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1.
Front Immunol ; 15: 1379023, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39104533

RESUMO

Antibody-mediated complement-dependent cytotoxicity (CDC) on malignant cells is regulated by several complement control proteins, including the inhibitory complement factor H (fH). fH consists of 20 short consensus repeat elements (SCRs) with specific functional domains. Previous research revealed that the fH-derived SCRs 19-20 (SCR1920) can displace full-length fH on the surface of chronic lymphocytic leukemia (CLL) cells, which sensitizes CLL cells for e.g. CD20-targeting therapeutic monoclonal antibody (mAb) induced CDC. Therefore, we constructed lentiviral vectors for the generation of cell lines that stably produce mAb-SCR-fusion variants starting from the clinically approved parental mAbs rituximab, obinutuzumab and ofatumumab, respectively. Flow-cytometry revealed that the modification of the mAbs by the SCRs does not impair the binding to CD20. Increased in vitro lysis potency compared to their parental mAbs was corroborated by showing specific and dose dependent target cell elimination by CDC when compared to their parental mAbs. Lysis of CLL cells was not affected by the depletion of NK cells, suggesting that antibody-dependent cellular cytotoxicity plays a minor role in this context. Overall, this study emphasizes the crucial role of CDC in the elimination of CLL cells by mAbs and introduces a novel approach for enhancing CDC by directly fusing fH SCR1920 with mAbs.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos , Antígenos CD20 , Fator H do Complemento , Leucemia Linfocítica Crônica de Células B , Rituximab , Humanos , Antígenos CD20/imunologia , Antígenos CD20/genética , Fator H do Complemento/imunologia , Fator H do Complemento/metabolismo , Fator H do Complemento/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Rituximab/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linhagem Celular Tumoral
2.
Eur Urol Oncol ; 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38851995

RESUMO

BACKGROUND AND OBJECTIVE: While collagen density has been associated with poor outcomes in various cancers, its role in prostate cancer (PCa) remains elusive. Our aim was to analyze collagen-related transcriptomic, proteomic, and urinome alterations in the context of detection of clinically significant PCa (csPCa, International Society of Urological Pathology [ISUP] grade group ≥2). METHODS: Comprehensive analyses for PCa transcriptome (n = 1393), proteome (n = 104), and urinome (n = 923) data sets focused on 55 collagen-related genes. Investigation of the cellular source of collagen-related transcripts via single-cell RNA sequencing was conducted. Statistical evaluations, clustering, and machine learning models were used for data analysis to identify csPCa signatures. KEY FINDINGS AND LIMITATIONS: Differential expression of 30 of 55 collagen-related genes and 34 proteins was confirmed in csPCa in comparison to benign prostate tissue or ISUP 1 cancer. A collagen-high cancer cluster exhibited distinct cellular and molecular characteristics, including fibroblast and endothelial cell infiltration, intense extracellular matrix turnover, and enhanced growth factor and inflammatory signaling. Robust collagen-based machine learning models were established to identify csPCa. The models outcompeted prostate-specific antigen (PSA) and age, showing comparable performance to multiparametric magnetic resonance imaging (mpMRI) in predicting csPCa. Of note, the urinome-based collagen model identified four of five csPCa cases among patients with Prostate Imaging-Reporting and Data System (PI-IRADS) 3 lesions, for which the presence of csPCa is considered equivocal. The retrospective character of the study is a limitation. CONCLUSIONS AND CLINICAL IMPLICATIONS: Collagen-related transcriptome, proteome, and urinome signatures exhibited superior accuracy in detecting csPCa in comparison to PSA and age. The collagen signatures, especially in cases of ambiguous lesions on mpMRI, successfully identified csPCa and could potentially reduce unnecessary biopsies. The urinome-based collagen signature represents a promising liquid biopsy tool that requires prospective evaluation to improve the potential of this collagen-based approach to enhance diagnostic precision in PCa for risk stratification and guiding personalized interventions. PATIENT SUMMARY: In our study, collagen-related alterations in tissue, and urine were able to predict the presence of clinically significant prostate cancer at primary diagnosis.

