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2.
Antimicrob Agents Chemother ; 66(9): e0041422, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-35972242

RESUMO

Drug-resistant Neisseria gonorrhoeae is a serious global health concern. New drugs are needed that can overcome existing drug resistance and limit the development of new resistances. Here, we describe the small molecule tricyclic pyrimidoindole JSF-2414 [8-(6-fluoro-8-(methylamino)-2-((2-methylpyrimidin-5-yl)oxy)-9H-pyrimido[4,5-b]indol-4-yl)-2-oxa-8-azaspiro[4.5]decan-3-yl)methanol], which was developed to target both ATP-binding regions of DNA gyrase (GyrB) and topoisomerase (ParE). JSF-2414 displays potent activity against N. gonorrhoeae, including drug-resistant strains. A phosphate pro-drug, JSF-2659, was developed to facilitate oral dosing. In two different animal models of Neisseria gonorrhoeae vaginal infection, JSF-2659 was highly efficacious in reducing microbial burdens to the limit of detection. The parent molecule also showed potent in vitro activity against high-threat Gram-positive organisms, and JSF-2659 was shown in a deep tissue model of vancomycin-resistant Staphylococcus aureus (VRSA) and a model of Clostridioides difficile-induced colitis to be highly efficacious and protective. JSF-2659 is a novel preclinical drug candidate against high-threat multidrug resistant organisms with low potential to develop new resistance.


Assuntos
Gonorreia , Staphylococcus aureus Resistente à Meticilina , Pró-Fármacos , Trifosfato de Adenosina , Animais , Antibacterianos/química , Antibacterianos/farmacologia , DNA Girase/genética , Farmacorresistência Bacteriana , Feminino , Gonorreia/tratamento farmacológico , Metanol/farmacologia , Staphylococcus aureus Resistente à Meticilina/metabolismo , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae , Fosfatos/farmacologia , Pró-Fármacos/farmacologia , Inibidores da Topoisomerase II/farmacologia
3.
Clin Infect Dis ; 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35640877

RESUMO

BACKGROUND: The CLEAR trial demonstrated that a multi-site body decolonization regimen reduced post-discharge infection and hospitalization in methicillin-resistant Staphylococcus aureus (MRSA) carriers. This report describes decolonization efficacy in clearing site-specific MRSA colonization during the trial. METHODS: We performed a large, multi-center, randomized clinical trial of MRSA decolonization among adult patients after hospital discharge with MRSA infection or colonization. Participants were randomized 1:1 to either MRSA prevention education or education plus decolonization with 4% topical chlorhexidine daily, 0.12% oral chlorhexidine rinse twice daily, and 2% nasal mupirocin twice daily. The intervention was given for five consecutive days twice monthly. Participants were swabbed in the nares, throat, axilla/groin, and wound (if applicable) at baseline, 1, 3, 6, and 9 months after randomization. The primary outcomes of this report are follow-up colonization differences between groups. RESULTS: Among 2,121 participants, 1,058 were randomized to the decolonization group. By one month, MRSA colonization was lower in the decolonization group compared to the education only group (OR = 0.44 [95% Confidence Interval 0.36-0.54, p≤0.001). Similar magnitude of reduction was seen in the nares (OR = 0.34 [0.27-0.42], p < 0.001) throat (OR = 0.55 [0.42-0.73], p < 0.001), and axilla/groin (OR = 0.57 [0.43-0.75], p < 0.001). These differences persisted through month 9 except at the wound site, which had a relatively small sample size. Higher regimen adherence was associated with lower MRSA colonization (p≤0.01). CONCLUSION: In a randomized clinical trial, a repeated post-discharge decolonization regimen for MRSA carriers reduced MRSA colonization overall and at multiple body sites. Higher treatment adherence was associated with greater reductions in MRSA colonization.

