RESUMEN
Germinal centers (GCs) form in secondary lymphoid organs in response to infection and immunization and are the source of affinity-matured B cells. The duration of GC reactions spans a wide range, and long-lasting GCs (LLGCs) are potentially a source of highly mutated B cells. We show that rather than consisting of continuously evolving B cell clones, LLGCs elicited by influenza virus or SARS-CoV-2 infection in mice are sustained by progressive replacement of founder clones by naive-derived invader B cells that do not detectably bind viral antigens. Rare founder clones that resist replacement for long periods are enriched in clones with heavily mutated immunoglobulins, including some with very high affinity for antigen, that can be recalled by boosting. Our findings reveal underappreciated aspects of the biology of LLGCs generated by respiratory virus infection and identify clonal replacement as a potential constraint on the development of highly mutated antibodies within these structures.
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Linfocitos B , Centro Germinal , Infecciones por Virus ARN , Animales , Ratones , Linfocitos B/citología , Linfocitos B/inmunología , Células Clonales , COVID-19 , Centro Germinal/citología , Centro Germinal/inmunología , SARS-CoV-2 , Gripe Humana , Infecciones por Virus ARN/inmunología , Infecciones por Virus ARN/patología , Infecciones por Virus ARN/virologíaRESUMEN
Stem cells are highly resistant to viral infection compared to their differentiated progeny; however, the mechanism is mysterious. Here, we analyzed gene expression in mammalian stem cells and cells at various stages of differentiation. We find that, conserved across species, stem cells express a subset of genes previously classified as interferon (IFN) stimulated genes (ISGs) but that expression is intrinsic, as stem cells are refractory to interferon. This intrinsic ISG expression varies in a cell-type-specific manner, and many ISGs decrease upon differentiation, at which time cells become IFN responsive, allowing induction of a broad spectrum of ISGs by IFN signaling. Importantly, we show that intrinsically expressed ISGs protect stem cells against viral infection. We demonstrate the in vivo importance of intrinsic ISG expression for protecting stem cells and their differentiation potential during viral infection. These findings have intriguing implications for understanding stem cell biology and the evolution of pathogen resistance.
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Inmunidad Innata , Células Madre Pluripotentes/inmunología , Virosis/inmunología , Animales , Células Cultivadas , Femenino , Células HEK293 , Humanos , Interferones/metabolismo , Masculino , Ratones , Ratones Endogámicos NOD , Células Madre Pluripotentes/virología , Especificidad de la EspecieRESUMEN
SARS-CoV-2 infection or vaccination produces neutralizing antibody responses that contribute to better clinical outcomes. The receptor-binding domain (RBD) and the N-terminal domain (NTD) of the spike trimer (S) constitute the two major neutralizing targets for antibodies. Here, we use NTD-specific probes to capture anti-NTD memory B cells in a longitudinal cohort of infected individuals, some of whom were vaccinated. We found 6 complementation groups of neutralizing antibodies. 58% targeted epitopes outside the NTD supersite, 58% neutralized either Gamma or Omicron, and 14% were broad neutralizers that also neutralized Omicron. Structural characterization revealed that broadly active antibodies targeted three epitopes outside the NTD supersite including a class that recognized both the NTD and SD2 domain. Rapid recruitment of memory B cells producing these antibodies into the plasma cell compartment upon re-infection likely contributes to the relatively benign course of subsequent infections with SARS-CoV-2 variants, including Omicron.
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COVID-19 , Glicoproteína de la Espiga del Coronavirus , Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Epítopos , Humanos , Células B de Memoria , SARS-CoV-2RESUMEN
Interferon-stimulated genes (ISGs) act in concert to provide a tight barrier against viruses. Recent studies have shed light on the contribution of individual ISG effectors to the antiviral state, but most have examined those acting on early, intracellular stages of the viral life cycle. Here, we applied an image-based screen to identify ISGs inhibiting late stages of influenza A virus (IAV) infection. We unraveled a directly antiviral function for the gene SERPINE1, encoding plasminogen activator inhibitor 1 (PAI-1). By targeting extracellular airway proteases, PAI-1 inhibits IAV glycoprotein cleavage, thereby reducing infectivity of progeny viruses. This was biologically relevant for IAV restriction in vivo. Further, partial PAI-1 deficiency, attributable to a polymorphism in human SERPINE1, conferred increased susceptibility to IAV in vitro. Together, our findings reveal that manipulating the extracellular environment to inhibit the last step in a virus life cycle is an important mechanism of the antiviral response.
