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1.
J Neurol Sci ; 432: 120089, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34942546

RESUMO

INTRODUCTION: Immunomodulatory therapies, including the use of immune checkpoint inhibitors (ICIs), have made a profound impact on treatment of advanced cancers in recent decades. Neurologic immune-related adverse events (irAEs) related to use of these agents are rare but potentially fatal sequelae. This systematic reviewed aimed to describe onset, clinical features, treatment, and outcome of neurological irAEs following ICI usage. METHODS: A systematic literature search was conducted to identify all case reports (n = 168) and case series (n = 29) describing neurological irAEs (n = 255 patients). Patient demographics, clinical features, and clinical courses were extracted and used to assess statistical relationships between reported variables. RESULTS: Of reports describing neurological irAEs related to ICI use, the majority of cases were in men (66%) and patients above the age of fifty (85%). Disorders of the peripheral nervous system (PNS, 83%) were more common than central nervous system involvement. Neuromuscular disorders were the most common type of neurological irAE (e.g. myasthenia gravis, 36%), followed by peripheral neuropathies (16%), followed by all CNS disorders combined (15%). Most cases presented within the first 5 doses of ICI treatment. Most patients improved clinically, but 24% of cases were fatal. Mortality was highest in patients with neuromuscular irAEs, such as myasthenia gravis and myositis. CONCLUSION: This systematic literature review describes the largest collection of neurological irAEs to date including both CNS and PNS manifestations of ICIs. The information described herein can be used to better inform monitoring and treatment of patients undergoing treatment with ICIs.

2.
J Neurol ; 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34800168

RESUMO

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a serious viral infection associated with disease-modifying therapies (DMT) for multiple sclerosis (MS) including sphingosine 1-phosphate receptor (S1PR) modulators. The objective of this review was to investigate the characteristics of PML in MS patients associated with drugs of the S1PR modulator. METHODS: We conducted a literature review and analysis of 24 patients from 12 publications in PubMed, SCOPUS and EMBASE. This is a descriptive analysis and study of characteristics of PML associated fingolimod and related S1PR modulator group of DMT. RESULTS: A total of 24 cases of PML in MS patients treated with fingolimod were identified. Of these, 21 cases contained data regarding changes in the expanded disability status scale (EDSS). One case of PML in association with ozanimod treatment in a clinical trial was also identified. In PML cases associated with fingolimod, the mean age at the time of PML diagnosis was 50.91 ± 11.5 years. All patients were treated with fingolimod for more than 24 months. Compared to patients who improved or were stable, in terms of EDSS, after symptomatic management of PML, the non-improved groups were significantly older. There were no fatalities in either group during the reported follow-up period. CONCLUSION: The incidence of PML appears to be extremely low in MS patients treated with S1PR modulators. Risk of PML increases with increase in duration of treatment with S1PR modulators like fingolimod, and increased age at the time of PML diagnosis is associated with worse prognosis.

3.
Pharmacotherapy ; 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34767652

RESUMO

INTRODUCTION: Filgrastim is a human granulocyte colony-stimulating factor (G-CSF). There are limited data on dosing filgrastim in obesity. The objective of this study was to compare filgrastim pharmacokinetic parameters for morbidly obese and non-obese patients after a single subcutaneous dose of filgrastim dosed per actual body weight. METHODS: This prospective, matched-pair study (NCT01719432) included patients ≥18 years of age, receiving filgrastim at 5 µg/kg with a weight >190% of their ideal body weight (IBW) for "morbidly obese" patients or within 80%-124% of IBW for matched-control patients. The control group was prospectively matched for age (within 10 years), degree of neutropenia, and gender. Filgrastim doses were not rounded to vial size, to allow more accurate assessment of exposure. Blood samples were collected at 0 (prior to dose), 2, 4, 6, 8, 12, and 24 h after the first subcutaneous administration of filgrastim. RESULTS: A total of 30 patients were enrolled in this prospective pharmacokinetic study, with 15 patients assigned to each arm. Non-compartmental analysis showed that the systemic clearance (Cl) was 0.111 ± 0.041 ml/min in the morbidly obese group versus 0.124 ± 0.045 ml/min in the non-obese group (p = 0.44). Additionally, the mean area under the curve (AUC0-24h ) was 49.3 ± 13.9 ng/ml × min in the morbidly obese group versus 46.3 ± 16.8 ng/mL x min in the non-obese group (p = 0.6). No differences were seen in maximum concentrations (Cmax ) between the two groups (morbidly obese: 48.1 ± 14.7 ng/ml vs. non-obese: 49.2 ± 20.7 ng/ml (p = 0.87)). The morbidly obese group had a numerically higher, but not statistically significant, increase in time to maximum concentration (Tmax ) compared to the non-obese group (544 ± 145 min vs 436 ± 156 min (p = 0.06), respectively). CONCLUSION: Calculating subcutaneous filgrastim doses using actual body weight appears to produce similar systemic exposure in morbidly obese and non-obese patients with severe neutropenia.