4.
Heliyon ; 10(7): e28358, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38689972

RESUMO

The development of single-cell omics tools has enabled scientists to study the tumor microenvironment (TME) in unprecedented detail. However, each of the different techniques may have its unique strengths and limitations. Here we directly compared two commercially available high-throughput single-cell RNA sequencing (scRNA-seq) technologies - droplet-based 10X Chromium vs. microwell-based BD Rhapsody - using paired samples from patients with localized prostate cancer (PCa) undergoing a radical prostatectomy. Although high technical consistency was observed in unraveling the whole transcriptome, the relative abundance of cell populations differed. Cells with low mRNA content such as T cells were underrepresented in the droplet-based system, at least partly due to lower RNA capture rates. In contrast, microwell-based scRNA-seq recovered less cells of epithelial origin. Moreover, we discovered platform-dependent variabilities in mRNA quantification and cell-type marker annotation. Overall, our study provides important information for selection of the appropriate scRNA-seq platform and for the interpretation of published results.

7.
Bone Marrow Transplant ; 59(7): 936-941, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38493275

RESUMO

ATOS is a prospective observational study evaluating the outcome of patients receiving anti-human T-lymphocyte immunoglobulin (ATLG) in unrelated donor transplantation. Primary endpoint was severe GvHD and relapse-free survival (SGRFS). GvHD prophylaxis consisted of ATLG and CSA/ MTX or MMF. Outcome was compared to the ATLG arm of our prospective randomized phase III multicenter trial trial (RCT) [1, 2]. 165 patients, median age 54 (18; 77) years, with haematological malignancies with early (45.5%), intermediate (17.6%), and advanced (37.0%) disease were included. ATLG dose differed between centers according to local practise (median total ATLG dose of 46 (IQR 32-60, range 15-91) mg/kg). Median follow-up was 70 months. Estimated probabilities at 5 years follow up were for SGRFS 0.27, OS 0.52, DFS 0.43, NRM 0.23, relapse 0.34, acute GvhD °III/IV 0.13, severe chronic GvHD 0.27. OS rates differed dependent on disease status. An effect of the given ATLG dose could not be separated from potential center effects. Despite higher age and more advanced disease in ATOS, outcome was similar to the ATLG arm of our RCT. This long-term, multicenter, experience in routine clinical practice confirms the GvHD-protective effect of ATLG without compromising relapse and non-relapse mortality rates.Clinical Trial Registry: German clinical trials register DRKS00004581.


Assuntos
Doadores não Relacionados , Humanos , Pessoa de Meia-Idade , Adulto , Masculino , Estudos Prospectivos , Feminino , Idoso , Adolescente , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto Jovem , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/mortalidade , Intervalo Livre de Doença , Seguimentos , Linfócitos T/imunologia
8.
J Clin Invest ; 134(5)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38426495

RESUMO

Colorectal cancer (CRC) is among the most common cancer types and the second deadliest malignancy for both sexes. Metastatic disease poses substantial therapeutic challenges, and peritoneal spread, in particular, reduces quality of life and has a dismal outcome. In this issue of the JCI, Berlin and authors have made considerable advancements in understanding the cellular and molecular composition of multivisceral CRC metastasis in a sophisticated murine orthotopic organoid model and in humans. The study provides unprecedented insights into the complex biology of the disease and points toward the development of compartmentalized immune-therapeutic strategies.


Assuntos
Neoplasias Colorretais , Qualidade de Vida , Humanos , Masculino , Feminino , Animais , Camundongos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética
9.
Front Immunol ; 15: 1358153, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38510260

RESUMO

Primary graft dysfunction (PGD) is a common complication after lung transplantation. A plethora of contributing factors are known and assessment of donor lung function prior to organ retrieval is mandatory for determination of lung quality. Specialized centers increasingly perform ex vivo lung perfusion (EVLP) to further assess lung functionality and improve and extend lung preservation with the aim to increase lung utilization. EVLP can be performed following different protocols. The impact of the individual EVLP parameters on PGD development, organ function and postoperative outcome remains to be fully investigated. The variables relate to the engineering and function of the respective perfusion devices, such as the type of pump used, functional, like ventilation modes or physiological (e.g. perfusion solutions). This review reflects on the individual technical and fluid components relevant to EVLP and their respective impact on inflammatory response and outcome. We discuss key components of EVLP protocols and options for further improvement of EVLP in regard to PGD. This review offers an overview of available options for centers establishing an EVLP program and for researchers looking for ways to adapt existing protocols.