4.
Am J Infect Control ; 50(7): 828-830, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35151772

RESUMO

Focused Multivector Ultraviolet technology rapidly killed the SARS-CoV-2 coronavirus in-vitro. Plates were inoculated with a mean of greater than 106 plaque forming units of USA-WA1 Washington index patient strain of SARS-CoV-2 and exposed to ultraviolet, resulting in mean reductions of 99.99% within 30 seconds, 99.999% within 60 seconds, and 99.9999% within 90 seconds. These results support the effectiveness of Focused Multivector Ultraviolet technology for SARS-CoV-2 disinfection.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/prevenção & controle , Desinfecção/métodos , Hospitais , Humanos , Tecnologia , Raios Ultravioleta
5.
Clin Lymphoma Myeloma Leuk ; 22(7): e443-e451, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35031227

RESUMO

BACKGROUND: This was an open-label, phase 1b study assessing the safety, tolerability, preliminary efficacy and pharmacokinetics of the combination of atezolizumab and obinutuzumab in patients with relapsed/refractory follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL). There is a mechanistic rationale suggesting that this combination may enhance recruitment of both innate and adaptive immunity and be effective against CD20+ B-cell malignancies. MATERIALS AND METHODS: The study consisted of a safety evaluation stage and an expansion stage. Patients received obinutuzumab 1000 mg intravenously (IV) in cycle (C) 1, obinutuzumab plus atezolizumab 1200 mg IV for C2-8, and atezolizumab only from C9. Primary endpoints were to identify a recommended phase 2 dose (RP2D) for atezolizumab, and safety and tolerability in the safety and expansion stages. RESULTS: A total of 49 patients were enrolled (FL, n = 26; DLBCL, n = 23), with a median of 2 prior lines of treatment. The RP2D for atezolizumab was 1200 mg IV every 3 weeks. Adverse events reported in ≥ 20% of patients were fatigue (15 patients [31%]), nausea (13 patients [27%]), cough, and diarrhea (10 patients [20%] each). Objective response rate was 54% in the FL cohort (complete response [CR] rate: 23%) and 17% in the DLBCL cohort (CR: 4%). Median progression-free survival was 9 months for FL and 3 months for DLBCL. Median overall survival was not estimable for FL and 9 months for DLBCL. CONCLUSION: The combination of obinutuzumab and atezolizumab was determined to be safe and tolerable, with no new toxicities observed.


Assuntos
Linfoma Folicular , Linfoma Difuso de Grandes Células B , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos
6.
Nature ; 601(7894): 606-611, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34987225

RESUMO

Gram-negative bacteria are responsible for an increasing number of deaths caused by antibiotic-resistant infections1,2. The bacterial natural product colistin is considered the last line of defence against a number of Gram-negative pathogens. The recent global spread of the plasmid-borne mobilized colistin-resistance gene mcr-1 (phosphoethanolamine transferase) threatens the usefulness of colistin3. Bacteria-derived antibiotics often appear in nature as collections of similar structures that are encoded by evolutionarily related biosynthetic gene clusters. This structural diversity is, at least in part, expected to be a response to the development of natural resistance, which often mechanistically mimics clinical resistance. Here we propose that a solution to mcr-1-mediated resistance might have evolved among naturally occurring colistin congeners. Bioinformatic analysis of sequenced bacterial genomes identified a biosynthetic gene cluster that was predicted to encode a structurally divergent colistin congener. Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens expressing mcr-1 and intrinsically resistant pathogens with chromosomally encoded phosphoethanolamine transferase genes. These Gram-negative bacteria include extensively drug-resistant Acinetobacter baumannii and intrinsically colistin-resistant Neisseria gonorrhoeae, which, owing to a lack of effective treatment options, are considered among the highest level threat pathogens4. In a mouse neutropenic infection model, a biphenyl analogue of macolacin proved to be effective against extensively drug-resistant A. baumannii with colistin-resistance, thus providing a naturally inspired and easily produced therapeutic lead for overcoming colistin-resistant pathogens.


Assuntos
Antibacterianos , Colistina , Farmacorresistência Bacteriana , Bactérias Gram-Negativas , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/enzimologia , Acinetobacter baumannii/genética , Animais , Antibacterianos/farmacologia , Vias Biossintéticas/genética , Colistina/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Etanolaminas , Genes Bacterianos , Genoma Bacteriano , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Bactérias Gram-Negativas/genética , Camundongos , Testes de Sensibilidade Microbiana , Família Multigênica , Neutropenia/tratamento farmacológico , Neutropenia/microbiologia , Plasmídeos , Transferases (Outros Grupos de Fosfato Substituídos)
7.
Blood Adv ; 6(4): 1255-1263, 2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-34666347