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Virus de la Influenza A/fisiología , Inhibidor 1 de Activador Plasminogénico/metabolismo , Serpina E2/metabolismo , Animales , Línea Celular , Humanos , Inmunidad Innata , Ratones Endogámicos C57BL , Inhibidor 1 de Activador Plasminogénico/genética , Sistema Respiratorio/enzimología , Sistema Respiratorio/virología , Serina Proteasas/metabolismo , Serpina E2/genéticaRESUMEN
A key effector route of the Sugar Code involves lectins that exert crucial regulatory controls by targeting distinct cellular glycans. We demonstrate that a single amino-acid substitution in a banana lectin, replacing histidine 84 with a threonine, significantly reduces its mitogenicity, while preserving its broad-spectrum antiviral potency. X-ray crystallography, NMR spectroscopy, and glycocluster assays reveal that loss of mitogenicity is strongly correlated with loss of pi-pi stacking between aromatic amino acids H84 and Y83, which removes a wall separating two carbohydrate binding sites, thus diminishing multivalent interactions. On the other hand, monovalent interactions and antiviral activity are preserved by retaining other wild-type conformational features and possibly through unique contacts involving the T84 side chain. Through such fine-tuning, target selection and downstream effects of a lectin can be modulated so as to knock down one activity, while preserving another, thus providing tools for therapeutics and for understanding the Sugar Code.
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Lectinas de Plantas/química , Lectinas de Plantas/genética , Fármacos Anti-VIH/química , Secuencia de Carbohidratos , Ingeniería Genética , Mitógenos/química , Modelos Moleculares , Simulación de Dinámica Molecular , Musa/químicaRESUMEN
Monoclonal antibodies with neutralizing activity against SARS-CoV-2 have demonstrated clinical benefits in cases of mild-to-moderate SARS-CoV-2 infection, substantially reducing the risk for hospitalization and severe disease1-4. Treatment generally requires the administration of high doses of these monoclonal antibodies and has limited efficacy in preventing disease complications or mortality among hospitalized patients with COVID-195. Here we report the development and evaluation of anti-SARS-CoV-2 monoclonal antibodies with optimized Fc domains that show superior potency for prevention or treatment of COVID-19. Using several animal disease models of COVID-196,7, we demonstrate that selective engagement of activating Fcγ receptors results in improved efficacy in both preventing and treating disease-induced weight loss and mortality, significantly reducing the dose required to confer full protection against SARS-CoV-2 challenge and for treatment of pre-infected animals. Our results highlight the importance of Fcγ receptor pathways in driving antibody-mediated antiviral immunity and exclude the possibility of pathogenic or disease-enhancing effects of Fcγ receptor engagement of anti-SARS-CoV-2 antibodies upon infection. These findings have important implications for the development of Fc-engineered monoclonal antibodies with optimal Fc-effector function and improved clinical efficacy against COVID-19 disease.
