodos , Linfoma de Células B/terapia , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Complexo CD3/imunologia , Ensaios Clínicos como Assunto , Citotoxicidade Imunológica/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Ativação Linfocitária/efeitos dos fármacos , Linfoma de Células B/imunologia , Terapia de Alvo MolecularRESUMO
OBJECTIVES/HYPOTHESIS: Systemic glucocorticoids (GC)s are employed to treat various voice disorders. However, GCs have varying pharmacodynamic properties with adverse effects ranging from changes in epithelial integrity, skeletal muscle catabolism, and altered body weight. We sought to characterize the acute temporal effects of systemic dexamethasone and methylprednisolone on vocal fold (VF) epithelial glucocorticoid receptor (GR) nuclear translocation, epithelial tight junction (ZO-1) expression, thyroarytenoid (TA) muscle fiber morphology, and body weight using an established pre-clinical model. We hypothesized dexamethasone and methylprednisolone will elicit changes in VF epithelial GR nuclear translocation, epithelial ZO-1 expression, TA muscle morphology, and body weight compared to placebo-treated controls. METHODS: Forty-five New Zealand white rabbits received intramuscular injections of methylprednisolone (4.5 mg; n = 15), dexamethasone (450 µg; n = 15), or volume matched saline (n = 15) into the iliocostalis/longissimus muscle for 6 consecutive days. Vocal folds from 5 rabbits from each treatment group were harvested at 1-, 3-, or 7 days following the final injection and subjected to immunohistochemistry for ZO-1 and GR as well as TA muscle fiber cross-sectional area (CSA) measures. RESULTS: Dexamethasone increased epithelial GR nuclear translocation and ZO-1 expression 1-day following injections compared to methylprednisolone (P = .024; P = .012). Dexamethasone and methylprednisolone increased TA CSA 1-day following injections (P = .011). Methylprednisolone decreased body weight 7 days following injections compared to controls (P = .004). CONCLUSIONS: Systemic dexamethasone may more efficiently activate GR in the VF epithelium with a lower risk of body weight loss, suggesting a role for more refined approaches to GC selection for laryngeal pathology.
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Glucocorticoides , Prega Vocal , Animais , Coelhos , Peso Corporal , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Injeções Intramusculares , Músculos Laríngeos , Metilprednisolona/farmacologia , Prega Vocal/efeitos dos fármacos , Prega Vocal/patologiaRESUMO
Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of â¼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.
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Neoplasias Pulmonares , Mutação Puntual , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Humanos , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Animais , Camundongos , Linhagem Celular TumoralRESUMO
OBJECTIVES: Functional outcomes following microflap surgery for vocal fold pathology are favorable. Although the stratified squamous epithelium appears to heal rapidly, persistent physiologic tissue alterations are likely. We sought to elucidate key biochemical processes including recruitment of immune cells, regulation of cellular junction proteins, and long-term alterations to epithelial tissue permeability following microflap with an eye toward enhanced clinical outcomes. METHODS: Forty New Zealand rabbits were assigned to eight groups (n = 5/group): no-injury control or bilateral microflap with survival for 0 h, 12 h, 1 day, 3 days, 7 days, 30 days, and 60 days post-microflap. The epithelium was dissected from one vocal fold and transepithelial resistance was quantified. The contralateral fold was subjected to transmission electron microscopy. Images were evaluated by a blinded rater and paracellular space dilation was quantified using ImageJ. Immune cell infiltration was evaluated and recorded qualitatively. RESULTS: Increased innate immune response was observed 12 h as well as 7 and 30 days after microflap. At 60 days following injury, decreased epithelial resistance was observed. Paracellular spaces were dilated at all time-points following injury. CONCLUSIONS: The vocal fold epithelium was significantly altered at 60 days following microflap. The implications for this tissue phenotype are unclear. However, compromised epithelial barrier function is implicated in various diseases and may increase the risk of subsequent injury. LEVEL OF EVIDENCE: NA Laryngoscope, 133:350-356, 2023.
