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1.
Med ; 5(3): 190-200.e5, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38359838

RESUMO

BACKGROUND: Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations. Our aim was to determine the feasibility of PAP in a complex population, including high levels of treatment resistance in major depressive and bipolar disorder and patients with baseline suicidality and significant comorbidity. We also evaluated flexible repeated doses over a 6-month period. METHODS: Adults with treatment-resistant depression as part of major depressive or bipolar II disorder without psychosis or a substance use disorder were eligible to participate. Subjects were randomized to immediate treatment or waitlist control, with all eventually receiving PAP. Participants had one, two, or three psilocybin sessions with a fixed dose of 25 mg. Each dose was accompanied by preparation and integration psychotherapy sessions. Acceptability, safety, tolerability, and efficacy were evaluated (this study was registered at ClinicalTrials.gov: NCT05029466). FINDINGS: Participants were randomized to immediate treatment (n = 16) or delayed treatment (n = 14). 29/30 were retained to the week-2 primary endpoint. Adverse events were transient, with no serious adverse events. Greater reductions in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) were observed in the immediate treatment arm compared to the waitlist period arm with a large hedge's g effect size of 1.07 (p < 0.01). Repeated doses were associated with further reductions in MADRS scores compared to baseline. CONCLUSIONS: PAP was feasible in complex patients with preliminary antidepressant efficacy and adequate safety and tolerability. Repeated doses were associated with greater reductions in depression severity. FUNDING: This work was funded by Brain and Cognition Discovery Foundation (BCDF), Usona, and Braxia Scientific.


Assuntos
Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Adulto , Humanos , Psilocibina/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/induzido quimicamente , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antidepressivos/efeitos adversos , Psicoterapia
3.
Ann Vasc Surg ; 100: 155-164, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37852366

RESUMO

BACKGROUND: Operative risk for supra-aortic trunk (SAT) surgical revascularization for occlusive disease, particularly transthoracic reconstruction (TR), remains ill-defined. This study sought to describe and compare 30-day outcomes of TR and extra-anatomic (ER) SAT surgical reconstruction for an occlusive indication across the United States over a contemporary 15-year period. METHODS: Using the National Surgical Quality Improvement Program, TR and ER performed during 2005-2019 were identified. Procedures performed for nonocclusive indications and those concomitant with coronary or valve operations were excluded. Rates of stroke, death, myocardial infarction (MI) and these as composite outcome (S/D/M) were compared. Logistic regression with stabilized inverse probability weighting (IPW) was used to compare groups via average treatment effect (ATE) while adjusting for covariate imbalances. RESULTS: Over the 15-year period, 166 TR and 1,900 ER patients were identified. The majority of ERs were carotid-subclavian bypass (n = 1,344; 70.7%) followed by carotid-carotid bypass (n = 261; 13.7%) and subclavian/carotid transpositions (n = 123; 6.5%). TR consisted of aorto-SAT bypass (n = 120; 72.3%) and endarterectomy (n = 46; 27.7%). The median age was 64 years for TR and 65 years in ER (P = 0.039). Those undergoing TR were more often women (69.0% vs. 56.9%; P = 0.001) and less likely to have undergone previous cardiac surgery (9.2% vs. 20.8%; P = 0.006). TR were also less frequently hypertensive (68.1% vs. 75.4%; P = 0.038) and had statistically lower preoperative creatinine levels (0.86 vs 0.91; P = 0.002). Unadjusted rates of MI (0.6% vs. 1.3%; P = 0.72) and stroke (3.6% vs. 1.9%; P = 0.15) were similar between groups with mortality (3.6% vs. 1.5%; P = 0.05) and S/D/M (6.6% vs. 3.9%; P = 0.10) trending higher with TR. IPWs could be calculated for 1,754 patients (148 TR; 1,606 ER). The estimated probability of S/D/M was 3.8% in the ER group and 6.2% in TR; no difference was seen in ATE (2.4%; 95% confidence interval [CI]: -1.5 to 6.2; P = 0.23). No differences were seen in individual component ATEs (stroke: 3.0% vs. 1.7%; ATE = 1.3%; 95% CI: -3.9 to 1.3; P = 0.32; mortality: 3.8% vs. 1.4%; ATE = 2.4%; 95% CI: -5.6 to 0.7; P = 0.13). Secondary outcomes showed TR patients were more likely to have non-home discharge (18.7% vs. 6.6%; ATE = 12.1%; 95% CI: 5.0-19.2; P < 0.001) and longer lengths of stay (6.1 vs. 4.0; ATE = 2.2 days; 95% CI: 0.9-3.4; P < 0.001). Moreover, TR patients were more likely to require transfusion (22.7% vs. 5.0%; ATE = 17.7%; 95% CI: 10.2-25.2; P < 0.001) and develop sepsis (2.7% vs. 0.2%; ATE = 2.5%; 95% CI: 0.1-5.0; P = 0.04). CONCLUSIONS: Transthoracic and extra-anatomic surgical reconstruction of the SATs for occlusive disease have similar operative cardiovascular risk. However, morbidity tends to be higher with TR due to higher transfusion requirements, sepsis risk, and need for facility stay. These results suggest ER as a first-line approach in those with proper disease anatomy is reasonable with lower morbidity, while TR remains justified in appropriate patients.