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Anticuerpos Monoclonales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , COVID-19/inmunología , Fragmentos Fc de Inmunoglobulinas/inmunología , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/farmacología , Anticuerpos Neutralizantes/uso terapéutico , Cricetinae , Modelos Animales de Enfermedad , Femenino , Humanos , Fragmentos Fc de Inmunoglobulinas/química , Fragmentos Fc de Inmunoglobulinas/farmacología , Inmunoglobulina G/química , Inmunoglobulina G/inmunología , Masculino , Ratones , Profilaxis Pre-Exposición , Receptores de IgG/química , Receptores de IgG/inmunología , Resultado del TratamientoRESUMEN
More than one year after its inception, the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains difficult to control despite the availability of several working vaccines. Progress in controlling the pandemic is slowed by the emergence of variants that appear to be more transmissible and more resistant to antibodies1,2. Here we report on a cohort of 63 individuals who have recovered from COVID-19 assessed at 1.3, 6.2 and 12 months after SARS-CoV-2 infection, 41% of whom also received mRNA vaccines3,4. In the absence of vaccination, antibody reactivity to the receptor binding domain (RBD) of SARS-CoV-2, neutralizing activity and the number of RBD-specific memory B cells remain relatively stable between 6 and 12 months after infection. Vaccination increases all components of the humoral response and, as expected, results in serum neutralizing activities against variants of concern similar to or greater than the neutralizing activity against the original Wuhan Hu-1 strain achieved by vaccination of naive individuals2,5-8. The mechanism underlying these broad-based responses involves ongoing antibody somatic mutation, memory B cell clonal turnover and development of monoclonal antibodies that are exceptionally resistant to SARS-CoV-2 RBD mutations, including those found in the variants of concern4,9. In addition, B cell clones expressing broad and potent antibodies are selectively retained in the repertoire over time and expand markedly after vaccination. The data suggest that immunity in convalescent individuals will be very long lasting and that convalescent individuals who receive available mRNA vaccines will produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants.
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Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/sangre , COVID-19/inmunología , SARS-CoV-2/inmunología , Adulto , Anciano , Anticuerpos Monoclonales/inmunología , Linfocitos B/inmunología , Ensayo de Inmunoadsorción Enzimática , Epítopos/inmunología , Femenino , Humanos , Memoria Inmunológica/inmunología , Masculino , Persona de Mediana Edad , SARS-CoV-2/química , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Factores de TiempoRESUMEN
Type III interferons (IFN-λs) signal through a heterodimeric receptor complex composed of the IFN-λR1 subunit, specific for IFN-λs, and interleukin-10Rß (IL-10Rß), which is shared by multiple cytokines in the IL-10 superfamily. Low affinity of IL-10Rß for cytokines has impeded efforts aimed at crystallizing cytokine-receptor complexes. We used yeast surface display to engineer a higher-affinity IFN-λ variant, H11, which enabled crystallization of the ternary complex. The structure revealed that IL-10Rß uses a network of tyrosine residues as hydrophobic anchor points to engage IL-10 family cytokines that present complementary hydrophobic binding patches, explaining its role as both a cross-reactive but cytokine-specific receptor. H11 elicited increased anti-proliferative and antiviral activities in vitro and in vivo. In contrast, engineered higher-affinity type I IFNs did not increase antiviral potency over wild-type type I IFNs. Our findings provide insight into cytokine recognition by the IL-10R family and highlight the plasticity of type III interferon signaling and its therapeutic potential.
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Interferones/inmunología , Receptores de Interferón/inmunología , Receptores de Interleucina-10/inmunología , Animales , Línea Celular , Cristalografía por Rayos X , Citometría de Flujo , Humanos , Ratones , Reacción en Cadena de la Polimerasa , Resonancia por Plasmón de SuperficieRESUMEN
During the coronavirus disease-2019 (COVID-19) pandemic, severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) has led to the infection of millions of people and has claimed hundreds of thousands of lives. The entry of the virus into cells depends on the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2. Although there is currently no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-21-5. Here we report on 149 COVID-19-convalescent individuals. Plasma samples collected an average of 39 days after the onset of symptoms had variable half-maximal pseudovirus neutralizing titres; titres were less than 50 in 33% of samples, below 1,000 in 79% of samples and only 1% of samples had titres above 5,000. Antibody sequencing revealed the expansion of clones of RBD-specific memory B cells that expressed closely related antibodies in different individuals. Despite low plasma titres, antibodies to three distinct epitopes on the RBD neutralized the virus with half-maximal inhibitory concentrations (IC50 values) as low as 2 ng ml-1. In conclusion, most convalescent plasma samples obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/análisis , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/análisis , Anticuerpos Antivirales/análisis , Especificidad de Anticuerpos , COVID-19 , Vacunas contra la COVID-19 , Infecciones por Coronavirus/prevención & control , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Neutralización , Pandemias , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas Virales/inmunología , Adulto JovenRESUMEN
