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1.
JAMA ; 327(7): 652-661, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35085383

RESUMO

Importance: Lung transplantation is a potentially lifesaving treatment for patients who are critically ill due to COVID-19-associated acute respiratory distress syndrome (ARDS), but there is limited information about the long-term outcome. Objective: To report the clinical characteristics and outcomes of patients who had COVID-19-associated ARDS and underwent a lung transplant at a single US hospital. Design, Setting, and Participants: Retrospective case series of 102 consecutive patients who underwent a lung transplant at Northwestern University Medical Center in Chicago, Illinois, between January 21, 2020, and September 30, 2021, including 30 patients who had COVID-19-associated ARDS. The date of final follow-up was November 15, 2021. Exposures: Lung transplant. Main Outcomes and Measures: Demographic, clinical, laboratory, and treatment data were collected and analyzed. Outcomes of lung transplant, including postoperative complications, intensive care unit and hospital length of stay, and survival, were recorded. Results: Among the 102 lung transplant recipients, 30 patients (median age, 53 years [range, 27 to 62]; 13 women [43%]) had COVID-19-associated ARDS and 72 patients (median age, 62 years [range, 22 to 74]; 32 women [44%]) had chronic end-stage lung disease without COVID-19. For lung transplant recipients with COVID-19 compared with those without COVID-19, the median lung allocation scores were 85.8 vs 46.7, the median time on the lung transplant waitlist was 11.5 vs 15 days, and preoperative venovenous extracorporeal membrane oxygenation (ECMO) was used in 56.7% vs 1.4%, respectively. During transplant, patients who had COVID-19-associated ARDS received transfusion of a median of 6.5 units of packed red blood cells vs 0 in those without COVID-19, 96.7% vs 62.5% underwent intraoperative venoarterial ECMO, and the median operative time was 8.5 vs 7.4 hours, respectively. Postoperatively, the rates of primary graft dysfunction (grades 1 to 3) within 72 hours were 70% in the COVID-19 cohort vs 20.8% in those without COVID-19, the median time receiving invasive mechanical ventilation was 6.5 vs 2.0 days, the median duration of intensive care unit stay was 18 vs 9 days, the median post-lung transplant hospitalization duration was 28.5 vs 16 days, and 13.3% vs 5.5% required permanent hemodialysis, respectively. None of the lung transplant recipients who had COVID-19-associated ARDS demonstrated antibody-mediated rejection compared with 12.5% in those without COVID-19. At follow-up, all 30 lung transplant recipients who had COVID-19-associated ARDS were alive (median follow-up, 351 days [IQR, 176-555] after transplant) vs 60 patients (83%) who were alive in the non-COVID-19 cohort (median follow-up, 488 days [IQR, 368-570] after lung transplant). Conclusions and Relevance: In this single-center case series of 102 consecutive patients who underwent a lung transplant between January 21, 2020, and September 30, 2021, survival was 100% in the 30 patients who had COVID-19-associated ARDS as of November 15, 2021.


Assuntos
COVID-19/complicações , Transplante de Pulmão , Síndrome do Desconforto Respiratório/cirurgia , Adulto , Idoso , Oxigenação por Membrana Extracorpórea , Feminino , Humanos , Transplante de Pulmão/mortalidade , Masculino , Pessoa de Meia-Idade , Respiração Artificial , Síndrome do Desconforto Respiratório/etiologia , Estudos Retrospectivos , Resultado do Tratamento
3.
Commun Biol ; 4(1): 663, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34079066

RESUMO

The reciprocal interactions between pathogens and hosts are complicated and profound. A comprehensive understanding of these interactions is essential for developing effective therapies against infectious diseases. Interferon responses induced upon virus infection are critical for establishing host antiviral innate immunity. Here, we provide a molecular mechanism wherein isoform switching of the host IKKε gene, an interferon-associated molecule, leads to alterations in IFN production during EV71 infection. We found that IKKε isoform 2 (IKKε v2) is upregulated while IKKε v1 is downregulated in EV71 infection. IKKε v2 interacts with IRF7 and promotes IRF7 activation through phosphorylation and translocation of IRF7 in the presence of ubiquitin, by which the expression of IFNß and ISGs is elicited and virus propagation is attenuated. We also identified that IKKε v2 is activated via K63-linked ubiquitination. Our results suggest that host cells induce IKKε isoform switching and result in IFN production against EV71 infection. This finding highlights a gene regulatory mechanism in pathogen-host interactions and provides a potential strategy for establishing host first-line defense against pathogens.