RESUMO

Our group has recently demonstrated that chimeric antigen receptor T-cell therapy targeting the CD30 antigen (CD30.CAR-T) is highly effective in patients with relapsed and refractory (r/r) classical Hodgkin lymphoma (cHL). Despite high rates of clinical response, relapses and progression were observed in a subset of patients. The objective of this study was to characterize clinical and correlative factors associated with progression-free survival (PFS) after CD30.CAR-T cell therapy. We evaluated correlatives in 27 patients with r/r cHL treated with lymphodepletion and CD30.CAR-T cells. With a median follow-up of 9.5 months, 17 patients (63%) progressed, with a median PFS of 352 days (95% confidence interval: 116-not reached), and 2 patients died (7%) with a median overall survival of not reached. High metabolic tumor volume (MTV, >60 mL) immediately before lymphodepletion and CD30.CAR-T cell infusion was associated with inferior PFS (log rank, P = .02), which persisted after adjusting for lymphodepletion and CAR-T dose (log rank, P = .01 and P = .006, respectively). In contrast, receiving bridging therapy, response to bridging therapy, CD30.CAR-T expansion/persistence, and percentage of CD3+PD-1+ lymphocytes over the first 6 weeks of therapy were not associated with differences in PFS. In summary, this study reports an association between high baseline MTV immediately before lymphodepletion and CD30.CAR-T cell infusion and worse PFS in patients with r/r cHL. This trial was registered at www.clinicaltrials.gov as #NCT02690545.


Assuntos
Doença de Hodgkin , Receptores de Antígenos Quiméricos , Doença de Hodgkin/terapia , Humanos , Antígeno Ki-1 , Recidiva Local de Neoplasia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo , Carga Tumoral
9.
PLoS Pathog ; 17(10): e1010025, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34714894

RESUMO

The global SARS-CoV-2 coronavirus pandemic continues to be devastating in many areas. Treatment options have been limited and convalescent donor plasma has been used by many centers to transfer passive neutralizing antibodies to patients with respiratory involvement. The results often vary by institution and are complicated by the nature and quality of the donor plasma itself, the timing of administration and the clinical aspects of the recipients. SARS-CoV-2 infection is known to be associated with an increase in the blood concentrations of several inflammatory cytokines/chemokines, as part of the overall immune response to the virus and consequential to mediated lung pathology. Some of these correlates contribute to the cytokine storm syndrome and acute respiratory distress syndrome, often resulting in fatality. A Phase IIa clinical trial at our institution using high neutralizing titer convalescent plasma transfer gave us the unique opportunity to study the elevations of correlates in the first 10 days after infusion. Plasma recipients were divided into hospitalized COVID-19 pneumonia patients who did not (Track 2) or did (Track 3) require mechanical ventilation. Several cytokines were elevated in the patients of each Track and some continued to rise through Day 10, while others initially increased and then subsided. Furthermore, elevations in MIP-1α, MIP-1ß and CRP correlated with disease progression of Track 2 recipients. Overall, our observations serve as a foundation for further study of these correlates and the identification of potential biomarkers to improve upon convalescent plasma therapy and to drive more successful patient outcomes.


Assuntos
COVID-19/terapia , Quimiocinas/sangue , Citocinas/sangue , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , COVID-19/imunologia , Feminino , Humanos , Imunização Passiva , Isotipos de Imunoglobulinas/sangue , Masculino , Pessoa de Meia-Idade
10.
Blood Adv ; 5(23): 5179-5189, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34516611

RESUMO

Although an expanding array of effective treatments has resulted in recent improvement in survival of patients with mantle cell lymphoma (MCL), outcomes remain heterogeneous, and identification of prognostic factors remains a priority. We assessed the prognostic impact of time to progression of disease (POD) after first-line therapy among 455 patients with relapsed MCL. Patients were categorized by duration of first remission as PRF/POD6, defined as progressive disease during induction or POD within 6 months of diagnosis (n = 65; 14%); POD6-24, defined as POD between 6 and 24 months after diagnosis (n = 153; 34%); and POD>24, defined as POD >24 months after diagnosis (n = 237; 53%). The median overall survival from POD (OS2) was 1.3 years (95% confidence interval [CI], 0.9-2.4) for patients with PRF/POD6, 3 years (95% CI, 2-6.8) for those with POD6-24, and 8 years (95% CI, 6.2-NR) for those with POD>24. Median OS2 was inferior in patients with early POD (defined as PRF/POD6 or POD6-24) after both intensive and less intensive frontline treatment. The prognostic performance of time until POD was replicated in an independent cohort of 245 patients with relapsed MCL, with median OS2 of 0.3 years (95% CI, 0.1-0.5) for PRF/POD6, 0.8 years (95% CI, 0.6-0.9) for POD6-24, and 2.4 years (95% CI 2.1-2.7) for POD>24. Early POD is associated with inferior OS2 in patients with relapsed MCL, identifying a high-risk population for future prospective studies.