Vaccination will likely be a key component of strategies to curtail or prevent future sarbecovirus pandemics and to reduce the prevalence of infection and disease by future SARS-CoV-2 variants. A "pan-sarbecovirus" vaccine, that provides maximum possible mitigation of human disease, should elicit neutralizing antibodies with maximum possible breadth. By positioning multiple different receptor binding domain (RBD) antigens in close proximity on a single immunogen, it is postulated that cross-reactive B cell receptors might be selectively engaged. Heteromultimeric vaccines could therefore elicit individual antibodies that neutralize a broad range of viral species. Here, we use model systems to investigate the ability of multimeric sarbecovirus RBD immunogens to expand cross-reactive B cells and elicit broadly reactive antibodies. Homomultimeric RBD immunogens generated higher serum neutralizing antibody titers than the equivalent monomeric immunogens, while heteromultimeric RBD immunogens generated neutralizing antibodies recognizing each RBD component. Moreover, RBD heterodimers elicited a greater fraction of cross-reactive germinal center B cells and cross-reactive RBD binding antibodies than did homodimers. However, when serum antibodies from RBD heterodimer-immunized mice were depleted using one RBD component, neutralization activity against the homologous viral pseudotype was removed, but neutralization activity against pseudotypes corresponding to the other RBD component was unaffected. Overall, simply combining divergent RBDs in a single immunogen generates largely separate sets of individual RBD-specific neutralizing serum antibodies that are mostly incapable of neutralizing viruses that diverge from the immunogen components.
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Anticuerpos Neutralizantes , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Animales , Ratones , Humanos , Anticuerpos Antivirales , Pruebas de Neutralización , Vacunación , Glicoproteína de la Espiga del Coronavirus/químicaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-ß are found in â¼20% of deceased patients across age groups, and in â¼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
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Anticuerpos Neutralizantes , Autoanticuerpos , Autoinmunidad , COVID-19 , Interferón Tipo I , SARS-CoV-2 , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/sangre , Autoanticuerpos/sangre , COVID-19/inmunología , COVID-19/mortalidad , Femenino , Humanos , Interferón Tipo I/inmunología , Masculino , Persona de Mediana Edad , RiesgoRESUMEN
We present a detailed analysis of multiphysics simulation results to evaluate the threshold for catastrophic optical damage (COD) of high-power laser diodes under misaligned external optical feedback. Three different chip designs are investigated: the non-injecting mirror concept, the non-absorbing mirror concept and the introduction of an additional energy barrier within the waveguide near the front facet. Furthermore, a modification of the external resonator that promises a lower sensitivity towards misalignments is considered. The dependence of the COD threshold on the additional design parameters (bandgap change, modification length, focal length) and the impact of the different approaches on electro-optical efficiency as well as beam quality are analyzed. Compared to the initial design, the different chip design concepts promise an increase of the achievable output power by 8%, 27% and 27% respectively, whereas the modified resonator fully prevents feedback-induced failure.
RESUMEN
BACKGROUND: Intralymphatic immunotherapy (ILIT) represents a promising novel approach treating allergic diseases. However, no standardized procedures or recommendations have been established or reported, despite the recognized fact that treatment efficacy relies on the ability to inject the allergen intranodally. OBJECTIVE: We aim to provide a critical appraisal of ILIT as a method of allergen immunotherapy and to deliver practical recommendations for accurate ILIT. METHODS: One hundred and seventy-three ILIT injections were performed in 28 (47%) women and 32 (53%) men with median age of 29 years (21-59). The injections were ultrasound-guided and recorded for retrospective analysis with respect to injection location, needle visibility, medication release, and patient characteristics. RESULTS: The results show that the correct positioning of the needle within the lymph node (LN) was most critical. If the whole length of the needle bevel was not inserted into the LN, substance backflush into the interstitium was observed. Selecting a more superficial LN and inserting the needle at a smaller angle towards the LN significantly improved needle visibility in the ultrasound. Longitudinal results showed that continuous practice significantly correlated with improved needle visibility and more accurate ILIT injections. CONCLUSION: Based on our results and practical experience, we propose several recommendations for LN selection and the correct handling of ultrasound probe and needle. We are confident that ILIT standardization and training will be important as to meet the goals of good safety and efficacy of ILIT.