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Prega Vocal , Cicatrização , Animais , Coelhos , Prega Vocal/patologia , EpitélioRESUMO
OBJECTIVES/HYPOTHESIS: Glucocorticoids (GC)s are commonly employed to treat vocal fold (VF) pathologies. However, VF atrophy has been associated with intracordal GC injections. Dexamethasone-induced skeletal muscle atrophy is well-documented in other tissues and believed to be mediated by increased muscle proteolysis via upregulation of Muscle Ring Finger (MuRF)-1 and Atrogin-1. Mechanisms of dexamethasone-mediated VF atrophy have not been described. This pilot study employed in vitro and in vivo models to investigate the effects of dexamethasone on VF epithelium, thyroarytenoid (TA) muscle, and TA-derived myoblasts. We hypothesized that dexamethasone will increase atrophy-associated gene expression in TA muscle and myoblasts and decrease TA muscle fiber size and epithelial thickness. STUDY DESIGN: In vitro, pre-clinical. METHODS: TA myoblasts were isolated from a female Sprague-Dawley rat and treated with 1 µM dexamethasone for 24-h. In vivo, 15 New Zealand white rabbits were randomly assigned to three treatment groups: (1) bilateral intracordal injection of 40 µL dexamethasone (10 mg/ml; n = 5), (2) volume-matched saline (n = 5), and (3) untreated controls (n = 5). Larynges were harvested 7-days post-injection. Across in vivo and in vitro experimentation, MuRF-1 and Atrogin-1 mRNA expression were measured via RT-qPCR. TA muscle fiber cross-sectional area (CSA) and epithelial thickness were also quantified in vivo. RESULTS: Dexamethasone increased MuRF-1 gene expression in TA myoblasts. Dexamethasone injection, however, did not alter atrophy-associated gene expression, TA CSA, or epithelial thickness in vivo. CONCLUSION: Dexamethasone increased atrogene expression in TA myoblasts, providing foundational insight into GC induced atrophic gene transcription. Repeated dexamethasone injections may be required to elicit atrophy in vivo. LEVEL OF EVIDENCE: NA Laryngoscope, 133:2264-2270, 2023.
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Doenças da Laringe , Prega Vocal , Feminino , Ratos , Animais , Coelhos , Projetos Piloto , Prega Vocal/patologia , Ratos Sprague-Dawley , Glucocorticoides , Atrofia Muscular/tratamento farmacológico , Doenças da Laringe/patologia , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Músculo Esquelético/metabolismoRESUMO
Facial trauma accounts of 7% to 10% of emergency department visits in the United States every year. The management of facial soft tissue trauma is an essential skill for the facial plastic surgeon. Understanding preoperative evaluation, repair/management of concomitant injuries, postoperative care, and scar treatment help the facial plastic surgeon obtain the best functional and aesthetic results for the patient. Treating the face by subunit and avoiding common pitfalls is the key to achieving optimal results. This article can serve as a basis for surgical pearls and considerations when evaluating and repairing facial soft tissue trauma.
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Traumatismos Faciais , Procedimentos de Cirurgia Plástica , Lesões dos Tecidos Moles , Cicatriz/cirurgia , Traumatismos Faciais/cirurgia , Hematoma/etiologia , Hematoma/cirurgia , Humanos , Lesões dos Tecidos Moles/cirurgiaRESUMO
BACKGROUND AND OBJECTIVES: Otalgia can be primary/otogenic or secondary as a referred pain from another site, which can be difficult to establish owing to various causes and the complex innervation of the ear. In our center, we observed a large group of patients with unexplained otalgia that had a higher prevalence of migraine. We hypothesized that migraine may cause secondary otalgia. This study then aimed to determine the prevalence of migraine-associated otalgia and evaluate the efficacy of migraine treatment. SUBJECTS AND METHODS: This 2-year retrospective study was conducted at a busy otology clinic. Patients were identified using diagnostic codes corresponding to otalgia. The prevalence of migraine-associated otalgia was determined, and the efficacy of migraine treatment was evaluated in these patients. The interventions included prophylactic and abortive migraine treatments. Statistical analysis was conducted to compare between the pre- and post-treatment symptoms. RESULTS: A total of 208 patients with otalgia were identified. Sixty-four out of ninety patients with unexplained otalgia met the criteria for migraine; of them, 30 patients had an adequate follow-up and were thus included in the evaluation of treatment efficacy. Otalgia improved in 87% of the patients who received migraine treatment. After treatment, the mean pain score and headache frequency significantly decreased from 7 to 2 and from 27 to 9 days per month, respectively (p<0.001). CONCLUSIONS: Migraine should be considered as a source of secondary otalgia, and patients should receive treatment as they often respond to migraine treatment.