Assuntos
Lesão Pulmonar , Transplante de Pulmão , Humanos , Pulmão , Perfusão/métodos , Transplante de Pulmão/efeitos adversos , Transplante de Pulmão/métodos , Doadores de Tecidos
10.
Ann Hematol ; 103(6): 2123-2131, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38436671

RESUMO

Monoclonal antibodies, as tixagevimab/cilgavimab, have been introduced as prophylaxis against COVID-19 infections in high-risk populations. However, data on efficacy are limited. This study investigates efficacy and tolerability of tixagevimab/cilgavimab in hematological patients under real-life conditions. Tixagevimab/cilgavimab was administered to 155 hematological patients (March-August 2022) at two Austrian centres. S/RBD-antibody assessments were performed before (T0), four weeks (T1), and six months (T2) after application. Side effects, the occurrence of COVID-19 infections, and the course of S/RBD-antibody titres were analysed retrospectively in relation to clinical variables. 155 hematological patients, who refused tixagevimab/cilgavimab, were included as a control group to compare the frequency of COVID-19 infections. Of all immunised patients (52.3% males; 91% triple vaccinated), 25.8% had a COVID-19 breakthrough infection (76% mild) compared to 43.9% in the control group. Patients with chronic lymphocytic leukaemia (CLL)/lymphoma were at highest risk of a COVID-19 infection (OR = 2.21; 95% CI 1.05-4.65; p = 0.037). After immunisation, a steep increase in median antibody levels (1193.4BAU/ml, IQR 0-2318.94) was observed in 67.8%, followed by a rapid decrease between T1 and T2 (465.95BAU/ml, IQR 0-1900.65.3) with the greatest declines in CLL/lymphoma (848.7BAU/ml, IQR 0-1949.6, p = 0.026). Side-effects occurred in 21.2% (CTCAE I/II). These real-world data indicate that S/RBD antibodies respond rapidly after passive immunisation in all hematological patients without safety concerns. Given the rapid decline in S/RBD antibodies, early booster immunisations should be considered for future scenarios in this vulnerable group.


Assuntos
Anticorpos Monoclonais Humanizados , COVID-19 , Neoplasias Hematológicas , SARS-CoV-2 , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/complicações , Idoso , COVID-19/prevenção & controle , COVID-19/imunologia , COVID-19/epidemiologia , COVID-19/complicações , Estudos Retrospectivos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , SARS-CoV-2/imunologia , Adulto , Idoso de 80 Anos ou mais , Imunização Passiva , Anticorpos Antivirais/sangue , Infecções Irruptivas
12.
Trends Cancer ; 10(5): 457-474, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38360439

RESUMO

Neutrophils represent the most abundant myeloid cell subtype in the non-small-cell lung cancer (NSCLC) tumor microenvironment (TME). By anti- or protumor polarization, they impact multiple aspects of tumor biology and affect sensitivity to conventional therapies and immunotherapies. Single-cell RNA sequencing (scRNA-seq) analyses have unraveled an extensive neutrophil heterogeneity, helping our understanding of their pleiotropic role. In this review we summarize recent data and models on tumor-associated neutrophil (TAN) biology, focusing on the diversity that evolves in response to tumor-intrinsic cues. We categorize available transcriptomic profiles from different cancer entities into a defined set of neutrophil subclusters with distinct phenotypic properties, to step beyond the traditional binary N1/2 classification. Finally, we discuss potential ways to exploit these neutrophil states in the setting of anticancer therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neutrófilos , Microambiente Tumoral , Humanos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/terapia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/efeitos dos fármacos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/terapia , Imunoterapia/métodos , Análise de Célula Única/métodos , Animais , Transcriptoma
13.
Leukemia ; 38(4): 781-787, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38278960