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Desensibilización Inmunológica , Hipersensibilidad , Humanos , Femenino , Masculino , Desensibilización Inmunológica/métodos , Adulto , Inyecciones Intralinfáticas , Persona de Mediana Edad , Hipersensibilidad/terapia , Adulto Joven , Alérgenos/administración & dosificación , Alérgenos/inmunología , Estudios Retrospectivos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/diagnóstico por imagen , Ultrasonografía Intervencional/métodosRESUMEN
PURPOSE: In late 2022, a surge of severe S. pyogenes infections was reported in several European countries. This study assessed hospitalizations and disease severity of community-acquired bacterial infections with S. pyogenes, S. pneumoniae, N. meningitidis, and H. influenzae among children in North Rhine-Westphalia (NRW), Germany, during the last quarter of 2022 compared to long-term incidences. METHODS: Hospital cases due to bacterial infections between October and December 2022 were collected in a multicenter study (MC) from 59/62 (95%) children's hospitals in NRW and combined with surveillance data (2016-2023) from the national reference laboratories for streptococci, N. meningitidis, and H. influenzae. Overall and pathogen-specific incidence rates (IR) from January 2016 to March 2023 were estimated via capture-recapture analyses. Expected annual deaths from the studied pathogens were calculated from national death cause statistics. RESULTS: In the MC study, 153 cases with high overall disease severity were reported with pneumonia being most common (59%, n = 91). IRs of bacterial infections declined at the beginning of the COVID-19 pandemic and massively surged to unprecedented levels in late 2022 and early 2023 (overall hospitalizations 3.5-fold), with S. pyogenes and S. pneumoniae as main drivers (18-fold and threefold). Observed deaths during the study period exceeded the expected number for the entire year in NRW by far (7 vs. 0.9). DISCUSSION: The unprecedented peak of bacterial infections and deaths in late 2022 and early 2023 was caused mainly by S. pyogenes and S. pneumoniae. Improved precautionary measures are needed to attenuate future outbreaks.
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Infecciones Comunitarias Adquiridas , Brotes de Enfermedades , Humanos , Alemania/epidemiología , Infecciones Comunitarias Adquiridas/epidemiología , Infecciones Comunitarias Adquiridas/microbiología , Niño , Preescolar , Lactante , Brotes de Enfermedades/estadística & datos numéricos , Adolescente , Femenino , Masculino , Hospitalización/estadística & datos numéricos , Infecciones Bacterianas/epidemiología , Incidencia , Recién Nacido , Streptococcus pyogenesRESUMEN
BACKGROUND: Reports from case series suggest that operative outcomes are comparable amongst different age groups following surgery with curative intent for non-small cell lung cancer (NSCLC). The purpose of this study was to compare morbidity and mortality after NSCLC surgery in older patients (≥ 75 years) versus younger patients (< 75 years) and identify independent predictive risk factors. METHODS: We identified 2015 patients with postoperative stages IA to IIIA according to AJCC/UICC 7th edition who had undergone NSCLC surgery with curative intent at a single specialized lung cancer center from January 2010 to December 2015. A matched-pair analysis was performed on 227 older patients and corresponding 227 younger patients. Short-term surgical outcomes were postoperative morbidity, length of hospital stay, 30-day and 90-day mortality. Long-term operative outcomes were disease-free and overall survival. RESULTS: 454 patients were included in the matched-pair analysis. 36% of younger patients developed postoperative complications versus 42% in older patients (p = 0.163). Age was not significantly associated with the occurrence of postoperative complications. Median length of hospital stay was 14 days in older patients and 13 days in younger patients (p = 0.185). 90-day mortality was 2.2% in younger patients compared to 4% in older patients (p = 0.424). In patients aged 75 and older impaired performance status (ECOG ≥ 1) was associated with decreased overall survival (HR = 2.15, CI 1.34-3.46), as were preoperative serum C-reactive protein / albumin ratio ≥ 0.3 (HR = 1.95, CI 1.23-3.11) and elevated preoperative serum creatinine levels ≥ 1.1 mg/dl (HR = 1.84, CI 1.15-2.95). In the younger cohort male sex (HR = 2.26, CI 1.17-4.36), postoperative stage III disease (HR 4.61, CI 2.23-9.54) and preoperative anemia (hemoglobin < 12 g/dl) (HR 2.09, CI 1.10-3.96) were associated with decreased overall survival. CONCLUSIONS: Lung resection for NSCLC in older patients is associated with postoperative morbidity and mortality comparable to those of younger patients. In older patients, physical activity, comorbidities and nutritional status are related to survival and should influence the indication for surgery rather than age alone.