4.
Crit Care Explor ; 3(10): e547, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34651135

RESUMO

To assess 30-day mortality in coronavirus disease 2019 acute respiratory distress syndrome patients transferred from rural Appalachian hospitals. DESIGN: Retrospective case controlled, based on consecutive patients transferred and admitted from rural hospitals to a tertiary-care ICU. The primary outcome was all-cause 30-day mortality. Kaplan-Meier method and log-rank test were used in the survival data analysis. SETTING: Medical ICU, West Virginia University Hospital, Morgantown, WV. PATIENTS: All adult patients admitted to the ICU for coronavirus disease 2019 disease between September 30, 2020, and December 2, 2020. INTERVENTION: Not applicable. MEASUREMENTS AND MAIN RESULTS: Seventy-nine consecutive coronavirus disease 2019 patients were admitted to the ICU during the defined period. Overall mortality of the cohort was 54%. Of the 79 patients, 50 were transferred from critical access hospitals/rural facilities with coronavirus disease 2019-induced acute respiratory distress syndrome. A control group consisted of 39 patients admitted to the ICU with noncoronavirus disease 2019 acute respiratory distress syndrome who were intubated and mechanically ventilated. Thirty-day mortality in patients with coronavirus disease 2019 admitted to the ICU was significantly higher than the control group (68% vs 42%) (p = 0.034). Mean Sequential Organ Failure Assessment scores were similar in both coronavirus disease 2019 acute respiratory distress syndrome group and controls. Intubation in patients 70 years or older and mechanical ventilation for over 5 days was associated with significantly higher mortality. CONCLUSIONS: Our data on critically ill and mechanically ventilated coronavirus disease 2019 acute respiratory distress syndrome patients transferred from critical access hospitals/rural facilities have increased mortality compared with noncoronavirus disease 2019 acute respiratory distress syndrome controls. These data suggest that lack or delay in access to tertiary care may impact coronavirus disease 2019 outcome in rural areas. Intubated patients 70 years old or more and mechanical ventilation for over 5 days may be a risk factor for increased mortality. These data may help physicians and hospital administrators in rural areas for optimal utilization of limited resources.

5.
Brain Sci ; 11(10)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34679418

RESUMO

BACKGROUND: The data on neurological manifestations in COVID-19 patients has been rapidly increasing throughout the pandemic. However, data on CNS and PNS inflammatory disorders in COVID-19 with respect to CSF, serum and neuroimaging markers is still lacking. METHODS: We screened all articles resulting from a search of PubMed, Google Scholar and Scopus, using the keywords "SARS-CoV-2 and neurological complication", "SARS-CoV-2 and CNS Complication" and "SARS-CoV-2 and PNS Complication" looking for transverse myelitis, vasculitis, acute disseminated encephalomyelitis, acute hemorrhagic necrotizing encephalitis (AHNE), cytotoxic lesion of the corpus callosum (CLOCC) and Guillain-Barré syndrome (GBS), published between 1 December 2019 to 15 July 2021. RESULTS: Of the included 106 CNS manifestations in our study, CNS inflammatory disorders included transverse myelitis (17, 14.7%), AHNE (12, 10.4%), ADEM (11, 9.5%), CLOCC/MERS (10, 8.6%) and vasculitis (4, 3.4%). Others were nonspecific encephalopathy, encephalitis, seizures and stroke. Most patients were >50 years old (75, 70.8%) and male (64, 65.3%). Most (59, 63.4%) were severe cases of COVID-19 and 18 (18%) patients died. Of the included 94 PNS manifestations in our study, GBS (89, 92.7%) was the most common. Most of these patients were >50 years old (73, 77.7%) and male (59, 64.1%). Most (62, 67.4%) were non-severe cases of COVID-19, and ten patients died. CONCLUSION: Our comprehensive review of the clinical and paraclinical findings in CNS and PNS manifestations of COVID-19 provide insights on the pathophysiology of SARS-CoV-2 and its neurotropism. The higher frequency and severity of CNS manifestations should be noted by physicians for increased vigilance in particular COVID-19 cases.