RESUMO

Tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) has become part of routine care for patients with a sustained deep molecular response (DMR). Approximately 50% experience a molecular relapse upon TKI cessation. Most of them quickly regain DMR upon TKI resumption. Whether these patients can achieve a second treatment-free remission (TFR) remains unclear. DAstop2 (ClinicalTrials.gov ID: NCT03573596) is a prospective study including patients with a failed first TFR attempt re-treated with any TKI for ≥ one year. Upon entering the study, patients received the TKI dasatinib for additional two years. Patients with sustained DMR for ≥1 year qualified for a second TKI stop. Ninety-four patients were included between Oct 2017-Dec 2021. At the time of data analysis, 62 patients had attempted a 2nd stop. After a median follow-up of 27 months from 2nd stop, TFR rates were 61, 56 and 46% at 6, 12 and 24 months respectively. No progression to advanced stage disease was seen and 87% had re-achieved MR4 within a median of 3 months from TKI re-initiation. In summary, we show that a 2nd TFR attempt after dasatinib treatment is safe, feasible and TFR rates seem in the range of those reported in trials of a first TKI stop.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Dasatinibe/efeitos adversos , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Indução de Remissão , Resultado do Tratamento
14.
Neuropsychologia ; 193: 108761, 2024 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-38104856

RESUMO

The corpus callosum (CC) has been identified as an important structure in the context of cognitive aging (Fling et al., 2011). Interhemispheric transfer time (IHTT) is regularly used in order to estimate interhemispheric integration enabled by the CC (Marzi, 2010; Nowicka and Tacikowski, 2011). However, only little is known with regards to the relationship between IHTT and the structural properties of the CC with only few studies with specific samples and methods available (Whitford et al., 2011). Thus, the present study aimed at investigating this relationship applying an event-related potentials (ERP) based approach of estimating IHTT as well as diffusion weighted imaging (DWI) with fractional anisotropy (FA) as an indicator of white matter integrity (WMI) of the genu, corpus and splenium of the CC. 56 healthy older adults performed a Dimond Task while ERPs were recorded and underwent DWI scanning. IHTT derived from posterior electrode sites correlated significantly with FA of the splenium (r = -0.286*, p = .03) but not the corpus (r = -0.187, p = .08) or genu (r = -0.189, p = .18). The present results support the notion that IHTT is related to WMI of the posterior CC. It may be concluded that ERP based IHTT is a suitable indicator of CC structure and function, however, likely specific to the interhemispheric transfer of visual information. Future studies may wish to confirm these findings in a more divers sample further exploring the precise interrelation between IHTT and structural or functional properties of the CC.


Assuntos
Corpo Caloso , Substância Branca , Humanos , Idoso , Corpo Caloso/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Potenciais Evocados , Imagem de Difusão por Ressonância Magnética , Anisotropia
15.
Oncoimmunology ; 12(1): 2274130, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38126028