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Carcinoma de Pulmón de Células no Pequeñas , Tiempo de Internación , Neoplasias Pulmonares , Complicaciones Posoperatorias , Humanos , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Masculino , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Femenino , Anciano , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/mortalidad , Tasa de Supervivencia , Persona de Mediana Edad , Análisis por Apareamiento , Pronóstico , Factores de Edad , Anciano de 80 o más Años , Tiempo de Internación/estadística & datos numéricos , Estudios de Seguimiento , Factores de Riesgo , Neumonectomía/mortalidad , Neumonectomía/efectos adversos , Estudios Retrospectivos , Estadificación de Neoplasias , Morbilidad , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patologíaRESUMEN
Malignant primary tracheal tumours are rare. The most common histological subtypes are squamous cell carcinoma and adenoid cystic carcinoma. These two entities have different prognoses and growth patterns. Tracheobronchoscopy and thoracic sectional imaging are standard diagnostic tools for tumour staging and local evaluation. Complete surgical resection of the affected tracheal segment is the treatment of choice for limited disease without distant metastases. Incomplete gross tumour resection with additional irradiation is an acceptable therapeutic option for adenoid cystic carcinoma. Interventional endoscopy with tumour debulking or tracheal stenting and/or definitive mediastinal radiotherapy are treatment alternatives in either a locally advanced or palliative setting.
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Broncoscopía , Carcinoma Adenoide Quístico , Carcinoma de Células Escamosas , Estadificación de Neoplasias , Tráquea , Neoplasias de la Tráquea , Neoplasias de la Tráquea/cirugía , Neoplasias de la Tráquea/patología , Neoplasias de la Tráquea/diagnóstico , Neoplasias de la Tráquea/terapia , Neoplasias de la Tráquea/diagnóstico por imagen , Humanos , Carcinoma Adenoide Quístico/patología , Carcinoma Adenoide Quístico/cirugía , Carcinoma Adenoide Quístico/diagnóstico por imagen , Carcinoma Adenoide Quístico/terapia , Carcinoma Adenoide Quístico/diagnóstico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/diagnóstico por imagen , Tráquea/cirugía , Tráquea/patología , Tráquea/diagnóstico por imagen , Pronóstico , Terapia Combinada , Tomografía Computarizada por Rayos X , Stents , Cuidados PaliativosRESUMEN
The process of implementing early detection of lung cancer with low-dose CT (LDCT) in Germany has gained significant momentum in recent years. It is expected that the ordinance of the Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection (BMUV) on early detection of lung cancer, which has been commented on by the professional societies, will come into effect by the end of 2023. Based on this regulation, the Federal Joint Committee (G-BA) will set up a program for early lung cancer detection with LDCT in the near future. In this position paper, the specialist societies involved in lung cancer screening present concrete cornerstones for a uniform, structured and quality-assured early detection program for lung cancer in Germany to make a constructive contribution to this process.