Assuntos
Linfoma de Célula do Manto , Adulto , Humanos , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/tratamento farmacológico , Prognóstico , Estudos Prospectivos , Recidiva , Resultado do Tratamento
11.
ACS Infect Dis ; 7(8): 2508-2521, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34342426

RESUMO

We present the application of Bayesian modeling to identify chemical tools and/or drug discovery entities pertinent to drug-resistant Staphylococcus aureus infections. The quinoline JSF-3151 was predicted by modeling and then empirically demonstrated to be active against in vitro cultured clinical methicillin- and vancomycin-resistant strains while also exhibiting efficacy in a mouse peritonitis model of methicillin-resistant S. aureus infection. We highlight the utility of an intrabacterial drug metabolism (IBDM) approach to probe the mechanism by which JSF-3151 is transformed within the bacteria. We also identify and then validate two mechanisms of resistance in S. aureus: one mechanism involves increased expression of a lipocalin protein, and the other arises from the loss of function of an azoreductase. The computational and experimental approaches, discovery of an antibacterial agent, and elucidated resistance mechanisms collectively hold promise to advance our understanding of therapeutic regimens for drug-resistant S. aureus.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Preparações Farmacêuticas , Infecções Estafilocócicas , Animais , Teorema de Bayes , Camundongos , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus
12.
Case Rep Gastrointest Med ; 2021: 5583665, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394999

RESUMO

BACKGROUND: Late-onset posttransplant lymphoproliferative disorder (PTLD) after orthotopic heart transplantation is rare. Case Presentation. We present a rare diagnosis of small bowel stricture caused by healed lymphomatous ulcers in a patient with orthotopic heart transplantation and PTLD diagnosed 25 years after initial transplantation. We also demonstrate successful endoscopic balloon dilations that improved the patient's obstructive symptoms. CONCLUSION: It is important to consider stricture from healed lymphomatous ulcers in posttransplant patients presenting with obstructive symptoms.

13.
Am J Hematol ; 96(11): 1374-1384, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34324220

RESUMO

Clinical outcomes and predictors of survival in patients with newly diagnosed mantle cell lymphoma (MCL) treated in the rituximab era (2000-2015) at 12 US academic centers were assessed to identify determinants of survival across age groups. Objectives were to characterize and compare practice patterns, outcomes and prognostic factors for survival in younger patients (age < 65) and older patients (age ≥ 65 years). Among 1162 patients included, 697 were younger and 465 were older. In younger patients, 2-year progression free survival (PFS) and overall survival (OS) rates were 79% and 92% respectively; blastoid histology, ECOG ≥ 2, and lack of maintenance rituximab (MR) remained statistically relevant to poor OS on univariate analysis (UVA) and multivariate analysis (MVA). In older patients, 2-year PFS and OS rates were 67% and 86% respectively; lack of maintenance rituximab remained significantly associated with inferior PFS and OS on UVA and MVA (p < 0.001). Two-year PFS rates were 79%, and 67% and 2-year OS rates were 92% and 86% for ages < 65 and ≥ 65 respectively (p < 0.001). First-line high-dose cytarabine exposure and/or MR lessened the negative impact of age on survival. Taken collectively, survival outcomes for older patients remain inferior to those of younger patients in the rituximab era. However, maintenance rituximab and potentially high-dose cytarabine-based induction can mitigate the negative impact of age on survival.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Rituximab/uso terapêutico , Fatores Etários , Idoso , Feminino , Humanos , Linfoma de Célula do Manto/epidemiologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
14.
Curr Gastroenterol Rep ; 23(7): 10, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34212281