RESUMO

Cancer associated fibroblasts (CAF) are known to orchestrate multiple components of the tumor microenvironment, whereas the influence of the whole stromal-fibroblast compartment is less understood. Here, an extended stromal fibroblast signature was investigated to define its impact on immune cell infiltration. The lung cancer adenocarcinoma (LUAD) data set of the cancer genome atlas (TCGA) was used to test whole stroma signatures and cancer-associated fibroblast signatures for their impact on prognosis. 3D cell cultures of the NSCLC cancer cell line A549 together with the fibroblast cell line SV80 were used in combination with infiltrating peripheral blood mononuclear cells (PBMC) for in-vitro investigations. Immune cell infiltration was assessed via flow cytometry, chemokines were analyzed by immunoassays and RNA microarrays. Results were confirmed in specimens from NSCLC patients by flow cytometry or immunohistochemistry as well as in the TCGA data set. The TCGA analyses correlated the whole stromal-fibroblast signature with an improved outcome, whereas no effect was found for the CAF signatures. In 3D microtumors, the presence of fibroblasts induced infiltration of B cells and CD69+CD4+ T cells, which was linked to an increased expression of CCL13 and CXCL16. The stroma/lymphocyte interaction was confirmed in NSCLC patients, as stroma-rich tumors displayed an elevated B cell count and survival in the local cohort and the TCGA data set. A whole stromal fibroblast signature was associated with an improved clinical outcome in lung adenocarcinoma and in vitro and in vivo experiments suggest that this signature increases B and T cell recruitment via induction of chemokines.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Leucócitos Mononucleares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Adenocarcinoma de Pulmão/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Quimiocinas/genética , Quimiocinas/metabolismo , Microambiente Tumoral
16.
Dtsch Med Wochenschr ; 148(22): 1431-1436, 2023 11.
Artigo em Alemão | MEDLINE | ID: mdl-37918427

RESUMO

Myelodysplastic syndromes (MDS) represent a heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myeloid leukemia (AML).Recent developments include the classification and the estimation of prognosis. In 2022 the former 2016 WHO classification was replaced by the ICC and WHO 2022 classification. Both classifications have included precursor lesions (CHIP and ICUS), both distinguish between three molecularly cytogenetically defined subgroups - del(5q), TP53, SF3B1 - and morphologically defined subgroups with differences in blast threshold (WHO: 20%; ICC: 10%) for the differentiation from AML. However, although prognostic factors influenced the classification-subgroups, it is important to distinguish the prognosis, which is crucial for optimal therapeutic decision making. Since 2022, the IPSS-M has been available for this purpose, which represents an expansion of the well-established IPSS-R. It could improve prognosis estimation by adding molecular data, recently this could have been confirmed in real world cohorts. The IPSS-M also represents an important extension with regard to prognosis estimation for patients with therapy-related MDS.In 2020 Luspatercept has been approved for transfusion-dependent lower risk MDS patients harboring ring sideroblasts ± an SF3B1 mutation after failure of an erythropoiesis stimulating agent. The COMMANDS trial has just reported an interim analysis, where the superiority of luspatercept in the 1st line compared to erythropoietin could be demonstrated. In addition, data from the phase III trial with Imeltelstat give reason to hope that we will be able to offer a new second-line therapy to LR-MDS patients. For higher risk MDS patients azacitidine therapy remains the standard of care, results of phase III trials of combination therapies must be awaited.


Assuntos
Anemia , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Prognóstico , Azacitidina/uso terapêutico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Anemia/tratamento farmacológico
17.
Haematologica ; 2023 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-37941409

RESUMO

The role of autologous-allogeneic tandem stem cell transplantation (alloTSCT) followed by maintenance as upfront treatment for multiple myeloma (MM) is controversial. Between 2008 and 2014 a total of 217 MM patients with a median age of 51 years were included by 20 German centers within an open-label, parallel-group, multi-center clinical trial to compare alloTSCT to auto tandem transplantation TSCT (autoTSCT) followed by a 2-year maintenance therapy with thalidomide (100 mg/d) in both arms with respect to relapse/progression-free survival (PFS) and other relevant outcomes. A total of 178 patients underwent second SCT (allo n = 132 and auto n = 46). PFS at 4 years after the second SCT was 47% (CI: 38-55%) for alloTSCT and 35% (CI: 21-49%) for autoTSCT (p = 0.26). This difference increased to 22% at 8 years (p = 0.10). The cumulative incidences of non-relapse mortality (NRM) and of relapse at 4 years were 13% (CI: 8-20%) and 2% (CI: 0.3-2%) (p = 0.044) and 40% (CI: 33-50%) and 63% (CI: 50-79%) for alloTSCT and autoTSCT (p = 0.04), respectively. The difference for relapse/progression increased to 33% (alloTSCT: 44%, autoTSCT: 77%) at a median follow-up of 82 months (p = 0.002). Four-year OS was 66% (CI: 57-73%) for alloTSCT and 66% (CI: 50-78%) for auto TSCT (p = 0.91) and 8-year OS was 52% and 50% (p = 0.87), respectively. AlloTSCT followed by thalidomide maintenance reduced the rate of recurrence or progression during a follow-up period of up to 10 years but failed to improve PFS significantly.