6.
J Neuroimmunol ; 360: 577721, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34547511

RESUMO

Background High efficacy disease modifying therapies (DMT) in the management of Multiple Sclerosis (MS) have a favorable effect on relapse rate and disability progression; however, they can expose patients to significant risks, such as progressive multifocal leukoencephalopathy (PML). Objective The study aims to investigate prognostic factors that can determine outcome in MS-related PML patients. Methods We conducted a literature review and meta-analysis of 194 patients from 62 articles in PubMed, SCOPUS and EMBASE. Results Out of 194 patients (66.5% women, 33.5% men), 81% had progression in their EDSS score by at least 1 point from the time of PML diagnosis (EDSS-P group). The remaining patients had either stable or improved EDSS (EDSS-S group). In univariate analysis, older age at the time of PML diagnosis was associated with higher probability of disability accumulation and worsening of EDSS by at least 1 point (mean age = 44.8, p = 0.046). After adjusting for other variables, age at time of PML diagnosis remained a significant predictive variable in the multivariable logistic model (OR = 0.93, 95% CI: 0.88-0.99, p = 0.037). Natalizumab is the most commonly associated DMT linked to PML, followed by fingolimod and others including dimethyl fumarate, ocrelizumab, alemtuzumab. Among the different treatments used, no therapeutic agent was found to be superior in improving post-PML EDSS. Conclusions Younger age and lower JCV viral load at the time of PML diagnosis were associated with better outcome in MS-associate PML, while none of the PML therapies was superior over the others or associated with favorable outcome.

8.
Oncogene ; 40(37): 5651-5664, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34326467

RESUMO

Metastatic breast cancer causes most breast cancer-associated deaths, especially in triple negative breast cancers (TNBC). The metastatic drivers of TNBCs are still poorly understood, and effective treatment non-existent. Here we reveal that the presence of Aurora-A Kinase (AURKA) in the nucleus and metastatic dissemination are molecularly connected through HIF1 (Hypoxia-Inducible Factor-1) signaling. Nuclear AURKA activates transcription of "hypoxia-induced genes" under normoxic conditions (pseudohypoxia) and without upregulation of oxygen-sensitive HIF1A subunit. We uncover that AURKA preferentially binds to HIF1B and co-localizes with the HIF complex on DNA. The mass-spectrometry analysis of the AURKA complex further confirmed the presence of CBP and p300 along with other TFIIB/RNApol II components. Importantly, the expression of multiple HIF-dependent genes induced by nuclear AURKA (N-AURKA), including migration/invasion, survival/death, and stemness, promote early cancer dissemination. These results indicate that nuclear, but not cytoplasmic, AURKA is a novel driver of early metastasis. Analysis of clinical tumor specimens revealed a correlation between N-AURKA presence and decreased patient survival. Our results establish a mechanistic link between two critical pathways in cancer metastasis, identifying nuclear AURKA as a crucial upstream regulator of the HIF1 transcription complex and a target for anti-metastatic therapy.

9.
Res Nurs Health ; 44(5): 854-863, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34196013

RESUMO

Fidelity (consistency of intervention implementation) is essential to rigorous research. Intervention fidelity maintains study internal validity, intervention reproducibility, and transparency in the research conduct. The purpose of this manuscript is to describe intervention fidelity strategies/procedures developed for a pilot study testing a new palliative care nursing intervention (FamPALcare) for families managing advanced lung disease. The procedures described herein are based on the fidelity best practices recommendations from the NIH Consortium. An evidence-based checklist guided observational ratings of the fidelity procedures used and the intervention content implemented in each intervention session. Descriptive data on how participants understood (received), enacted, or used the intervention information were summarized. The fidelity checklist observational scores found ≥93% of the planned intervention content was implemented, and the fidelity strategies were adhered to consistently during each intervention session. The small variation (7%) in implementation was expected and related to participants' varying experiences, input, and/or questions. The helpfulness scale items include participants' ability to use home care resources, to anticipate and manage end-of-life symptoms, and to use Advance Directive forms. The high ratings (M = 4.4) on the 1-5 (very helpful) Likert Helpfulness Scale verified participants utilized the information from the intervention. Furthermore, there was an improvement in patients' breathlessness scores and completion of Advance Directive forms at 3 months after baseline. It is essential to plan intervention fidelity strategies to use throughout a study and to report fidelity results.