Assuntos
Enterovirus Humano A/imunologia , Enterovirus Humano A/patogenicidade , Quinase I-kappa B/genética , Quinase I-kappa B/imunologia , Processamento Alternativo , Linhagem Celular , Genes de Troca , Células HEK293 , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Quinase I-kappa B/metabolismo , Imunidade Inata/genética , Fator Regulador 7 de Interferon/metabolismo , Interferon beta/biossíntese , Isoenzimas/genética , Isoenzimas/imunologia , Fosforilação , Ubiquitina/metabolismo
4.
Sci Rep ; 11(1): 5802, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707599

RESUMO

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukaemia (ALL), a high-risk subtype characterised by genomic alterations that activate cytokine receptor and kinase signalling, is associated with inferior outcomes in most childhood ALL clinical trials. Half of the patients with Ph-like ALL have kinase rearrangements or fusions. We examined the frequency and spectrum of these fusions using a retrospective cohort of 212 newly diagnosed patients with childhood B-cell ALL. Samples without known chromosomal alterations were subject to multiplex reverse transcription polymerase chain reaction to identify known Ph-like kinase fusions. Immunoglobulin heavy chain locus (IGH) capture and kinase capture were applied to samples without known kinase fusions. We detected known kinase fusions in five of 212 patients, comprising EBF1-PDGFRB, ETV6-ABL1, ZC3HAV1-ABL2, EPOR-IGH, and CNTRL-ABL1. Two patients with P2RY8-CRLF2 were identified. Patients with non-Ph kinase fusions had inferior 5-year event-free survival and overall survival compared with patients with other common genetic alterations. The prevalence of non-Ph kinase fusions in our Taiwanese cohort was lower than that reported in Caucasian populations. Future clinical trials with tyrosine kinase inhibitors may be indicated in Taiwan because of the inferior outcomes for B-cell ALL with kinase fusions.


Assuntos
Proteínas de Fusão Oncogênica/metabolismo , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Proteínas Quinases/metabolismo , Sequência de Bases , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Deleção de Genes , Rearranjo Gênico/genética , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Lactente , Masculino , Proteínas de Neoplasias/metabolismo , Intervalo Livre de Progressão , Taiwan
5.
Contemp Clin Trials ; 103: 106294, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33515781

RESUMO

BACKGROUND: Several studies report a high prevalence of non-adherence to prescribed immunosuppressive (IS) medications among kidney transplant recipients (KTRs), yet few interventions have been effective for helping patients sustain appropriate post-transplant adherence. We describe a multifaceted, evidence-based, medication adherence monitoring strategy ('TAKE IT') that leverages available transplant center resources to identify potential medication non-adherence and other concerns earlier to prevent complications that could result from inadequate IS adherence. METHODS: The TAKE IT strategy includes: 1) medication adherence mobile application; 2) routine, online patient self-reported adherence assessments; 3) care alert notifications via the electronic health record (EHR) directed to transplant coordinators; 4) quarterly adherence reports to monitor IS values and summarize adherence trends; 5) deployment of adherence support tools tailored to specific adherence concerns. To test the TAKE IT intervention, we will conduct a two-arm, patient-randomized controlled trial at two large, diverse transplant centers (Northwestern University, Mayo Clinic, AZ) with planned recruitment of 450 KTRs (n = 225 per site) within 2 years of transplantation and 2 years of follow-up. Study assessments will take place at baseline, 6 weeks, 6, 12, 18 and 24 months. The primary effectiveness outcome is medication adherence via pill count, secondary outcomes include self-reported adherence and clinical outcomes. Process outcomes and cost-effectiveness will also be examined. CONCLUSION: The TAKE IT trial presents an innovative approach to monitoring and optimizing medication adherence among a population taking complex medication regimens. This trial seeks to evaluate the effectiveness and feasibility of this strategy compared to usual care.