Assuntos
Estenose das Carótidas , Endarterectomia das Carótidas , Infarto do Miocárdio , Sepse , Acidente Vascular Cerebral , Humanos , Feminino , Estados Unidos , Pessoa de Meia-Idade , Estenose das Carótidas/cirurgia , Resultado do Tratamento , Infarto do Miocárdio/etiologia , Morbidade , Estudos Retrospectivos , Fatores de Risco , Endarterectomia das Carótidas/efeitos adversos
4.
Ann Surg Oncol ; 30(10): 6152-6158, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37505352

RESUMO

PURPOSE: To determine the feasibility and acceptability of using a patient decision aid (DA) for women with elevated breast cancer risk who are considering MRI screening. METHODS: This pilot study employed a mixed methods design to develop, modify, and test an interactive DA. The DA was administered among a consecutive patient sample with an estimated Tyrer-Cuzick v.8 lifetime breast cancer risk of 20% or greater and without a pathologic genetic mutation. The decisional conflict scale was used to measure decisional conflict. Post-intervention provider and patient feedback evaluated shared decision-making, feasibility, and acceptability. RESULTS: Twenty-four patients participated, with a median age of 44 years. Prior to DA use, sixteen patients (67%) were unsure whether to add MRI to their screening, six patients elected MRI (25%), and two patients declined MRI (8%). Following DA use, thirteen of sixteen of the initially undecided participants (81%) established a preference, with eleven electing to add MRI screening. Of participants with an initial preference, all maintained the same decision following use of the DA. Prior to the DA, the median decisional conflict score among participants was 25% (range 0-60%) compared with 0% (range 0-25%) after the DA. Healthcare providers reported that the DA was useful and easily incorporated into clinical workflow. CONCLUSIONS: This pilot study shows that there may be a benefit to DA utilization in the high-risk breast cancer clinic to guide shared decision-making in establishing a screening preference. The findings warrant further research to test the use of the DA in a larger, multi-site trial.


Assuntos
Neoplasias da Mama , Adulto , Feminino , Humanos , Neoplasias da Mama/genética , Tomada de Decisões , Técnicas de Apoio para a Decisão , Detecção Precoce de Câncer , Projetos Piloto , Pessoa de Meia-Idade
6.
Transfusion ; 62(12): 2470-2479, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36278434

RESUMO

BACKGROUND: Myelodysplastic syndrome (MDS) is a marrow failure disease. As patients often require chronic transfusion, many develop red blood cell (RBC) alloimmunization or immune-mediated platelet refractoriness. MDS represents a spectrum of diseases with specific categorizations and genetic abnormalities, and we set out to determine if these characteristics predispose patients to antibody formation. STUDY DESIGN AND METHODS: A natural language search identified MDS patients with pre-transfusion testing from 2015 to 2020. Marrow reports, cytogenetic results, and next-generation sequencing panels were gathered. Transfusion history and testing were collected from the laboratory information system. RESULTS: The group consisted of 226 biopsy-proven MDS patients. The prevalence of RBC alloimmunization was 11.1% (25 of 226). Half (23 of 46) of all RBC alloantibodies were against Rh (C, c, E, e) and Kell (K) antigens. There was a relative enrichment for JAK2 positivity among the RBC alloimmunized group. A total of 7.1% (16 of 226) of patients had immune-mediated platelet refractoriness and had increased transfusion requirements (p ≤ 0.01). No disease type or genetic abnormality was significantly associated with alloimmunization or immune-mediated platelet refractoriness. DISCUSSION: While JAK2 specific mutations were enriched among RBC alloimmunized patients, this association failed to reach statistical significance in our single-center cohort. Further study using larger patient cohorts is warranted. Overall, this cohort of MDS patients had very similar RBC alloimmunization prevalence and anti-RBC antibody specificities as other recent literature. Our data reinforce the finding that MDS patients are at greater risk for alloimmunization and support the use of extended phenotype matching for these at-risk patients.


Assuntos
Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Antígenos HLA , Eritrócitos
7.
Oncol Nurs Forum ; 49(5): 471-479, 2022 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-36067239

RESUMO

OBJECTIVES: To determine the feasibility and acceptability of using a decision aid (DA) in a breast surgery clinic. SAMPLE & SETTING: 42 patients with minimally suspicious mammograms and two physicians participated in this study at an outpatient breast specialty clinic in Virginia. METHODS & VARIABLES: A quasiexperimental single group pilot study was conducted to determine the feasibility of DecisionKEYS, a theory-based, interactive DA intervention. Patients with minimally suspicious mammogram results chose between breast biopsy or close imaging follow-up. The Decisional Conflict Scale was used to measure decisional conflict. The Decision-Making Quality Scale was used to evaluate the overall decision process. Postintervention physician and patient feedback evaluated feasibility and acceptability. RESULTS: Participants and physicians rated the DA as helpful. Decisional Conflict Scale scores were low before and after the intervention. Physicians reported the DA was feasible for workflow, and the majority reported using the DA in making final recommendations. Management recommendation (breast biopsy, close imaging follow-up) changed in 26 of 42 cases from pre- to postintervention. The majority of participants underwent breast biopsy. IMPLICATIONS FOR NURSING: The feasibility and acceptability of the DA were beneficial to patients and clinic workflow.