Assuntos
Serviços de Assistência Domiciliar/estatística & dados numéricos , Serviços de Assistência Domiciliar/normas , Neoplasias Pulmonares/terapia , Pesquisa em Enfermagem/normas , Cuidados Paliativos/estatística & dados numéricos , Cuidados Paliativos/normas , Qualidade da Assistência à Saúde/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Lista de Checagem/métodos , Lista de Checagem/normas , Feminino , Guias como Assunto , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reprodutibilidade dos Testes
10.
Am Surg ; : 31348211030464, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196595

RESUMO

BACKGROUND/OBJECTIVE: Cavity shave margins (CSMs) decrease rate of positive margins and need for re-excision. Recurrence data following breast-conserving surgery (BCS) are not always available in large cancer registries. We sought to define our recurrence and survival data in BCS with routine excision of CSMs. METHODS: A single institution, 10-year retrospective review of breast cancer patients who underwent BCS with routine CSMs was conducted. Cavity shave margin technique was standard. Cox proportional hazard analyses and the Kaplan-Meier method were used to estimate recurrence and survival. RESULTS: Breast-conserving surgery with CSM was performed in 839 patients. Re-excision rate to achieve negative margins was 8.5%. Fifty-two patients (75%) underwent margin re-excision vs 18 patients (25%) underwent salvage mastectomy. Positive margin rate stratified by tumor histology was highest for invasive lobular carcinoma followed by mixed invasive ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS), followed by pure DCIS and lowest for IDC. Length of follow-up was (4.7 ± 2.6, years). Overall recurrence rate (locoregional and systemic) was 4.3%: highest in patients with negative lumpectomy margin but positive CSM (L-S+ = 15%) followed by positive lumpectomy and CSMs (L+S+ = 14%), followed by patients with positive lumpectomy margin but negative CSMs (L+S- = 13%) and lowest for negative lumpectomy and CSM (L-S- = 5%), (P = .0008). There was no difference in 5-year breast cancer-specific survival between the 4 subgroups: 96% for L-S-, 86.7% L-S+, 94.7% L+S+ and 90% L+S- (P = .094). CONCLUSIONS: Recurrence following BCS with CSMs can be stratified based on both lumpectomy and cavity shave margin positivity. Routine excision of CSMs allows identification of these patient subsets.

11.
South Med J ; 114(7): 424-431, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34215896

RESUMO

OBJECTIVES: Obesity can be an independent predictor of fibrosis in tissues, including the liver, heart, and skin. We evaluated a rural Appalachian cohort of idiopathic pulmonary fibrosis (IPF) for its relation to obesity. METHODS: Using American Thoracic Society 2018 diagnostic guidelines, an IPF cohort was systematically identified at an Appalachian academic medical center (2015-2019). The cohort was categorized in subgroups of body mass index (BMI) <30 or BMI ≥30 kg/m2. Demographics, clinical variables, and treatment details were collected retrospectively and evaluated for their associations with obesity. RESULTS: In our IPF cohort (N = 138), a usual interstitial pneumonia pattern was less prevalent in the obese group (n = 49) relative to the nonobese group (69% vs 85%, respectively). The obese group was younger (mean age 73.27 ± 9.12 vs 77.97 ± 9.59 years) and had a higher prevalence of hypertension (90% vs 72%), hyperlipidemia (83% vs 68%), diabetes mellitus (47% vs 25%), sleep-disordered breathing (47% vs 25%), chronic pain disorders (28% vs 15%), and deep vein thrombosis (19% vs 7%). An increased proportion of obese-IPF patients was seen at a tertiary or an interstitial lung disease center, with more surgical lung biopsies performed and incident diagnosis (ie, within 6 months of presentation) assigned. Only a minority of patients underwent lung transplantation (3.6%), all of them from the obese-IPF subgroup. Approximately 30% of the total IPF cohort died, with a lower mortality observed in the obese group (35% vs 20%, P = 0.017). An increasing BMI predicted a better survival in the total IPF cohort (BMI 25-29.9, 20-24.9, and <20 had mortality rates of 20%, 47%, and 75%, respectively; P < 0.001). CONCLUSIONS: Our study represents a first known effort to develop an IPF cohort in a rural Appalachian region. Although they shared an increased burden of comorbidities, the obese subgroup showed less advanced fibrosis with a lower mortality rate relative to nonobese subgroup, suggesting a potential "obesity paradox" in IPF. The study findings significantly advance our understanding of challenges posed by IPF in a rural population that also suffers from an alarming rate of obesity. We highlight the need for the multidisciplinary management of these patients and prospective studies to better define this complex relation.