18.
Int J Antimicrob Agents ; 62(6): 107014, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37866472

RESUMO

Antimicrobial resistance (AMR) is a major global public health threat, particularly affecting patients in resource-poor settings. Comprehensive surveillance programmes are essential to reducing the high mortality and morbidity associated with AMR and are integral to informing treatment decisions and guidelines, appraising the effectiveness of intervention strategies, and directing development of new antibacterial agents. Various surveillance programmes exist worldwide, including those administered by government bodies or funded by the pharmaceutical industry. One of the largest and longest running industry-sponsored AMR surveillance programme is the Study for Monitoring Antimicrobial Resistance Trends (SMART), which recently completed its 20th year. The SMART database has grown to almost 500 000 isolates from over 200 sites in more than 60 countries, encompassing all major geographic regions and including many sites in low- and middle-income countries. The SMART surveillance programme has evolved in scope over time, including additional antibacterial agents, pathogens and infection sites, in line with changing epidemiology and medical need. Surveillance data from SMART and similar programmes have been used successfully to detect emerging resistance threats and AMR patterns in specific countries and regions, thus informing national and local clinical treatment guidelines. The SMART database can be accessed readily by physicians and researchers globally, which may be especially valuable to those from countries with limited healthcare resources, where surveillance and resistance data are rarely collected. Continued participation from as many sites as possible worldwide and maintenance of adequate funding are critical factors to fully realising the potential of large-scale AMR surveillance programmes into the future.


Assuntos
Antibacterianos , Farmacorresistência Bacteriana , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico
20.
Int J Antimicrob Agents ; 62(4): 106952, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37582478

RESUMO

INTRODUCTION: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections and decrease hospitalisation and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, whereas molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir because it is associated with fewer drug-drug interactions and contraindications. A caveat for molnupiravir is the mode of action induces viral mutations. Mortality rate reduction with molnupiravir was less pronounced than that with nirmatrelvir/ritonavir in patients without haematological malignancy. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, molnupiravir and nirmatrelvir/ritonavir were compared in a cohort of patients with haematological malignancies. METHODS: Clinical data from patients treated with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and severity of baseline haematological malignancy to controls treated with nirmatrelvir/ritonavir. RESULTS: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (interquartile range [IQR] 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 56.9% (n=66) of the patients had controlled baseline haematological malignancy, 12.9% (n=15) had stable disease, and 30.2% (n=35) had active disease at COVID-19 onset in each group. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of patients in the two groups were vaccinated (molnupiravir n=77, 66% vs. nirmatrelvir/ritonavir n=87, 75%), more of those treated with nirmatrelvir/ritonavir had received four vaccine doses (n=27, 23%) compared with those treated with molnupiravir (n=5, 4%) (P<0.001). No differences were detected in COVID-19 severity (P=0.39) or hospitalisation (P=1.0). No statistically significant differences were identified in overall mortality rate (P=0.78) or survival probability (d30 P=0.19, d60 P=0.67, d90 P=0.68, last day of follow up P=0.68). Deaths were either attributed to COVID-19, or the infection was judged by the treating physician to have contributed to death. CONCLUSIONS: Hospitalisation and mortality rates with molnupiravir were comparable to those with nirmatrelvir/ritonavir in high-risk patients with haematological malignancies and COVID-19. Molnupiravir is a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy.


Assuntos
COVID-19 , Neoplasias Hematológicas , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Tratamento Farmacológico da COVID-19 , Ritonavir/uso terapêutico , SARS-CoV-2 , Europa (Continente)/epidemiologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/tratamento farmacológico , Antivirais/uso terapêutico
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