Assuntos
Transplante de Rim , Adesão à Medicação , Projetos de Pesquisa , Humanos , Tecnologia da Informação , Rim , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplantados
7.
Oncol Lett ; 20(5): 166, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32934733

RESUMO

Anoikis resistance has been observed in various types of cancers in which anchorage-independent growth is a crucial step for cancer metastasis. Therefore, agents interfering with this specific cancer cell behavior may be integrated into novel antimetastatic strategies. Monascin (MS), a secondary metabolite found in Monascus species, is a known potent chemopreventive compound used for treating metabolic complications; however, the effect of MS on anoikis resistance has not been investigated. In this study, 4T1 breast cells were treated with MS under either suspension or adhesion conditions. The higher cytotoxicity of MS was more potent against suspended cells than against adherent cells. This selective cytotoxicity was due to the induction of anoikis, which was evidenced by changes in cell aggregation, caspase activity, and Annexin V/propidium iodide binding as well as the results of systemic metastasis in an animal model. Furthermore, MS inhibited E-cadherin and ß-catenin expression in the cells; the treated cells formed spherical aggregates, which suggested that anchorage-independent growth was prevented by MS. These results provide new insights into the mechanisms underlying the growth-preventing effect of MS on cancer cells and indicate the potential ability of MS to suppress metastasis.

8.
Chin Med ; 15: 77, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760434

RESUMO

BACKGROUND: Cisplatin (CDDP) is a chemotherapeutic drug which also causes adverse side effects. Glechoma hederacea is a traditional Chinese herb belonging to the Labiatae family and has many biological activities. Our previous study indicated that rosmarinic acid (RA) was the most abundant phytochemical in G. hederacea. However, the antioxidant or anti-inflammatory effects of the combined treatment of G. hederacea, RA and CDDP on human renal cell carcinoma (RCC) 786-O cells have not been clearly demonstrated. We aimed to investigate the bioefficacy of hot water extracts of G. hederacea (HWG) and RA in inhibiting RCC 786-O cell activity and its synergism with CDDP against metastatic renal cancer cell. METHODS: Bioactivities of the combination treatment of HWG, RA, HWG/CDDP and RA/CDDP were assessed using the MTT assay and transwell migration, and the crude extract/compound efficacy was evaluated using wound healing migration assays, flow cytometry and western blotting. RESULTS: Our study indicates that CDDP inhibits 786-O cell proliferation and migration and HWG and RA protect against these effects. On the other hand, HWG and RA demonstrate a low cytotoxic effect in human renal proximal tubular epithelial cell line -2 (HK-2 cells). Cell cycle analysis found that HWG/CDDP and RA/CDDP combined treatment exerted cytotoxicity by inducing G2/M arrest and apoptosis. RA in combined with CDDP significantly inhibiting the expression of p-FAK (Tyr 925) in RCC 786-O cells in vitro. CONCLUSION: We propose that the inhibition of RA on RCC 786-O cell invasion and migration may partly occur through the downregulation of FAK phosphorylation. The HWG/CDDP and RA/CDDP combined treatments may be effective strategies for intervention of RCC 786-O cell activity.

10.
Front Med (Lausanne) ; 7: 229, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32613001

RESUMO

Hypertension is one of the most common cardiovascular co-morbidities after successful kidney transplantation. It commonly occurs in patients with other metabolic diseases, such as diabetes mellitus, hyperlipidemia, and obesity. The pathogenesis of post-transplant hypertension is complex and is a result of the interplay between immunological and non-immunological factors. Post-transplant hypertension can be divided into immediate, early, and late post-transplant periods. This classification can help clinicians determine the etiology and provide the appropriate management for these complex patients. Volume overload from intravenous fluid administration is common during the immediate post-transplant period and commonly contributes to hypertension seen early after transplantation. Immunosuppressive medications and donor kidneys are associated with post-transplant hypertension occurring at any time point after transplantation. Transplant renal artery stenosis (TRAS) and obstructive sleep apnea (OSA) are recognized but common and treatable causes of resistant hypertension post-transplantation. During late post-transplant period, chronic renal allograft dysfunction becomes an additional cause of hypertension. As these patients develop more substantial chronic kidney disease affecting their allografts, fibroblast growth factor 23 (FGF23) increases and is associated with increased cardiovascular and all-cause mortality in kidney transplant recipients. The exact relationship between increased FGF23 and post-transplant hypertension remains poorly understood. Blood pressure (BP) targets and management involve both non-pharmacologic and pharmacologic treatment and should be individualized. Until strong evidence in the kidney transplant population exists, a BP of <130/80 mmHg is a reasonable target. Similar to complete renal denervation in non-transplant patients, bilateral native nephrectomy is another treatment option for resistant post-transplant hypertension. Native renal denervation offers promising outcomes for controlling resistant hypertension with no significant procedure-related complications. This review addresses the epidemiology, pathogenesis, and specific etiologies of post-transplant hypertension including TRAS, calcineurin inhibitor effects, OSA, and failed native kidney. The cardiovascular and survival outcomes related to post-transplant hypertension and the utility of 24-h blood pressure monitoring will be briefly discussed. Antihypertensive medications and their mechanism of actions relevant to kidney transplantation will be highlighted. A summary of guidelines from different professional societies for BP targets and antihypertensive medications as well as non-pharmacological interventions, including bilateral native nephrectomy and native renal denervation, will be reviewed.