Assuntos
Técnicas de Apoio para a Decisão , Detecção Precoce de Câncer , Humanos , Tomada de Decisões , Mamografia , Projetos Piloto
8.
Semin Thorac Cardiovasc Surg ; 34(1): 172-179, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33689923

RESUMO

Intensive care unit (ICU) costs comprise a significant proportion of the total inpatient charges for cardiac surgery. No reliable method for predicting intensive care unit length of stay following cardiac surgery exists, making appropriate staffing and resource allocation challenging. We sought to develop a predictive model to anticipate prolonged ICU length of stay (LOS). All patients undergoing coronary artery bypass grafting (CABG) and/or valve surgery with a Society of Thoracic Surgeons (STS) predicted risk score were evaluated from an institutional STS database. Models were developed using 2014-2017 data; validation used 2018-2019 data. Prolonged ICU LOS was defined as requiring ICU care for at least three days postoperatively. Predictive models were created using lasso regression and relative utility compared. A total of 3283 patients were included with 1669 (50.8%) undergoing isolated CABG. Overall, 32% of patients had prolonged ICU LOS. Patients with comorbid conditions including severe COPD (53% vs 29%, P < 0.001), recent pneumonia (46% vs 31%, P < 0.001), dialysis-dependent renal failure (57% vs 31%, P < 0.001) or reoperative status (41% vs 31%, P < 0.001) were more likely to experience prolonged ICU stays. A prediction model utilizing preoperative and intraoperative variables correctly predicted prolonged ICU stay 76% of the time. A preoperative variable-only model exhibited 74% prediction accuracy. Excellent prediction of prolonged ICU stay can be achieved using STS data. Moreover, there is limited loss of predictive ability when restricting models to preoperative variables. This novel model can be applied to aid patient counseling, resource allocation, and staff utilization.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Cirurgia Torácica , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Humanos , Unidades de Terapia Intensiva , Tempo de Internação , Fatores de Risco , Resultado do Tratamento
9.
PLoS One ; 16(10): e0258452, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34624059

RESUMO

BACKGROUND: Telemedicine has been rapidly adopted in the wake of the COVID-19 pandemic. There is limited work surrounding demographic and socioeconomic disparities that may exist in telemedicine utilization. This study aimed to examine demographic and socioeconomic differences in surgical patient telemedicine usage during the COVID-19 pandemic. METHODS: Department of Surgery outpatients seen from July 1, 2019 to May 31, 2020 were stratified into three visit groups: pre-COVID-19 in-person, COVID-19 in-person, or COVID-19 telemedicine. Generalized linear models were used to examine associations of sex, race/ethnicity, Distressed Communities Index (DCI) scores, MyChart activation, and insurance status with telemedicine usage during the COVID-19 pandemic. RESULTS: 14,792 patients (median age 60, female [57.0%], non-Hispanic White [76.4%]) contributed to 21,980 visits. Compared to visits before the pandemic, telemedicine visits during COVID-19 were more likely to be with patients from the least socioeconomically distressed communities (OR, 1.31; 95% CI, 1.08,1.58; P = 0.005), with an activated MyChart (OR, 1.38; 95% CI, 1.17-1.64; P < .001), and with non-government or commercial insurance (OR, 2.33; 95% CI, 1.84-2.94; P < .001). Adjusted comparison of telemedicine visits to in person visits during COVID-19 revealed telemedicine users were more likely to be female (OR, 1.38, 95% CI, 1.10-1.73; P = 0.005) and pay with non-government or commercial insurance (OR, 2.77; 95% CI, 1.85-4.16; P < .001). CONCLUSIONS: During the first three months of the COVID-19 pandemic, telemedicine was more likely utilized by female patients and those without government or commercial insurance compared to patients who used in-person visits. Interventions using telemedicine to improve health care access might consider such differences in utilization.


Assuntos
COVID-19/epidemiologia , Acessibilidade aos Serviços de Saúde , Disparidades em Assistência à Saúde , Pandemias , SARS-CoV-2 , Telemedicina , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Procedimentos Cirúrgicos Operatórios
10.
J Immunother Cancer ; 9(8)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34413169