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Detección Precoz del Cáncer , Neoplasias Pulmonares , Humanos , Tomografía Computarizada por Rayos X , Neoplasias Pulmonares/diagnóstico por imagen , Alemania , Sociedades Médicas , Tamizaje MasivoRESUMEN
BACKGROUND: In 2022, an update of the German lung cancer guideline, first published in 2010 and revised in 2018, was released. This article aims to show the process of updating, developing, and implementing guideline-based quality indicators (QI) into the certification system for lung cancer centers (LCC). METHODS: A multidisciplinary and interprofessional working group revised the guideline QIs from 2018 using the strong recommendations of the guideline update, a systematic review for QIs, and the results of the implemented QIs from LCC. RESULTS: For 4 out of 8 indicators from the 2018 guideline, the LCC showed an improved implementation of the requirements in the last 3 years (2018-2020). For 3 indicators, the median of the results was constant at a very high level (≥96% or 100%). Only the "adjuvant cisplatin-based chemotherapy" indicator showed declining values between 2018 and 2020. The target values and plausibility limits were well achieved by LCC. After updating the guideline, one QI from 2018 was not included in the new QI set due to the small denominator population. Based on the new strong recommendations, 8 new QIs were defined. From the QI set of the guideline update, 13 of 15 indicators (7 since 2018 and 6 from 2022 on) were adopted into the certification program. CONCLUSIONS: The guideline recommendations are implemented by LCC at a high level. The process presented confirms the successful implementation of the so-called quality cycle in oncology. The QIs developed by the German Guideline Program in Oncology (GGPO) are adopted by the certification program. The implementation of the QI is measured in LCC, evaluated by the German Cancer Society (DKG), and reflected back to the GGPO. The "real world" data have led to the deletion of one QI and show a high implementation of most QIs in LCC.
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Neoplasias Pulmonares , Indicadores de Calidad de la Atención de Salud , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapiaRESUMEN
The process of implementing early detection of lung cancer with low-dose CT (LDCT) in Germany has gained significant momentum in recent years. It is expected that the ordinance of the Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection (BMUV) on early detection of lung cancer, which has been commented on by the professional societies, will come into effect by the end of 2023. Based on this regulation, the Federal Joint Committee (G-BA) will set up a program for early lung cancer detection with LDCT in the near future. In this position paper, the specialist societies involved in lung cancer screening present concrete cornerstones for a uniform, structured and quality-assured early detection program for lung cancer in Germany to make a constructive contribution to this process.
Asunto(s)
Detección Precoz del Cáncer , Neoplasias Pulmonares , Humanos , Tomografía Computarizada por Rayos X , Neoplasias Pulmonares/diagnóstico por imagen , Factores de Riesgo , Alemania , Tamizaje MasivoRESUMEN
BACKGROUND & AIMS: A number of genetic polymorphisms have been associated with susceptibility to or protection against non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms remain unknown. Here, we focused on the rs738409 C>G single nucleotide polymorphism (SNP), which produces the I148M variant of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and is strongly associated with NAFLD. METHODS: To enable mechanistic dissection, we developed a human pluripotent stem cell (hPSC)-derived multicellular liver culture by incorporating hPSC-derived hepatocytes, hepatic stellate cells, and macrophages. We first applied this liver culture to model NAFLD by utilising a lipotoxic milieu reflecting the circulating levels of disease risk factors in affected individuals. We then created an isogenic pair of liver cultures differing only at rs738049 and compared NAFLD phenotype development. RESULTS: Our hPSC-derived liver culture recapitulated many key characteristics of NAFLD development and progression including lipid accumulation and oxidative stress, inflammatory response, and stellate cell activation. Under the lipotoxic conditions, the I148M variant caused the enhanced development of NAFLD phenotypes. These differences were associated with elevated IL-6/signal transducer and activator of transcription 3 (STAT3) activity in liver cultures, consistent with transcriptomic data of liver biopsies from individuals carrying the rs738409 SNP. Dampening IL-6/STAT3 activity alleviated the I148M-mediated susceptibility to NAFLD, whereas boosting it in wild-type liver cultures enhanced NAFLD development. Finally, we attributed this elevated IL-6/STAT3 activity in liver cultures carrying the rs738409 SNP to increased NF-κB activity. CONCLUSIONS: Our study thus reveals a potential causal link between elevated IL-6/STAT3 activity and 148M-mediated susceptibility to NAFLD. IMPACT AND IMPLICATIONS: An increasing number of genetic variants manifest in non-alcoholic fatty liver disease (NAFLD) development and progression; however, the underlying mechanisms remain elusive. To study these variants in human-relevant systems, we developed an induced pluripotent stem cell-derived multicellular liver culture and focused on a common genetic variant (i.e. rs738409 in PNPLA3). Our findings not only provide mechanistic insight, but also a potential therapeutic strategy for NAFLD driven by this genetic variant in PNPLA3. Our liver culture is therefore a useful platform for exploring genetic variants in NAFLD development.