RESUMO

PURPOSE OF REVIEW: Hepatobiliary complications are common in Roux-en-Y gastric bypass (RYGB) patients. Despite development of multiple surgical and endoscopic access techniques over the years, ERCP using standard duodenoscope remains challenging in these patients due to the altered anatomy. RECENT FINDINGS: Limited success with enteroscope-assisted and laparoscope-assisted ERCP led to the evolution of the novel EUS-directed transgastric ERCP (EDGE) procedure, with variations of this technique termed as Gastric Access Temporary for Endoscopy (GATE), EUS-guided TransGastric ERCP (EUS-TG-ERCP), EUS-guided GastroGastrostomy-assisted ERCP (EUS-GG-ERCP), and EUS-directed transgastric intervention (EDGI). EDGE has high technical (100%) and clinical success rates (60-100%), lower adverse event rate (1.5-7.6%), and up to 20% access stent migration rate; without any significant weight changes. EDGE has significantly shorter procedure time (73vs184min), post-procedural hospital stays (0.8vs2.65 days) and is more cost effective compared to other modalities. EDGE technique addresses the challenges of RYGB anatomy as a minimally invasive, clinically successful, fully endoscopic, and cost-effective option. We present a literature review of the EDGE technique from its inception to current, in addition to reviewing other access techniques, their advantages, disadvantages and outcomes.


Assuntos
Colangiopancreatografia Retrógrada Endoscópica/métodos , Endossonografia/métodos , Derivação Gástrica , Derivação Gástrica/efeitos adversos , Humanos , Estômago/cirurgia
15.
Cancer ; 127(21): 3991-3997, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34289094

RESUMO

BACKGROUND: Aggressive large B-cell lymphomas (LBCLs) are curable, but previous studies have shown inferior outcomes in minorities. Nurse navigation programs can improve patient outcomes by providing patient support. This study presents the outcomes of White and minority patients with aggressive LBCL at an institution with an active nurse navigation program. METHODS: The authors prospectively collected baseline characteristics, treatment regimens, and outcome data for patients with aggressive LBCL. Navigation encounters were characterized as low or high intensity. Overall survival (OS) and progression-free survival (PFS) were calculated with Kaplan-Meier methods. Baseline characteristics were compared with Fisher exact tests. RESULTS: Two hundred four consecutive patients (47 minority patients and 157 White patients) were included. Results were presented as minorities versus Whites. There were no differences in prognostic scores (Revised International Prognostic Index score of 3-5, 43% vs 47%; P = .50), frontline chemotherapy (98% vs 96%; P = .68), or the incidence of relapsed/refractory disease (40% vs 38%; P = .74). For relapsed/refractory LBCL, similar proportions of patients underwent hematopoietic stem cell transplantation (32% vs 29%; P > .99) or chimeric antigen receptor T-cell therapy (16% vs 19%; P > .99). Enrollment in clinical trials was comparable (17% vs 14%; P = .64). More than 85% received nurse navigation, but minorities had higher intensity navigation encounters (42% vs 21%; P = .01). The 2-year OS rates were 81% and 76% for minorities and Whites, respectively (P = .27); the 2-year PFS rates were 62% and 65%, respectively (P = .78). CONCLUSIONS: This study shows similar survival between Whites and minorities with aggressive LBCL, which was likely due to equal access to guideline-concordant therapy. Minorities received higher intensity navigation encounters, which may have helped them to overcome socioeconomic disadvantages.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Acesso aos Serviços de Saúde , Humanos , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B/terapia , Intervalo Livre de Progressão , Estudos Retrospectivos
16.
J Extracell Vesicles ; 10(8): e12110, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34122779

RESUMO

Circulating nucleic acids, encapsulated within small extracellular vesicles (EVs), provide a remote cellular snapshot of biomarkers derived from diseased tissues, however selective isolation is critical. Current laboratory-based purification techniques rely on the physical properties of small-EVs rather than their inherited cellular fingerprints. We established a highly-selective purification assay, termed EV-CATCHER, initially designed for high-throughput analysis of low-abundance small-RNA cargos by next-generation sequencing. We demonstrated its selectivity by specifically isolating and sequencing small-RNAs from mouse small-EVs spiked into human plasma. Western blotting, nanoparticle tracking, and transmission electron microscopy were used to validate and quantify the capture and release of intact small-EVs. As proof-of-principle for sensitive detection of circulating miRNAs, we compared small-RNA sequencing data from a subset of small-EVs serum-purified with EV-CATCHER to data from whole serum, using samples from a small cohort of recently hospitalized Covid-19 patients. We identified and validated, only in small-EVs, hsa-miR-146a and hsa-miR-126-3p to be significantly downregulated with disease severity. Separately, using convalescent sera from recovered Covid-19 patients with high anti-spike IgG titers, we confirmed the neutralizing properties, against SARS-CoV-2 in vitro, of a subset of small-EVs serum-purified by EV-CATCHER, as initially observed with ultracentrifuged small-EVs. Altogether our data highlight the sensitivity and versatility of EV-CATCHER.