12.
Support Care Cancer ; 29(12): 7925-7930, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34191128

RESUMO

A theoretical pharmacokinetic interaction mediated through L-amino acid transporter 1 and 2 exists between gabapentin (GP) and pregabalin (PG) with melphalan. Peripheral neuropathy is a common toxicity of various multiple myeloma regimens commonly utilized prior to autologous hematopoietic cell transplant (auto-HCT) with high-dose melphalan (HD-Mel). Therefore, it is likely concurrent administration of either GP or PG will occur in patients receiving HD-Mel conditioning for auto-HCT, which could potentially increase cellular uptake and worsen the mucosal injury. A retrospective chart review of adult patients from January 2012 to July 2016 who received HD-Mel (140-200 mg/m2) at West Virginia University Medicine was performed to assess toxicity and outcomes in these patients. A total of 80 patients were included in the study, with 30 patients receiving GP or PG and 50 control patients. There were no significant differences in grade 2 or higher mucositis, admissions for nausea/vomiting/diarrhea, intravenous opioid requirements, oral topical therapies, antidiarrheal medication use, rescue anti-emetics, days of nausea or vomiting, pain scores, neutrophil or platelet engraftment, treatment-related mortality, progression-free survival, or overall survival. Our data suggest that it is safe to continue GP/PG therapy throughout HD-Mel therapy, with no negative transplant outcomes. Prospective studies or evaluations of larger databases are necessary to better characterize the clinical effect of concomitant therapy.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Gabapentina/administração & dosagem , Gabapentina/toxicidade , Humanos , Melfalan/administração & dosagem , Melfalan/toxicidade , Mieloma Múltiplo/tratamento farmacológico , Pregabalina/administração & dosagem , Pregabalina/toxicidade , Estudos Prospectivos , Estudos Retrospectivos , Transplantados , Condicionamento Pré-Transplante , Transplante Autólogo
13.
J Trauma Acute Care Surg ; 91(1): 148-153, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34144562

RESUMO

BACKGROUND: Geriatric ground level fall is a common admission diagnosis for trauma centers in the United States. Visual health has been linked to fall risk reduction in older adult but is rarely fully evaluated during a trauma admission. Using a commercial application and a questionnaire, we developed and tested a trauma provider eye examination (TPEE) to screen visual health. This study used the TPEE to (1) evaluate the prevalence of undiagnosed or undertreated visual disease in geriatric trauma patients and (2) determine the feasibility and reliability of the TPEE to screen for vision disease. METHODS: This prospective study included patients older than 60 years evaluated by the trauma service from June 2019 to May 2020. Patients with ocular or globe trauma were excluded. The primary outcome was significant abnormal vision (SAV) found using the TPEE. Ophthalmology performed a dilated examination as the criterion standard for comparison. We assessed the feasibility and reliability of the TPEE. Fisher's exact test and logistic model were used in the data analysis. RESULTS: Enrollment concluded with 96 patients. Mean age was 75 years, and fall (79%) was the most common mechanism of injury. Significant abnormal vision was common: undiagnosed disease was found in 39% and undertreated in 14%. Trauma provider examination was 94% sensitive and 92% specific for SAV cases. Congruence between TPEE and ophthalmology examination was highest in pupil examination (86%), visual fields (58%), and Amsler grid (52%). Multivariate analysis found that a combination of an abnormal Amsler test and abnormal visual field defect was significantly associated with SAV (odds ratio, 4.1; p = 0.03). CONCLUSION: Trauma provider eye examination screening can identify patients with visual deficits. Given the association between visual deficits and fall risk, older adults may benefit from such a screening or a formal ophthalmology referral. LEVEL OF EVIDENCE: Therapeutic/Care Management, level II.


Assuntos
Transtornos da Visão/epidemiologia , Seleção Visual/métodos , Ferimentos e Lesões/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Projetos Piloto , Estudos Prospectivos , Índices de Gravidade do Trauma , Acuidade Visual , West Virginia/epidemiologia
14.
Cancer Genet ; 256-257: 136-148, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34130230