RESUMO

BACKGROUND: We performed a clinical trial to evaluate safety and immunogenicity of a novel long peptide vaccine administered in combinations of incomplete Freund's adjuvant (IFA) and agonists for TLR3 (polyICLC) and TLR7/8 (resiquimod). We hypothesized that T cell responses to minimal epitope peptides (MEPs) within the long peptides would be enhanced compared with prior vaccines with MEP themselves and that T cell responses would be enhanced with TLR agonists, compared with IFA alone. METHODS: Participants with resected stage IIB-IV melanoma were vaccinated with seven long melanoma peptides (LPV7) from tyrosinase, gp100, MAGE-A1, MAGE-A10, and NY-ESO-1, each containing a known MEP for CD8+ T cells, plus a tetanus helper peptide (Tet) restricted by Class II MHC. Enrollment was guided by an adaptive design to one of seven adjuvant combinations. Vaccines were administered at weeks 1, 2, 3, 6, 9, 12 at rotating injection sites. T cell and IgG antibody (Ab) responses were measured with IFN-gamma ELIspot assay ex vivo and ELISA, respectively. RESULTS: Fifty eligible participants were assigned to seven study groups, with highest enrollment on arm E (LPV7+Tet+IFA+polyICLC). There was one dose-limiting toxicity (DLT) in Group E (grade 3 injection site reaction, 6% DLT rate). All other treatment-related adverse events were grades 1-2. The CD8+ T cell immune response rate (IRR) to MEPs was 18%, less than in prior studies using MEP vaccines in IFA. The CD8+ T cell IRR trended higher for IFA-containing adjuvants (24%) than adjuvants containing only TLR agonists (6%). Overall T cell IRR to full-length LPV7 was 30%; CD4+ T cell IRR to Tet was 40%, and serum Ab IRR to LPV7 was 84%. These IRRs also trended higher for IFA-containing adjuvants (36% vs 18%, 48% vs 24%, and 97% vs 60%, respectively). CONCLUSIONS: The LPV7 vaccine is safe with each of seven adjuvant strategies and induced T cell responses to CD8 MEPs ex vivo in a subset of patients but did not enhance IRRs compared with prior vaccines using short peptides. Immunogenicity was supported more by IFA than by TLR agonists alone and may be enhanced by polyICLC plus IFA. TRIAL REGISTRATION NUMBER: NCT02126579.


Assuntos
Melanoma/tratamento farmacológico , Receptores Toll-Like/uso terapêutico , Vacinas de Subunidades Antigênicas/uso terapêutico , Feminino , Humanos , Masculino , Fatores de Risco , Vacinas de Subunidades Antigênicas/farmacologia
11.
J Surg Res ; 267: 309-319, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34175585

RESUMO

BACKGROUND: Unplanned reoperations and unplanned readmissions can increase morbidity and mortality. Few studies however, have explored the association of reoperation and readmission among general surgery patients. Our aim was to examine this relationship in selected abdominal operations. METHODS: Data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Participant Use Data Files from 2014 to 2018 were utilized. Six groups of operations, defined by ACS NSQIP procedure codes for ventral hernia repair, colectomy, appendectomy, proctectomy, small bowel resection, and gastrectomy, were assessed. Patients discharged ≤ 14 days after operation were included in the study. This time period was selected to reduce ACS NSQIP 30 day post-surgery follow-up bias. Unplanned reoperations were defined as those occurring during the index hospitalization. The primary outcome was unplanned readmission that occurred ≤ 14 days from the date of discharge. Logistic regression models were used to examine variables associated with unplanned readmission for each procedure group. RESULTS: A total of 787,118 patients were included: ventral hernia repair 35.2%, colectomy 30.6%, appendectomy 26.5%, proctectomy 3.7%, small bowel resection 3.2%, and gastrectomy 0.8%. Unplanned reoperation was independently associated with unplanned readmission for ventral hernia repair (OR 2.84, 95% CI 2.28-3.54, P < 0.001), colectomy (OR 1.58, CI 1.42- 1.76, P < 0.001), appendectomy (OR 2.91, CI 2.21-3.84, P < 0.001), and proctectomy (OR 1.41, CI 1.10-1.81, P = 0.006). Other clinically relevant covariates associated with readmission were partially dependent functional status before colectomy (OR 1.34, CI 1.23-1.46, P < 0.001), ventral hernia repair (OR 1.79, CI 1.54-2.09, P < 0.001), and small bowel resection (OR 1.44, CI 1.18-1.77, P < 0.001; and ASA 4/5 classification for colectomy (OR 2.71, CI 2.36-3.11, P < 0.001), proctectomy (OR 2.10, CI 1.48-2.97, P < 0.001), ventral hernia repair (OR 8.19, CI 6.78-9.88, P < 0.001), appendectomy (OR 2.80, CI 2.35-3.34, P < 0.001), and small bowel resection (OR 3.42, CI 2.20-5.32, P < 0.001). ASA 2, ASA 3 classification, age, and sex were also associated with unplanned readmission for most procedures. CONCLUSIONS: Unplanned reoperations are associated with an increase in unplanned readmission after selected abdominal operations included in this study. This factor should be considered in discharge and follow-up planning to help reduce unplanned readmissions.