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Microbial interactions in harmful algal bloom (HAB) communities have been examined in marine systems, but are poorly studied in fresh waters. To investigate HAB-microbe interactions, we isolated bacteria with close associations to bloom-forming cyanobacteria, Microcystis spp., during a 2017 bloom in the western basin of Lake Erie. The genomes of five isolates (Exiguobacterium sp. JMULE1, Enterobacter sp. JMULE2, Deinococcus sp. JMULE3, Paenibacillus sp. JMULE4, and Acidovorax sp. JMULE5.) were sequenced on a PacBio Sequel system. These genomes ranged in size from 3.1 Mbp (Exiguobacterium sp. JMULE1) to 5.7 Mbp (Enterobacter sp. JMULE2). The genomes were analyzed for genes relating to critical metabolic functions, including nitrogen reduction and carbon utilization. All five of the sequenced genomes contained genes that could be used in potential signaling and nutrient exchange between the bacteria and cyanobacteria such as Microcystis. Gene expression signatures of algal-derived carbon utilization for two isolates were identified in Microcystis blooms in Lake Erie and Lake Tai (Taihu) at low levels, suggesting these organisms are active and may have a functional role during Microcystis blooms in aggregates, but were largely missing from whole water samples. These findings build on the growing evidence that the bacterial microbiome associated with bloom-forming algae have the functional potential to contribute to nutrient exchange within bloom communities and interact with important bloom formers like Microcystis.
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DNA Bacteriano/genética , Genoma Bacteriano , Proliferação Nociva de Algas/fisiologia , Metagenoma , Microcystis/genética , Percepção de Quorum/genética , Carbono/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Lagos/microbiologia , Microbiota/genética , Microcystis/classificação , Microcystis/metabolismo , Nitrogênio/metabolismo , Oxirredução , Filogenia , Transdução de Sinais , Estados UnidosRESUMO
The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.
Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Desenvolvimento de Medicamentos/organização & administração , Colaboração Intersetorial , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinase do Linfoma Anaplásico/genética , Criança , Ensaios Clínicos como Assunto , Indústria Farmacêutica/organização & administração , União Europeia/organização & administração , Humanos , Cooperação Internacional , Oncologia/organização & administração , Neoplasias/genética , Pediatria/organização & administração , Inibidores de Proteínas Quinases/farmacologia , Estados Unidos , United States Food and Drug Administration/organização & administraçãoRESUMO
OBJECTIVE: To define critical elements that contribute to successful parathyroidectomy based on a high-volume single-surgeon experience and explore learning curve characteristics. STUDY DESIGN: Systematic analysis of prospectively maintained quality assurance database. SETTING: Academic tertiary care endocrine surgery practice. SUBJECTS AND METHODS: In total, 4737 consecutive patients who underwent thyroid or parathyroid surgery from 2004 to 2020 were identified. Demographic data acquisition was undertaken on a subset of these patients who had initial surgery for primary hyperparathyroidism during the academic years 2005 to 2018. Patients with renal or syndromic hyperparathyroidism and those undergoing reoperative surgery were excluded. RESULTS: From 1710 patients who underwent parathyroid surgery, 1082 met inclusion criteria in order to focus on a homogeneous data set. These patients had a mean age of 60.1 ± 12.5 years and 76.4% were female. The overall cure rate was 98.3%, reflecting a success rate that increased from 95.5% during the first 200 cases to 99.7% over the final 300 cases. The complication rate was 1.7%. Over 2 decades, the patient phenotype evolved toward milder disease and smaller adenomas. A learning curve of 200 cases was required to become a proficient parathyroid surgeon; to achieve exceptional results required several hundred additional cases. Parathyroid surgery represents a higher proportion of an endocrine surgery practice than previously (54.0% in 2019 compared with 25.5% in 2004). CONCLUSION: A focused practice dedicated to endocrine surgery yields surgical volumes exceeding 500 cases annually. There has been a steady shift toward parathyroid surgery. A lengthy learning curve can be shortened by pursuit of several specific strategies that are outlined in detail.