11.
Sci Rep ; 10(1): 12074, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694622

RESUMO

Although the cure rate for childhood acute lymphoblastic leukemia (ALL) has exceeded 80% with contemporary therapy, relapsed ALL remains a leading cause of cancer-related death in children. Relapse-specific mutations can be identified by comprehensive genome sequencing and might have clinical significance. Applying whole-exome sequencing to eight triplicate samples, we identified in one patient relapse-specific mutations in the folylpolyglutamate synthetase (FPGS) gene, whose product catalyzes the addition of multiple glutamate residues (polyglutamation) to methotrexate upon their entry into the cells. To determine the prevalence of mutations of the FPGS mutations, and those of two important genes in the thiopurine pathway, NT5C2 and PRPS1, we studied 299 diagnostic and 73 relapsed samples in 372 patients. Three more FPGS mutants were identified in two patients, NT5C2 mutations in six patients, and PRPS1 mutants in two patients. One patient had both NT5C2 and PRPS1 mutants. None of these alterations were detected at diagnosis with a sequencing depth of 1000X, suggesting that treatment pressure led to increased prevalence of mutations during therapy. Functional characterization of the FPGS mutants showed that they directly resulted in decreased enzymatic activity, leading to significant reduction in methotrexate polyglutamation, and therefore likely contributed to drug resistance and relapse in these cases. Thus, besides genomic alterations in thiopurine metabolizing enzymes, the relapse-specific mutations of FPGS represent another critical mechanism of acquired antimetabolite drug resistance in relapsed childhood ALL.


Assuntos
Biomarcadores Tumorais , Mutação , Peptídeo Sintases/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Alelos , Criança , Pré-Escolar , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico
12.
Cancers (Basel) ; 12(6)2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32532105

RESUMO

Depressed colorectal neoplasm exhibits high malignant potential and shows rapid invasiveness. We investigated the genomic profile of depressed neoplasms and clarified the survival outcome and treatment response of the cancers arising from them. We examined 20 depressed and 13 polypoid neoplasms by genome-wide copy number analysis. Subsequently, we validated the identified copy number alterations (CNAs) in an independent cohort of 37 depressed and 42 polypoid neoplasms. Finally, the CNAs were tested as biomarkers in 530 colorectal cancers (CRCs) to clarify the clinical outcome of depressed neoplasms. CNAs in MYC, CCNA1, and BIRC7 were significantly enriched in depressed neoplasms and designated as the D-marker panel. CRCs with a D-marker panel have significantly shorter progression-free survival compared with those without (p = 0.012), especially in stage I (p = 0.049), stages T1+2 (p = 0.027), and proximal cancers (p = 0.002). The positivity of the D-marker panel was an independent risk factor of cancer progression (hazard ratio (95% confidence interval) = 1.52 (1.09-2.11)). Furthermore, the proximal CRCs with D-marker panels had worse overall and progression-free survival when taking oxaliplatin as chemotherapy than those that did not. The D-marker panel may help to optimize treatment and surveillance in proximal CRC and develop a molecular test. However, the current result remains preliminary, and further validation in prospective trials is warranted in the future.