Assuntos
Hérnia Ventral , Readmissão do Paciente , Hérnia Ventral/cirurgia , Humanos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Reoperação , Estudos Retrospectivos , Fatores de Risco
12.
J Gastrointest Surg ; 25(12): 3074-3083, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33948862

RESUMO

BACKGROUND: Readmissions are costly and inconvenient for patients, and occur frequently in hepatopancreatobiliary (HPB) surgery practice. Readmission prediction tools exist, but most have not been designed or tested in the HPB patient population. METHODS: Pancreatectomy and hepatectomy operation-specific readmission models defined as subspecialty readmission risk assessments (SRRA) were developed using clinically relevant data from merged 2014-15 ACS NSQIP Participant Use Data Files and Procedure Targeted datasets. The two derived procedure-specific models were tested along with 6 other readmission models in institutional validation cohorts in patients who had pancreatectomy or hepatectomy, respectively, between 2013 and 2017. Models were compared using area under the receiver operating characteristic curves (AUC). RESULTS: A total of 16,884 patients (9169 pancreatectomy and 7715 hepatectomy) were included in the derivation models. A total of 665 patients (383 pancreatectomy and 282 hepatectomy) were included in the validation models. Specialty-specific readmission models outperformed general models. AUC characteristics of the derived pancreatectomy and hepatectomy SRRA (pancreatectomy AUC=0.66, hepatectomy AUC=0.74), modified Readmission After Pancreatectomy (AUC=0.76), and modified Readmission Risk Score for hepatectomy (AUC=0.78) outperformed general models for readmission risk: LOS/2 + ASA integer-based score (pancreatectomy AUC=0.58, hepatectomy AUC=0.66), LACE Index (pancreatectomy AUC=0.54, hepatectomy AUC=0.62), Unplanned Readmission Nomogram (pancreatectomy AUC=0.52, hepatectomy AUC=0.55), and institutional ARIA (pancreatectomy AUC=0.46, hepatectomy AUC=0.58). CONCLUSION: HPB readmission risk models using 30-day subspecialty-specific data outperform general readmission risk tools. Hospitals and practices aiming to decrease readmissions in HPB surgery patient populations should use specialty-specific readmission reduction strategies.


Assuntos
Hepatectomia , Pancreatectomia , Readmissão do Paciente , Complicações Pós-Operatórias , Hepatectomia/efeitos adversos , Humanos , Pancreatectomia/efeitos adversos , Readmissão do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Curva ROC , Estudos Retrospectivos , Fatores de Risco
13.
J Immunother Cancer ; 9(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34035112

RESUMO

BACKGROUND: Experimental cancer vaccines are traditionally administered by injection in subcutaneous tissue or muscle, commonly with adjuvants that create chronic inflammatory depots. Injection of melanoma-derived peptides induces T cell responses; however, the depots that form following injection may inhibit optimization of the immune response. In skin, epidermal Langerhans cells (LC) are a dominant source of professional antigen presenting cells. We hypothesized that: (1) applying melanoma-derived peptides topically, in proximity to LC, could be immunogenic and safe, with low vaccine-site toxicity and (2) topical toll-like receptor 7 (TLR7) agonist would increase immunogenicity of the peptide vaccine. METHODS: Twelve melanoma peptides plus a tetanus helper peptide were combined with granulocyte macrophage colony stimulating factor (GM-CSF) and were administered topically on days 1, 8, and 15, to 28 patients randomized to one of four adjuvant preparations: (1) incomplete Freund's adjuvant (IFA); (2) IFA plus a TLR7 agonist (imiquimod) administered on days 0, 7, 14; (3) dimethyl sulfoxide (DMSO) or (4) DMSO+ imiquimod administered on day 0, 7, 14. Every 3 weeks thereafter (x 6), the peptides were combined with GM-CSF and were injected into the dermis and subcutis in an emulsion with IFA. Toxicities were recorded and immune responses assayed by ELIspot. RESULTS: CD8+ T cell responses to transdermal vaccination in DMSO occurred in 83% of participants in group 3 and 86% in group 4, and responses to vaccination in IFA were observed in 29% of participants in group 1 and 14% in group 2. Overall, 61% of participants had CD4+ T cell immune responses to the tetanus peptide, with large, durable responses in groups 3 and 4. Five of seven participants in group 4 had a severe rash, one that was dose limiting. Ten-year overall survival was 67% and disease-free survival was 44%. CONCLUSIONS: These data provide proof of principle for immunogenicity in humans of transdermal immunization using peptides in DMSO. Further study is warranted into the pharmacokinetics and immunobiology of TLR agonists as vaccine adjuvants during transcutaneous application. Overall survival is high, supporting further investigation of this immunization approach.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Imiquimode/administração & dosagem , Imunogenicidade da Vacina , Antígenos Específicos de Melanoma/administração & dosagem , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Receptor 7 Toll-Like/agonistas , Adjuvantes Imunológicos/efeitos adversos , Administração Cutânea , Adolescente , Adulto , Idoso , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Feminino , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/efeitos adversos , Adjuvante de Freund/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Imiquimode/efeitos adversos , Imiquimode/imunologia , Injeções Intradérmicas , Injeções Subcutâneas , Lipídeos/administração & dosagem , Lipídeos/efeitos adversos , Lipídeos/imunologia , Masculino , Melanoma/imunologia , Melanoma/metabolismo , Antígenos Específicos de Melanoma/efeitos adversos , Antígenos Específicos de Melanoma/imunologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Fatores de Tempo , Receptor 7 Toll-Like/metabolismo , Resultado do Tratamento , Vacinação , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologia , Adulto Jovem
14.
Neurooncol Pract ; 8(1): 40-47, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33664968