Assuntos
Adenoma/cirurgia , Hiperparatireoidismo Primário/cirurgia , Glândulas Paratireoides/cirurgia , Neoplasias das Paratireoides/cirurgia , Paratireoidectomia , Idoso , Feminino , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Glândulas Paratireoides/patologia , Paratireoidectomia/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Tireoidectomia , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: Facial nerve stimulation (FNS) is a complication of cochlear implantation (CI). This study compared the thickness and density of the bone separating the upper basal turn of the cochlea (UBTC) and the labyrinthine segment of the facial nerve (LSFN) on preoperative computed tomography (CT) in patients with and without FNS after CI. SUBJECTS AND METHODS: Adult patients who underwent CI from January 2011 to February 2017 with preoperative CT at a tertiary referral hospital were considered for this retrospective case-control study. Patients were divided into two groups: with FNS (n=4) and without FNS (n=53). The density and thickness of the bone between the LSFN and UBTC were measured on preoperative CT. Charts were reviewed for other parameters. RESULTS: A statistically significant difference was seen in the thickness (p=0.007) but not in the density (p=0.125) of the bone between the UBTC and LSFN. Four patients had FNS at the mid-range electrode arrays, and one of them additionally had FNS at the basal arrays. CONCLUSIONS: Decreased thickness of the bone between the UBTC and LSFN can explain postoperative FNS, confirming the histologic and radiologic findings in previous studies, which indicated that the thickness of the temporal bone between the LSFN and UBTC is less in patients who experience FNS. While the density in this region was also less, it was not statistically significant.
RESUMO
INTRODUCTION: In the absence of head-to-head trials, this analysis aimed to provide a fair indirect comparison of the efficacy between blinatumomab and inotuzumab ozogamicin (InO), two treatments for adult patients with relapsed or refractory acute lymphoblastic leukemia (R/R ALL) who received no more than one prior salvage therapy, by adjusting for cross-trial differences. METHODS: Patient-level data from the Phase 3 blinatumomab trial TOWER and published aggregated data from the Phase 3 InO trial INO-VATE-ALL were used to conduct matching-adjusted indirect comparisons. Patients with 2+ prior salvage therapies from TOWER were excluded because such patients were not included in INO-VATE-ALL. To ensure balance in the remaining patients, baseline characteristics for the TOWER patients were weighted to match the average baseline characteristics in INO-VATE-ALL, including sex, age, race, performance status, bone marrow blast, previous salvage therapy, previous allogeneic transplantation, complete remission with complete hematologic recovery (CR) to most recent induction therapy, and duration of first remission. Overall survival (OS), including median and restricted mean survival time (RMST) at 12 and 20.7 months, and CR were estimated and compared. RESULTS: A total of 310 patients in TOWER were included (blinatumomab, n = 203; standard of care chemotherapy, n = 107). After matching the listed baseline characteristics, the median OS was 9.3 months for blinatumomab and 7.7 months for InO (weighted log-rank test p = 0.4). The relative RMST at 12 months was 1.6 months longer for blinatumomab than for InO [95% CI (0.1, 3.2); p = 0.04]; at 20.7 months the RMST was not significantly different. The CR rates were similar [anchor-based difference = - 2.8%, 95% CI (- 17.5%, 11.9%); p = 0.71]. CONCLUSIONS: After adjusting for cross-trial differences, blinatumomab demonstrated a similar CR rate and potential OS benefit versus InO among adult patients with R/R ALL who received no more than one prior salvage therapy. Further studies are suggested to confirm this finding. FUNDING: Amgen.
Assuntos
Anticorpos Biespecíficos , Inotuzumab Ozogamicina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Indução de Remissão/métodos , Prevenção Secundária/métodos , Adulto , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Exame de Medula Óssea/métodos , Pesquisa Comparativa da Efetividade , Feminino , Humanos , Inotuzumab Ozogamicina/administração & dosagem , Inotuzumab Ozogamicina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Taxa de SobrevidaRESUMO
Outcomes for adults with relapsed/refractory acute lymphoblastic leukemia (ALL) are poor with chemotherapy, particularly in later salvage. The TOWER study examined survival, remission, bridge to allogeneic hematopoietic stem cell transplantation (HSCT), and safety with blinatumomab versus chemotherapy. This report examined outcomes separately for study treatment as first or later salvage. Adults with Philadelphia chromosome-negative B-cell precursor ALL relapsed/refractory to chemotherapy were randomly assigned 2:1 to receive blinatumomab by continuous infusion for 4 weeks in 6-week cycles, or standard salvage chemotherapy. Overall survival for blinatumomab versus chemotherapy was higher both in first salvage and in later salvage. Safety was similar between patients in first salvage and those in later salvage. Blinatumomab as later salvage was associated with higher complete remission rates and served as a bridge to allogeneic HSCT, supporting the use of blinatumomab in both settings. This study is registered at www.clinicaltrials.gov as #NCT02013167.