RESUMO

Cigarette smoking is a risk factor for the development of head and neck squamous cell carcinoma (HNSCC), partially due to tobacco-induced large-scale chromosomal copy-number alterations (CNAs). Identifying CNAs caused by smoking is essential in determining how gene expression from such regions impact tumor progression and patient outcome. We utilized The Cancer Genome Atlas (TCGA) whole genome sequencing data for HNSCC to directly identify amplified or deleted genes correlating with smoking pack-year based on linear modeling. Internal cross-validation identified 35 CNAs that significantly correlated with patient smoking, independent of human papillomavirus (HPV) status. The most abundant CNAs were chromosome 11q13.3-q14.4 amplification and 9p23.1/9p24.1 deletion. Evaluation of patient amplicons reveals four different patterns of 11q13 gene amplification in HNSCC resulting from breakage-fusion-bridge (BFB) events. . Predictive modeling identified 16 genes from these regions that denote poorer overall and disease-free survival with increased pack-year use, constituting a smoking-associated expression signature (SAES). Patients with altered expression of signature genes have increased risk of death and enhanced cervical lymph node involvement. The identified SAES can be utilized as a novel predictor of increased disease aggressiveness and poor outcome in smoking-associated HNSCC.


Assuntos
Variações do Número de Cópias de DNA/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Fumar/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Vértebras Cervicais/patologia , Amplificação de Genes , Predisposição Genética para Doença , Instabilidade Genômica/genética , Humanos , Metástase Linfática , Modelos Biológicos , Mutação/genética , Taxa de Mutação , Fatores de Risco , Resultado do Tratamento
15.
AAPS PharmSciTech ; 22(5): 191, 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34169366

RESUMO

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has demonstrated notable clinical activity in cancer immunotherapy, but it is limited by systemic toxicities, poor bioavailability, rapid clearance, and instability in vivo. Nanoparticles (NPs) may overcome these limitations and provide a mechanism for passive targeting of tumors. This study aimed to develop GM-CSF-loaded PLGA/PLGA-PEG NPs and evaluate them in vitro as a potential candidate for in vivo administration. NPs were created by a phase-separation technique that did not require toxic/protein-denaturing solvents or harsh agitation techniques and encapsulated GM-CSF in a more stable precipitated form. NP sizes were within 200 nm for enhanced permeability and retention (EPR) effect with negative zeta potentials, spherical morphology, and high entrapment efficiencies. The optimal formulation was identified by sustained release of approximately 70% of loaded GM-CSF over 24 h, alongside an average size of 143 ± 35 nm and entrapment efficiency of 84 ± 5%. These NPs were successfully freeze-dried in 5% (w/v) hydroxypropyl-ß-cyclodextrin for long-term storage and further characterized. Bioactivity of released GM-CSF was determined by observing GM-CSF receptor activation on murine monocytes and remained fully intact. NPs were not cytotoxic to murine bone marrow-derived macrophages (BMDMs) at concentrations up to 1 mg/mL as determined by MTT and trypan blue exclusion assays. Lastly, NP components generated no significant transcription of inflammation-regulating genes from BMDMs compared to IFNγ+LPS "M1" controls. This report lays the preliminary groundwork to validate in vivo studies with GM-CSF-loaded PLGA/PEG-PLGA NPs for tumor immunomodulation. Overall, these data suggest that in vivo delivery will be well tolerated.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/síntese química , Macrófagos/efeitos dos fármacos , Nanopartículas/química , Poliésteres/síntese química , Polietilenoglicóis/síntese química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Composição de Medicamentos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacocinética , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Poliésteres/administração & dosagem , Poliésteres/farmacocinética , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética
16.
Transpl Infect Dis ; 23(4): e13676, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34165853