RESUMO

BACKGROUND: Seizures are common among patients with low-grade glioma (LGG) and can significantly affect morbidity. We sought to determine the association between the clinical and molecular factors with seizure incidence and refractoriness in LGG patients. METHODS: We conducted a retrospective review at the University of Virginia in patients with LGG (World Health Organization, WHO Grade II) evaluated between 2002 and 2015. Descriptive statistics were calculated for variables of interest, and the Kaplan-Meier method was used to estimate survival curves, which were compared with the log-rank test. RESULTS: A total of 291 patients were included; 254 had molecular testing performed for presence of an isocitrate dehydrogenase (IDH) mutation and/or 1p/19q codeletion. Sixty-eight percent of patients developed seizures prior to LGG diagnosis; 41% of all patients had intractable seizures. Using WHO 2016 integrated classification, there was no significant difference in seizure frequency during preoperative and postoperative periods or in developing intractable seizures, though a trend toward increased preoperative seizure incidence among patients with the IDH mutation was identified (P = .09). Male sex was significantly associated with higher seizure incidence during preoperative (P < .001) and postoperative periods (P < .001); men were also more likely to develop intractable seizures (P = .01). CONCLUSIONS: Seizures are common among patients with LGG. Differences in preoperative or postoperative and intractable seizure rates by WHO 2016 classification were not detected. Our data showed a trend toward higher seizure incidence preoperatively in patients with IDH-mutant LGG. We describe a unique association between male sex and seizure incidence and intractability that warrants further study.

15.
Cancer Immunol Immunother ; 70(8): 2151-2164, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33454795

RESUMO

The strength and durability of systemic anti-tumor immune responses induced by cancer vaccines depends on adjuvants to support an immunogenic vaccine site microenvironment (VSME). Adjuvants include water-in-oil emulsions with incomplete Freund's adjuvant (IFA) and combinations of toll-like receptor (TLR) agonists, including a preparation containing TLR4 and TLR9 agonists with QS-21 (AS15). IFA-containing vaccines can promote immune cell accumulation at the VSME, whereas effects of AS15 are largely unexplored. Therefore, we assessed innate and adaptive immune cell accumulation and gene expression at the VSME after vaccination with AS15 and compared to effects with IFA. We hypothesized that AS15 would promote less accumulation of innate and adaptive immune cells at the VSME than IFA vaccines. In two clinical trials, patients with resected high-risk melanoma received either a multipeptide vaccine with IFA or a recombinant MAGE-A3 protein vaccine with AS15. Vaccine site biopsies were obtained after one or multiple vaccines. T cells accumulated early after vaccines with AS15, but this was not durable or of the same magnitude as vaccination in IFA. Vaccines with AS15 increased durable expression of DC- and T cell-related genes, as well as PD-L1 and IDO1, suggesting complex activation and regulation of innate and adaptive immune function with AS15. These changes were generally greater with vaccines containing IFA, but IFA induced reduction in myeloid suppressor cells markers. Evidence of tertiary lymphoid structure (TLS) formation was observed with both adjuvants. Our findings highlight adjuvant-dependent changes in immune features at the VSME that may impact systemic immune responses.


Assuntos
Imunidade Adaptativa/imunologia , Vacinas Anticâncer/imunologia , Imunidade Inata/imunologia , Melanoma/imunologia , Neoplasias Cutâneas/imunologia , Adjuvantes Imunológicos/farmacologia , Antígenos de Neoplasias/imunologia , Feminino , Adjuvante de Freund/imunologia , Humanos , Lipídeos/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Vacinação/métodos , Vacinas de Subunidades Antigênicas/imunologia
16.
J Immunother Cancer ; 9(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33479025

RESUMO

BACKGROUND: Peptide vaccines designed to stimulate melanoma-reactive CD4+ T cells can induce T cell and antibody (Ab) responses, associated with enhanced overall survival. We hypothesized that adding toll-like receptor 3 agonist polyICLC to an incomplete Freund's adjuvant (IFA) would be safe and would support strong, durable CD4+ T cell and Ab responses. We also hypothesized that oral low-dose metronomic cyclophosphamide (mCy) would be safe, would reduce circulating regulatory T cells (T-regs) and would further enhance immunogenicity. PARTICIPANTS AND METHODS: An adaptive design based on toxicity and durable CD4+ T cell immune response (dRsp) was used to assign participants with resected stage IIA-IV melanoma to one of four study regimens. The regimens included a vaccine comprising six melanoma peptides restricted by Class II MHC (6MHP) in an emulsion with IFA alone (Arm A), with IFA plus systemic mCy (Arm B), with IFA+ local polyICLC (Arm C), or with IFA+ polyICLC+ mCy (Arm D). Toxicities were recorded (CTCAE V.4.03). T cell responses were measured by interferon γ ELIspot assay ex vivo. Serum Ab responses to 6MHP were measured by ELISA. Circulating T-regs were assessed by flow cytometry. RESULTS: Forty-eight eligible participants were enrolled and treated. Early data on safety and dRsp favored enrollment on arm D. Total enrollment on Arms A-D were 3, 7, 6, and 32, respectively. Treatment-related dose-limiting toxicities (DLTs) were observed in 1/7 (14%) participants on arm B and 2/32 (6%) on arm D. None exceeded the 25% DLT threshold for early closure to enrollment for any arm. Strong durable T cell responses to 6MHP were detected ex vivo in 0%, 29%, 67%, and 47% of participants on arms A-D, respectively. IgG Ab responses were greatest for arms C and D. Circulating T-regs frequencies were not altered by mCy. CONCLUSIONS: 6MHP vaccines administered with IFA, polyICLC, and mCy were well tolerated. The dRsp rate for arm D of 47% (90% CI 32 to 63) exceeded the 18% (90% CI 11 to 26) rate previously observed with 6MHP in IFA alone. Vaccination with IFA+ polyICLC (arm C) also showed promise for enhancing T cell and Ab responses.