Assuntos
Vesículas Extracelulares/química , Técnicas Imunológicas/métodos , Animais , Secreções Corporais/química , COVID-19/sangue , COVID-19/fisiopatologia , Chlorocebus aethiops , MicroRNA Circulante , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células MCF-7 , Camundongos , Células RAW 264.7 , Índice de Gravidade de Doença , Células Vero
17.
OTO Open ; 5(2): 2473974X211016283, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34036239

RESUMO

OBJECTIVE: To characterize the relationship between severity of sleep apnea and coronavirus disease 2019 (COVID-19) hospitalization and severe illness. STUDY DESIGN: Retrospective cohort study. SETTING: Montefiore Health System in the Bronx, New York. METHODS: The data set consisted of adult patients with an active diagnosis of obstructive sleep apnea in the past 2 years and a positive severe acute respiratory syndrome coronavirus 2 quantitative polymerase chain reaction test at our institution between March 16, 2020, and May 26, 2020. Sleep apnea severity and continuous positive airway pressure compliance data were abstracted from the electronic medical record. The International Classification of Diseases, 10th Revision was used to classify comorbidities. RESULTS: A total of 461 patients with sleep apnea tested positive for COVID-19, of whom 149 were excluded for missing data in the electronic medical record. Patients with moderate and severe sleep apnea had higher rates of COVID-19 hospitalization compared to those with mild sleep apnea (P = .003). This association was reduced when accounting for confounders, most notably the Charlson Comorbidity Index, a measure of comorbid illness burden. Moderate and severe sleep apnea were associated with increased Charlson Comorbidity Indices, compared to mild sleep apnea (P = .01). Sleep apnea severity was not associated with a composite outcome of mechanical ventilation, intensive care unit admission, and death. CONCLUSION: Sleep apnea severity was associated with the Charlson Comorbidity Index and may be a risk factor for COVID-19 hospitalization. We found no evidence that sleep apnea severity among hospitalized patients was associated with a composite outcome of mechanical ventilation, intensive care unit admission, and death.

18.
Eur J Haematol ; 107(3): 301-310, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33973276

RESUMO

INTRODUCTION: While most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent-behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy. METHODS: Out of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high-dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non-intensive (n = 131). RESULTS: There was no difference in progression-free (PFS; P = .224) or overall survival (OS; P = .167) in deferred patients who received non-intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P = .015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model. CONCLUSIONS: These results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma de Célula do Manto/terapia , Idoso , Ciclofosfamida/uso terapêutico , Dexametasona/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Indução de Remissão/métodos , Estudos Retrospectivos , Tempo para o Tratamento , Transplante Autólogo , Vincristina/uso terapêutico
19.
Blood Adv ; 5(6): 1648-1659, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33710337

RESUMO

Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Retrospectivos , Transplante Autólogo
20.
JCI Insight ; 6(6)2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33571168

RESUMO

Here, we report on a phase IIa study to determine the intubation rate, survival, viral clearance, and development of endogenous Abs in patients with COVID-19 pneumonia treated with convalescent plasma (CCP) containing high levels of neutralizing anti-SARS-CoV-2 Abs. Radiographic and laboratory evaluation confirmed all 51 treated patients had COVID-19 pneumonia. Fresh or frozen CCP from donors with high titers of neutralizing Abs was administered. The nonmechanically ventilated patients (n = 36) had an intubation rate of 13.9% and a 30-day survival rate of 88.9%, and the overall survival rate for a comparative group based on network data was 72.5% (1625/2241). Patients had negative nasopharyngeal swab rates of 43.8% and 73.0% on days 10 and 30, respectively. Patients mechanically ventilated had a day-30 mortality rate of 46.7%; the mortality rate for a comparative group based on network data was 71.0% (369/520). All evaluable patients were found to have neutralizing Abs on day 3 (n = 47), and all but 1 patient had Abs on days 30 and 60. The only adverse event was a mild rash. In this study on patients with COVID-19 disease, we show therapeutic use of CCP was safe and conferred transfer of Abs, while preserving endogenous immune response.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , COVID-19/terapia , Imunoglobulina G/uso terapêutico , Plasma , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Idoso , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/imunologia , COVID-19/mortalidade , COVID-19/virologia , Convalescença , Feminino , Humanos , Imunização Passiva , Hospedeiro Imunocomprometido , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Pneumonia , Respiração Artificial
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