RESUMO

BACKGROUND: At our institution, antibiotic cycling for febrile neutropenia is utilized to increase heterogeneity of antibiotic exposure in patients who have undergone an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Development of acute graft-versus-host disease (aGVHD) has been associated with low diversity within stool microbiota. To date, discordant outcomes have been reported implicating anti-anaerobic antibiotic use with the development of aGVHD, and there is currently a lack of published data available in an antibiotic cycled environment. The objective of this study was to determine if there is a difference in the rate of aGVHD in patients who receive anti-anaerobic cycled antibiotics compared with other cycled antibiotics. METHODS: This was a retrospective, observational study evaluating rates of aGVHD in patients who received antibiotics with anaerobic vs non-anaerobic coverage post-allo-HSCT from January 2008 to January 2018. Univariate and multivariable analyses were performed to assess associations with aGVHD. Secondary outcomes include rate of all stages of aGVHD, progression-free survival, overall survival, 100-day treatment-related mortality (TRM), and 1-year TRM. RESULTS: A total of 273 patients were included in the study. Baseline characteristics were similar between groups, except patients who received anti-anaerobic antibiotics had more unrelated donors (P = .002), were more likely to get myeloablative preparatory regimens (P = .009), had less subtherapeutic calcineurin inhibitor serum concentrations (P = .001), and more often received T-cell depletion (P = .004). The incidence of grades II-IV aGVHD post-HSCT in patients who received anti-anaerobic antibiotics was 32.6% compared with 18.8% in patients who received other antibiotics (P = .015). Multivariable analysis showed that the occurrence of grades II-IV aGVHD was associated with cytomegalovirus reactivation (OR = 2.1, 95% CI = 1.0-4.5, P = .047), unrelated donors (OR = 6.1, 95% CI = 2.3-16.6, P < .001), and use of anti-anaerobic antibiotics (OR = 2.3, 95% CI = 1.1-4.8, P = .021). A 100-day TRM in patients who received anti-anaerobic antibiotics was 9.6% compared with 3.6% in patients who received other antibiotics (P = .046). One-year TRM in patients who received anti-anaerobic antibiotics was 25.2% compared with 13.8% in patients who received other antibiotics (P = .017). There was no statistically significant difference seen between groups in progression free survival or overall survival. CONCLUSION: Variability in baseline characteristics limits ability to make strong conclusions, but patients who received antibiotics with anaerobic coverage during the first 30 days after an allogeneic HSCT appeared to be at an increased risk of developing aGVHD and TRM. Larger well-controlled trials are warranted to further clarify these relationships.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Antibacterianos/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Retrospectivos , Doadores não Relacionados
17.
Viruses ; 13(5)2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063160

RESUMO

This study examines the clinical characteristics, outcomes and types of management in SARS-CoV-2 infected patients, in the hospitals affiliated with West Virginia University. We included patients from West Virginia with SARS-CoV-2 infection between 15 April to 30 December 2020. Descriptive analysis was performed to summarize the characteristics of patients. Regression analyses were performed to assess the association between baseline characteristics and outcomes. Of 1742 patients, the mean age was 47.5 years (±22.7) and 54% of patients were female. Only 459 patients (26.3%) reported at least one baseline symptom, of which shortness of breath was most common. More than half had at least one comorbidity, with hypertension being the most common. There were 131 severe cases (7.5%), and 84 patients (4.8%) died despite treatment. The mean overall length of hospital stay was 2.6 days (±6.9). Age, male sex, and comorbidities were independent predictors of outcomes. In this study of patients with SARS-CoV-2 infection from West Virginia, older patients with underlying co-morbidities had poor outcomes, and the in-hospital mortality was similar to the national average.


Assuntos
COVID-19/epidemiologia , COVID-19/terapia , Adulto , Idoso , COVID-19/mortalidade , Comorbidade/tendências , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Resultado do Tratamento , West Virginia/epidemiologia
18.
J Neurol ; 268(12): 4448-4478, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34009454

RESUMO

BACKGROUND: The literature on neurological manifestations in COVID-19 patients has been rapidly increasing with the pandemic. However, data on CNS inflammatory disorders in COVID-19 are still evolving. We performed a literature review of CNS inflammatory disorders associated with coronavirus disease-2019 (COVID-19). METHODS: We screened all articles resulting from a search of PubMed, Google Scholar and Scopus, using the keywords; "SARS-CoV-2 and neurological complication", "SARS-CoV-2 and CNS Complication" looking for reports of transverse myelitis, longitudinally extensive transverse myelitis, neuromyelitis optica, myelitis, Myelin Oligodendrocyte Glycoprotein Antibody Disorder (MOGAD), Acute Disseminated Encephalomyelitis (ADEM), Acute Hemorrhagic Necrotizing Encephalitis/Acute Hemorrhagic Leukoencephalitis (AHNE/AHLE), Cytotoxic lesion of the Corpus Callosum/Mild Encephalopathy Reversible Splenium Lesion(CLOCC/MERS) and Optic neuritis published between December 01, 2019 and March 15, 2021. RESULTS: Our literature search revealed 43 patients meeting the diagnosis of myelitis, including Transverse Myelitis, ADEM, AHNE/AHLE or CLOCC/MERS and Optic neuritis. Acute myelitis was most commonly associated with non-severe COVID-19 and all reported cases of AHNE/AHLE had severe COVID-19 infection. Based on IDSA/ATS criteria of either requiring vasopressor for septic shock or mechanical ventilation, 49% (n = 18) patients were considered to have a severe COVID infection. There were 7 (n = 19%) fatalities. CONCLUSION: To our knowledge, this is among the first reviews that includes the clinical features, neuroimaging, CSF findings and outcomes in COVID-19-associated CNS inflammatory disorders. Our observational review study reveals that although rare, myelitis, ADEM, AHNE and CLOCC can be associated with COVID-19 infection. Further studies using MRI imaging and CSF analysis in early diagnosis and intervention of these disorders are warranted.