13.
Int J Health Policy Manag ; 9(3): 128-132, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32202098

RESUMO

Holistic and multi-disciplinary responses should be prioritized given the depth and breadth through which corruption in the healthcare sector can cover. Here, taking the Peruvian context as an example, we will reflect on the issue of corruption in health systems, including corruption with roots within and outside the health sector, and ongoing efforts to combat it. Our reflection of why corruption in health systems in settings with individual and systemic corruption should be an issue that is taken more seriously in Peru and beyond aligns with broader global health goals of improving health worldwide. Addressing corruption also serves as a pragmatic approach to health system strengthening and weakens a barrier to achieving universal health coverage and Sustainable Development Goals related to health and justice. Moreover, we will argue that by pushing towards a practice of normalizing the conversation about corruption in health has additional benefits, including expanding the problematization to a wider audience and therefore engaging with communities. For young researchers and global health professionals with interests in improving health systems in the early career stages, corruption in health systems is an issue that could move to the forefront of the list of global health challenges. This is a challenge that is uniquely multi-disciplinary, spanning the health, economy, and legal sectors, with wider societal implications.


Assuntos
Programas Governamentais , Setor de Assistência à Saúde , Saúde Global , Humanos , Peru , Cobertura Universal do Seguro de Saúde
14.
Pathogens ; 9(2)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32075096

RESUMO

Enterovirus 71 (EV71) has become an important public health problem in the Asia-Pacific region in the past decades. EV71 infection might cause neurological and psychiatric complications and even death. Although an EV71 vaccine has been currently approved, there is no effective therapy for treating EV71-infected patients. Virus infections have been reported to shape host T cell receptor (TCR) repertoire. Therefore, understanding of host TCR repertoire in EV71 infection could better the knowledge in viral pathogenesis and further benefit the anti-viral therapy development. In this study, we used a mouse-adapted EV71 (mEV71) model to observe changes of host TCR repertoire in an EV71-infected central nervous system. Neonate mice were infected with mEV71 and mouse brainstem TCRß repertoires were explored. Here, we reported that mEV71 infection impacted host brainstem TCRß repertoire, where mEV71 infection skewed TCRß diversity, changed VJ combination usages, and further expanded specific TCRß CDR3 clones. Using bioinformatics analysis and ligand-binding prediction, we speculated the expanded TCRß CDR3 clone harboring CASSLGANSDYTF sequence was capable of binding cleaved EV71 VP1 peptides in concert with major histocompatibility complex (MHC) molecules. We observed that mEV71 infection shaped host TCRß repertoire and presumably expanded VP1-specific TCRß CDR3 in mEV71-infected mouse brainstem that integrated EV71 pathogenesis in central nervous system.

15.
J Anesth ; 33(3): 463-477, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31076946

RESUMO

Over the last decade, considerable progress has been made regarding infraclavicular brachial plexus block (ICB) in adults, especially since the introduction of ultrasound guidance. The advancements in ICB have been attributed to the development of various approaches to improve the success rate and reduce complications. This has also necessitated a unified nomenclature system to facilitate comparison among different approaches. This review aimed to propose an anatomical nomenclature system by classifying ICB approaches into proximal and distal ones to aid future research and provide practice advisories according to recent updates. We also comprehensively discuss various aspects of this nomenclature system. Our review suggests that ultrasound-guided ICB should be categorized as an advanced technique that should be performed under supervision and dual guidance. For one-shot block, the conventional distal approach is still preferred but should be modified to follow ergonomic practice, with the arm in the proper position. For continuous ICB, the proximal approach is promising for reducing local anesthetic volume and increasing efficacy. Nevertheless, further studies are warranted in this direction. We provide practice advisories to maximize safety and minimize adverse events, and recommend designing future studies on ICB according to these findings based on the unified nomenclature system.


Assuntos
Anestésicos Locais/administração & dosagem , Bloqueio do Plexo Braquial/métodos , Ultrassonografia de Intervenção/métodos , Adulto , Humanos
16.
Cell Microbiol ; 21(9): e13043, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31099182

RESUMO

Enterovirus 71 (EV71) is an emerging life-threatening pathogen particularly in the Asia-Pacific region. Apoptosis is a major pathogenic feature in EV71 infection. However, which molecular mechanism participating in EV71-induced apoptosis is not completely understood. Long noncoding RNAs (lncRNAs), a newly discovered class of regulatory RNA molecules, govern a wide range of biological functions through multiple regulatory mechanisms. Whether lncRNAs involved in EV71-induced apoptosis was investigated in this study. We conducted an apoptosis-oriented approach by integrating lncRNA and mRNA profilings. lnc-IRAK3-3 is down-regulated in EV71 infection and plays an important role in EV71 infection-induced apoptosis. Compensation of lnc-IRAK3-3 in EV71 infection promoted cell apoptosis wherein GADD45ß expression was increased and further triggered caspase3 and PARP cleavage. Using bioinformatics analysis and functional assays, lnc-IRAK3-3 could functionally sequester miR-891b and GADD45ß 3'UTR whereas miR-891b showed the inhibitory activity on GADD45ß expression. Taken together, lnc-IRAK3-3 has the ability capturing miR-891b to enforce GADD45ß expression and eventually promotes apoptosis. On the contrary, host cells suppress lnc-IRAK3-3 to relieve lnc-IRAK3-3-sequestered miR-891b, restrain GADD45ß, and attenuate apoptosis in EV71 infection that prevent host cells from severe damages. We discover a new molecular mechanism by which host cells counteract EV71-induced apoptosis through the lnc-IRAK3-3/miR-891b/GADD45ß axis partially.