Assuntos
Carboximetilcelulose Sódica/análogos & derivados , Ciclofosfamida/administração & dosagem , Adjuvante de Freund/administração & dosagem , Lipídeos/administração & dosagem , Melanoma/tratamento farmacológico , Poli I-C/administração & dosagem , Polilisina/análogos & derivados , Vacinas de Subunidades Antigênicas/administração & dosagem , Administração Metronômica , Administração Oral , Anticorpos/sangue , Linfócitos T CD4-Positivos/metabolismo , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Carboximetilcelulose Sódica/administração & dosagem , Carboximetilcelulose Sódica/efeitos adversos , Terapia Combinada , Ciclofosfamida/efeitos adversos , Feminino , Adjuvante de Freund/efeitos adversos , Humanos , Lipídeos/efeitos adversos , Masculino , Melanoma/imunologia , Melanoma/patologia , Estadiamento de Neoplasias , Poli I-C/efeitos adversos , Polilisina/administração & dosagem , Polilisina/efeitos adversos , Linfócitos T Reguladores/metabolismo , Resultado do Tratamento , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologia
17.
Neurology ; 96(7): e1063-e1069, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33361259

RESUMO

OBJECTIVE: To determine the incidence of venous thromboembolism (VTE) in lower-grade gliomas (LGGs, WHO grades II-III) and to stratify the risk of VTE by molecular subtype in gliomas grade II-IV, we performed a retrospective review of a large cohort of patients with glioma. METHODS: We performed a retrospective analysis of a cohort of 635 adult patients with glioma with molecular testing seen at the University of Virginia with a diagnosis of diffuse glioma established from January 2005 to August 2017. Estimates of cumulative incidence of VTE were calculated with death as competing risk; significance was determined using the Fine and Gray model. RESULTS: Of 256 patients with LGG, 81 were isocitrate dehydrogenase (IDH) wild-type; 113 IDH mutant, 1p/19q codeleted; and 62 IDH mutant, 1p/19q intact. With a median follow-up of 17.9 months, the overall cumulative incidence of VTE was 8.2% for grade II (147 patients), 9.2% for grade III (109 patients), and 30.5% for grade IV (334 patients). In grade II-IV patients, absence of an IDH mutation was associated with a threefold increase in VTE risk when compared to IDH-mutant patients (hazard ratio 3.06, 95% confidence interval 2.03-4.64). In patients with glioblastoma, there was no difference in VTE incidence according to O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. CONCLUSION: Patients with LGG have a higher VTE risk compared to the general population, which is decreased, but not eliminated, in the presence of an IDH mutation. MGMT promoter methylation in glioblastoma does not affect the incidence of VTE.


Assuntos
Neoplasias Encefálicas/complicações , Glioma/complicações , Isocitrato Desidrogenase/genética , Tromboembolia Venosa/epidemiologia , Adulto , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Feminino , Glioma/genética , Glioma/patologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Regiões Promotoras Genéticas , Estudos Retrospectivos , Risco , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/genética
18.
Front Immunol ; 11: 1516, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32765523

RESUMO

It has long been appreciated that immunoglobulins are not just the effector endpoint of humoral immunity, but rather have a complex role in regulating antibody responses themselves. Donor derived anti-RhD IgG has been used for over 50 years as an immunoprophylactic to prevent maternal alloimmunization to RhD. Although anti-RhD has dramatically decreased rates of hemolytic disease of the fetus and newborn (for the RhD alloantigen), anti-RhD also fails in some cases, and can even paradoxically enhance immune responses in some circumstances. Attempts to generate a monoclonal anti-RhD have largely failed, with some monoclonals suppressing less than donor derived anti-RhD and others enhancing immunity. These difficulties likely result, in part, because the mechanism of anti-RhD remains unclear. However, substantial evidence exists to reject the common explanations of simple clearance of RhD + RBCs or masking of antigen. Donor derived anti-RhD is a mixture of 4 different IgG subtypes. To the best of our knowledge an analysis of the role different IgG subtypes play in immunoregulation has not been carried out; and, only IgG1 and IgG3 have been tested as monoclonals. Multiple attempts to elicit alloimmune responses to human RhD epitopes in mice have failed. To circumvent this limitation, we utilize a tractable animal model of RBC alloimmunization using the human Kell glycoprotein as an antigen to test the effect of IgG subtype on immunoregulation by antibodies to RBC alloantigens. We report that the ability of an anti-RBC IgG to enhance, suppress (at the level of IgM responses), or have no effect is a function of the IgG subclass in this model system.