Assuntos
COVID-19 , Doenças do Sistema Nervoso Central/virologia , Mielite Transversa , COVID-19/líquido cefalorraquidiano , COVID-19/diagnóstico por imagem , Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Humanos , Glicoproteína Mielina-Oligodendrócito , Mielite Transversa/diagnóstico por imagem , Mielite Transversa/virologia , Neuroimagem , Estudos Observacionais como Assunto
19.
J Alzheimers Dis Rep ; 5(1): 187-206, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33981956

RESUMO

Background: Recent studies suggest meditation and music listening (ML) may improve cognitive and psychosocial outcomes in adults with subjective cognitive decline (SCD). However, lack of a usual care group has limited conclusions. Objective: To assess the: 1) feasibility of incorporating an enhanced usual care (EUC) comparator in a trial of Kirtan Kriya meditation (KK) and ML for adults experiencing SCD; and 2) preliminary effects of active treatment (KK/ML) versus an EUC program. Methods: Forty participants with SCD were randomized 1:1:2 to a 12-week KK, ML, or EUC program. KK and ML participants were asked to practice 12 minutes/day; EUC participants were given a comprehensive educational packet regarding healthy aging and strategies for improving/maintaining brain health and asked to record any activities or strategies used. Feasibility was assessed using measures of retention, adherence, treatment expectancies, and participant satisfaction, as well as information from exit questionnaires and daily practice/activity logs. Cognitive functioning, stress, mood, sleep-quality, and health-related quality of life (QOL) were measured pre- and post-intervention using well-validated instruments. Results: Thirty-two participants (80%) completed the 3-month study, with retention highest in the EUC group (p < 0.05). Active treatment participants averaged 6.0±0.4 practice sessions/week, and EUC participants, 7.5±0.6 brain health activities/week. Treatment expectancies were similar across groups. EUC participants indicated high satisfaction with the program and study. Despite limited study power, the active treatment group showed significantly greater gains in subjective memory functioning (ps≤0.025) and nonsignificant improvements in cognitive performance (TMT-B), perceived stress, QOL, and mood (ps≤0.08) compared to the EUC group. Conclusion: Findings of this pilot feasibility trial suggest incorporation of an EUC program is feasible, and that participation in a simple 12-week relaxation program may be helpful for adults with SCD versus engagement in an EUC program.

20.
Gastrointest Tumors ; 8(2): 81-86, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33981686

RESUMO

Introduction: In 2020, colorectal cancer will be the fourth most frequently diagnosed malignant neoplasm and the second leading cause of site-specific, cancer-related deaths in the USA. Notably, 80% of the new cases are, by staging criteria, potentially curable even those with completely resected stage 4 disease. If slightly more than half the losses can be attributed to metastatic disease at presentation, then the remaining portion of deaths may be linked to disease relapse after surgery and, if applicable, adjuvant chemotherapy. The inference that these therapies are not curative for a significant number of subjects poses a role for maintenance therapy. Objective: To assess event-free survival (EFS) of patients who received capecitabine as maintenance therapy following treatment according to current guidelines. Methods: Clinical outcomes data were collected for 35 subjects treated with capecitabine as maintenance therapy. Descriptive statistical analyses were conducted on collective data related to duration of maintenance therapy and disease or clinical status from surgery to initial event. Kaplan-Meier method and log-rank test were used to analyze EFS and overall survival. Results: Of the entire cohort, 26 subjects have no evidence of disease (NED), a median of 5.5 years from surgery. Kaplan-Meier analyses indicated a 5-year EFS rate of 74% (95% CI: 60-90%). Eighteen of these 26 patients received capecitabine ≥30 months. Eight of the 17 subjects treated with capecitabine therapy for <30 months developed progressive disease; the majority of the relapses occurred within 20 months of surgery. The difference between the two groups was statistically significant. Six subjects died, only two of who had metastatic disease at the time of death; the other four had NED at least 4 years from surgery. Five patients with resected stage 4 disease who received capecitabine as maintenance therapy were alive >5 years from surgery. Conclusion: The findings and analyses of this cohort of patients suggest that maintenance capecitabine therapy reduces the risk of disease progression and cancer-related death.

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