Assuntos
Apoptose/genética , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Biologia Computacional , Infecções por Enterovirus/genética , Interações Hospedeiro-Patógeno/genética , Humanos , MicroRNAs/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais/genética , Transcriptoma/genética
17.
Adv Ther ; 36(6): 1465-1479, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30941724

RESUMO

INTRODUCTION: Real-world data with extended-release tacrolimus (ER-T) are lacking in the USA. This study examined clinical outcomes and healthcare resource utilization in kidney transplant patients receiving ER-T in clinical practice. METHODS: This was a retrospective, single-center analysis (February-June 2016) using data from Northwestern University's Enterprise Data Warehouse. Adult patients receiving a kidney transplant in the preceding 4 years, treated de novo or converted to ER-T from immediate-release tacrolimus (IR-T) within 10 days post-transplantation, and maintained on ER-T (at least 3 months) were included. Patients were matched for demographic and clinical characteristics with IR-T-treated control patients. Endpoints included clinical outcomes and healthcare resource utilization up to 1 year post-transplantation. RESULTS: A total of 19 ER-T-treated patients were matched with 55 IR-T-treated patients. No ER-T-treated patients experienced biopsy-confirmed acute rejection (BCAR) or graft failure versus 3 (5.5%) and 3 (5.5%) IR-T-treated patients, respectively. Mean estimated glomerular filtration rate (eGFR), the number of all-cause outpatient visits, readmissions, and all-cause hospitalization days were comparable between groups. Tacrolimus trough levels, days to target level (6-10 ng/mL), and number of required dose adjustments were also similar. CONCLUSION: Real-world clinical outcomes and healthcare resource utilization were similar with ER-T and IR-T. Larger studies will need to investigate the trend toward fewer BCAR events, and increased graft survival with ER-T. FUNDING: Astellas Pharma Global Development, Inc. Plain language summary available for this article.


Assuntos
Inibidores de Calcineurina/uso terapêutico , Preparações de Ação Retardada/uso terapêutico , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Tacrolimo/uso terapêutico , Adulto , Idoso , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos , Adulto Jovem
18.
Cancer Med ; 8(5): 2179-2187, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30941903

RESUMO

Lung cancer is the leading cause of cancer death worldwide and cancer relapse accounts for the majority of cancer mortality. The mechanism is still unknown, especially in hereditary lung cancer without known actionable mutations. To identify genetic alternations involved in hereditary lung cancer and relapse is urgently needed. We collected genetic materials from a unique hereditary lung cancer patient's blood, first cancer tissue (T1), adjacent normal tissue (N1), relapse cancer tissue (T2), and adjacent normal tissue (N2) for whole genome sequencing. We identified specific mutations in T1 and T2, and attributed them to tumorigenesis and recurrence. These tumor specific variants were enriched in antigen presentation pathway. In addition, a lung adenocarcinoma cohort from the TCGA dataset was used to confirm our findings. Patients with high mutation burdens in tumor specific genes had decreased relapse-free survival (P = 0.017, n = 186). Our study may provide important insight for designing immunotherapeutic treatment for hereditary lung cancer.


Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Recidiva Local de Neoplasia/genética , Sequenciamento Completo do Genoma/métodos , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Apresentação de Antígeno , Biomarcadores Tumorais/genética , Estudos de Coortes , Feminino , Redes Reguladoras de Genes , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Recidiva Local de Neoplasia/mortalidade , Análise de Sobrevida
19.
Transpl Infect Dis ; 21(3): e13063, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30776166

RESUMO

BACKGROUND: Recurrent urinary tract infections (UTI) are an important cause of morbidity and mortality in renal transplant recipients (RTR). METHODS: In this retrospective study we gathered clinical data from patients prescribed methenamine hippurate to prevent recurrent UTI pre- and post-intervention. Thirty-eight RTR ≥18 years old at Northwestern Memorial Hospital from 2006-2017 were included in the final analysis. RESULTS: The median and range for follow-up days were 365 (299-365) pre- vs 314 (105-365) post-methenamine. Total UTI frequency (9.16 vs 5.01/1000 patient follow-up days), days of antibiotic therapy to treat UTI (215 vs 132/1000 patient follow-up days), and hospitalization due to UTI (2.64 vs 1.07/1000 patient follow-up days) decreased while patients took methenamine. Escherichia coli and Klebsiella pneumoniae were the most commonly identified cause of UTI both pre- and post-intervention. Drug resistant bacteria (ESBL-producing or VRE) affected 3 patients pre- and recurred in 1 of those patients plus 3 new patients post-methenamine. Methenamine had few adverse side effects for patients. One patient had nausea and 1 was intolerant. CONCLUSION: We found that methenamine is well tolerated and is useful in reducing UTI, antibiotic prescriptions, and hospitalization in RTR with recurrent UTI. Larger prospective studies are needed to confirm these findings.


Assuntos
Anti-Infecciosos Urinários/administração & dosagem , Bactérias/efeitos dos fármacos , Hipuratos/administração & dosagem , Transplante de Rim/efeitos adversos , Metenamina/análogos & derivados , Infecções Urinárias/prevenção & controle , Adulto , Anti-Infecciosos Urinários/efeitos adversos , Escherichia coli/efeitos dos fármacos , Feminino , Hipuratos/efeitos adversos , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Masculino , Metenamina/administração & dosagem , Metenamina/efeitos adversos , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Estudos Retrospectivos , Transplantados , Infecções Urinárias/microbiologia
20.
Eur J Nucl Med Mol Imaging ; 46(4): 810-820, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30635754

RESUMO

PURPOSE: (4S)-4-(3-18F-Fluoropropyl)-L-glutamate (FSPG) positron emission tomography (PET) reflects system xC- transporter (xCT) expression. FSPG PET has been used to detect brain, lung, breast and liver cancer with only modest success. There is no report on the use of FSPG PET in pancreatic ductal adenocarcinoma (PDAC), presumably because of normal xCT expression in the pancreas. Nonetheless, the tissue-specific expression of xCT in the pancreas suggests that FSPG PET may be ideal for identifying metastasized PDAC. METHODS: The performance of FSPG in detecting PDAC metastases was compared with that of 18F-fluorodeoxyglucose (FDG) in small-animal PET studies in seven PDAC tumour-bearing mice and in prospective PET/computed tomography (CT) studies in 23 patients with tissue-confirmed PDAC of stage III or stage IV. All PET/CT results were correlated with the results of histopathology or contrast-enhanced CT (ceCT) performed 3 and 6 months later. RESULTS: In the rodent model, FSPG PET consistently found more PDAC metastases earlier than FDG PET. FSPG PET showed a trend for a higher sensitivity, specificity and diagnostic accuracy than FDG PET in detecting PDAC metastases in a patient-based analysis: 95.0%, 100.0% and 95.7%, and 90.0%, 66.7% and 90.0%, respectively. In a lesion-based analysis, FSPG PET identified significantly more PDAC metastases, especially in the liver, than FDG PET (109 vs. 95; P = 0.0001, 95% CI 4.9-14.6). The tumour-to-background ratios for FSPG and FDG uptake on positive scans were similar (FSPG 4.2 ± 4.3, FDG 3.6 ± 3.0; P = 0.44, 95% CI -1.11 to 0.48), despite a lower tumour maximum standardized uptake value in FSPG-avid lesions (FSPG 4.2 + 2.3, FDG 7.7 + 5.7; P = 0.002, 95% CI 0.70-4.10). Because of the lower physiological activity of FSPG in the liver, FSPG PET images of the liver are more easy to interpret than FDG PET images, and therefore the use of FSPG improves the detection of liver metastasis. CONCLUSION: FSPG PET is superior to FDG PET in detecting metastasized PDAC, especially in the liver.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Fluordesoxiglucose F18 , Glutamatos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/efeitos adversos , Estudos Prospectivos , Segurança
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