Assuntos
Eritrócitos/imunologia , Imunidade Humoral , Imunoglobulina G/imunologia , Imunomodulação , Isoanticorpos/imunologia , Isoantígenos/imunologia , Receptores Fc/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Eritrócitos/metabolismo , Imunização Passiva , Camundongos , Camundongos Knockout
19.
J Immunother Cancer ; 8(1)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32385144

RESUMO

BACKGROUND: Phosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized by CD8 T-cells. These peptides are promising targets for cancer immunotherapy. Previous work identified an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) as one such target. The purpose of this study was to characterize a second phosphopeptide, from breast cancer antiestrogen resistance 3 (BCAR3), and to evaluate safety and immunogenicity of a novel immunotherapic vaccine comprising either or both of these phosphorylated peptides. METHODS: Phosphorylated BCAR3 protein was evaluated in melanoma and breast cancer cell lines by Western blot, and recognition by T-cells specific for HLA-A*0201-restricted phosphorylated BCAR3 peptide (pBCAR3126-134) was determined by 51Cr release assay and intracellular cytokine staining. Human tumor explants were also evaluated by mass spectrometry for presentation of pIRS2 and pBCAR3 peptides. For the clinical trial, participants with resected stage IIA-IV melanoma were vaccinated 6 times over 12 weeks with one or both peptides in incomplete Freund's adjuvant and Hiltonol (poly-ICLC). Adverse events (AEs) were coded based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V.4.03, with provision for early study termination if dose-limiting toxicity (DLT) rates exceeded 33%. The enrollment target was 12 participants evaluable for immune response to each peptide. T-cell responses were assessed by interferon-γ ELISpot assay. RESULTS: pBCAR3 peptides were immunogenic in vivo in mice, and in vitro in normal human donors, and T-cells specific for pBCAR3126-134 controlled outgrowth of a tumor xenograft. The pIRS21097-1105 peptide was identified by mass spectrometry from human hepatocellular carcinoma tumors. In the clinical trial, 15 participants were enrolled. All had grade 1 or 2 treatment-related AEs, but there were no grade 3-4 AEs, DLTs or deaths on study. T-cell responses were induced to the pIRS21097-1105 peptide in 5/12 patients (42%, 90% CI 18% to 68%) and to the pBCAR3126-134 peptide in 2/12 patients (17%, 90% CI 3% to 44%). CONCLUSION: This study supports the safety and immunogenicity of vaccines containing the cancer-associated phosphopeptides pBCAR3126-134 and pIRS21097-1105, and the data support continued development of immune therapy targeting phosphopeptides. Future studies will define ways to further enhance the magnitude and durability of phosphopeptide-specific immune responses. TRIAL REGISTRATION NUMBER: NCT01846143.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/efeitos adversos , Imunoterapia/efeitos adversos , Melanoma/terapia , Neoplasias Cutâneas/terapia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos de Neoplasias/genética , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Antígeno HLA-A2/genética , Antígeno HLA-A2/imunologia , Humanos , Imunogenicidade da Vacina , Imunoterapia/métodos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/imunologia , Masculino , Melanoma/imunologia , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Fosfopeptídeos/genética , Fosfopeptídeos/imunologia , Projetos Piloto , Estudo de Prova de Conceito , Neoplasias Cutâneas/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/genética , Vacinas de Subunidades Antigênicas/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Am J Surg ; 220(3): 682-686, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31983407

RESUMO

BACKGROUND: Independent associations between chronic liver disease, MELD, and postoperative outcomes among patients selected for liver resection have not been completely established. We hypothesized independent associations between MELD, cirrhosis, and postoperative mortality. METHODS: Patient-level data from the targeted hepatectomy module and ACS NSQIP PUF during 2014-2015 were merged. Multivariable regression models with interaction effect between MELD and liver texture (normal, congested/fatty, cirrhotic) tested the independent effects of covariates on mortality and morbidity. RESULTS: 3,530 patients were included, of whom 668 patients (19%) had cirrhosis. ACS NSQIP defined mortality (3.9%vs1.1%) and morbidity (23.5%vs15.8%) were higher in patients with cirrhosis (both p < 0.001). In multivariable models, cirrhosis (OR = 2.24; 95%CI:1.16-4.34, p = 0.016) and MELD (OR = 1.10; 95%CI:1.03-1.18, p = 0.007) were independently associated with mortality. MELD (OR = 1.04; 95%CI:1.002-1.08, p = 0.038) was associated with postoperative morbidity. CONCLUSIONS: Higher MELD and presence of cirrhosis have an independent negative effect on mortality after liver resection. MELD could be used to estimate postoperative risk in patients with and without cirrhosis.


Assuntos
Hepatectomia , Cirrose Hepática/complicações , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade , Seleção de Pacientes , Complicações Pós-Operatórias/mortalidade , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença
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