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BACKGROUND: Microsatellite instability (MSI) due to mismatch repair deficiency (dMMR) is common in colorectal cancer (CRC). These cancers are associated with somatic coding events, but the noncoding pathophysiological impact of this genomic instability is yet poorly understood. Here, we perform an analysis of coding and noncoding MSI events at the different steps of colorectal tumorigenesis using whole exome sequencing and search for associated splicing events via RNA sequencing at the bulk-tumor and single-cell levels. RESULTS: Our results demonstrate that MSI leads to hundreds of noncoding DNA mutations, notably at polypyrimidine U2AF RNA-binding sites which are endowed with cis-activity in splicing, while higher frequency of exon skipping events are observed in the mRNAs of MSI compared to non-MSI CRC. At the DNA level, these noncoding MSI mutations occur very early prior to cell transformation in the dMMR colonic crypt, accounting for only a fraction of the exon skipping in MSI CRC. At the RNA level, the aberrant exon skipping signature is likely to impair colonic cell differentiation in MSI CRC affecting the expression of alternative exons encoding protein isoforms governing cell fate, while also targeting constitutive exons, making dMMR cells immunogenic in early stage before the onset of coding mutations. This signature is characterized by its similarity to the oncogenic U2AF1-S34F splicing mutation observed in several other non-MSI cancer. CONCLUSIONS: Overall, these findings provide evidence that a very early RNA splicing signature partly driven by MSI impairs cell differentiation and promotes MSI CRC initiation, far before coding mutations which accumulate later during MSI tumorigenesis.
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Processamento Alternativo , Neoplasias Colorretais , Instabilidade de Microssatélites , Fator de Processamento U2AF , Neoplasias Colorretais/genética , Humanos , Fator de Processamento U2AF/genética , Fator de Processamento U2AF/metabolismo , Mutação , Sítios de Ligação , ÉxonsRESUMO
ABSTRACT: Pain perception and its modulation are fundamental to human learning and adaptive behavior. This study investigated the hypothesis that pain perception is tied to pain's learning function. Thirty-one participants performed a threat conditioning task where certain cues were associated with a possibility of receiving a painful electric shock. The cues that signaled potential pain or safety were regularly changed, requiring participants to continually establish new associations. Using computational models, we quantified participants' pain expectations and prediction errors throughout the task and assessed their relationship with pain perception and electrophysiological responses. Our findings suggest that subjective pain perception increases with prediction error, that is, when pain was unexpected. Prediction errors were also related to physiological nociceptive responses, including the amplitude of nociceptive flexion reflex and electroencephalography markers of cortical nociceptive processing (N1-P2-evoked potential and gamma-band power). In addition, higher pain expectations were related to increased late event-related potential responses and alpha/beta decreases in amplitude during cue presentation. These results further strengthen the idea of a crucial link between pain and learning and suggest that understanding the influence of learning mechanisms in pain modulation could help us understand when and why pain perception is modulated in health and disease.
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OBJECTIVES: Extracorporeal life support can lead to rapid reversal of hypoxemia but the benefits and harms of different oxygenation targets in severely ill patients are unclear. Our primary objective was to investigate the association between the Pa o2 after extracorporeal membrane oxygenation (ECMO) initiation and mortality in neonates treated for respiratory failure. DESIGN: Retrospective analysis of the Extracorporeal Life Support Organization (ELSO) Registry data, 2015-2020. PATIENTS: Newborns supported by ECMO for respiratory indication were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pa o2 24 hours after ECMO initiation (H24 Pa o2 ) was reported. The primary outcome was 28-day mortality. We identified 3533 newborns (median age 1 d [interquartile range (IQR), 1-3]; median weight 3.2 kg [IQR, 2.8-3.6]) from 198 ELSO centers, who were placed on ECMO. By 28 days of life, 731 (20.7%) had died. The median H24 Pa o2 was 85 mm Hg (IQR, 60-142). We found that both hypoxia (Pa o2 < 60 mm Hg) and moderate hyperoxia (Pa o2 201-300 mm Hg) were associated with greater adjusted odds ratio (aOR [95% CI]) of 28-day mortality, respectively: aOR 1.44 (95% CI, 1.08-1.93), p = 0.016, and aOR 1.49 (95% CI, 1.01-2.19), p value equals to 0.045. CONCLUSIONS: Early hypoxia or moderate hyperoxia after ECMO initiation are each associated with greater odds of 28-day mortality among neonates requiring ECMO for respiratory failure.
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Oxigenação por Membrana Extracorpórea , Sistema de Registros , Humanos , Oxigenação por Membrana Extracorpórea/mortalidade , Oxigenação por Membrana Extracorpórea/métodos , Recém-Nascido , Estudos Retrospectivos , Masculino , Feminino , Insuficiência Respiratória/terapia , Insuficiência Respiratória/mortalidade , Oxigênio , Hipóxia/mortalidade , Hipóxia/terapiaRESUMO
OBJECTIVES: Anemia and transfusion are common in cardiac surgery patients, and are associated with significant morbidity and mortality. Multiple perioperative interventions have been described to reduce blood transfusion, but are rarely combined altogether. The aim of this study was to compare the incidence of red blood cell (RBC) transfusion in adult patients undergoing cardiac surgery before and after the implementation of a perioperative patient blood management (PBM) program. DESIGN: Before-and-after observational study. SETTING: Single-center French university teaching hospital. PARTICIPANTS: Adult patients scheduled for cardiac surgery. INTERVENTIONS: Perioperative patient blood management program including pre-, intra-, and postoperative interventions aimed at identifying and correcting anemia, minimizing blood loss during surgery, and optimizing coagulation. MEASUREMENTS AND MAIN RESULTS: Four hundred thirty-four patients were included in the study from January 2021 to July 2022. The incidence of perioperative RBC transfusion (intraoperatively and during the first 2 postoperative days) was significantly reduced from 43% (90/213) in the pre-PBM period to 27% (60/221) in the post-PBM period (p < 0.001). The application of a PBM program was associated with a reduction in perioperative RBC transfusion by multivariate analysis (odds ratio 0.55, 95% CI 0.36-0.85, p = 0.007), and was associated with a reduction in the median number of RBC units transfused within transfused patients (p = 0.025). These effects persisted at day 30 after surgery (p = 0.029). CONCLUSION: A perioperative PBM program in adult patients undergoing cardiac surgery was associated with a significant reduction in perioperative RBC transfusion, which persisted at day 30.
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Anemia , Procedimentos Cirúrgicos Cardíacos , Adulto , Humanos , Transfusão de Eritrócitos , Transfusão de Sangue , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Hospitais UniversitáriosRESUMO
To evaluate the feasibility of continuous determination of the optimal mean arterial blood pressure (opt-MAP) according to cerebral autoregulation and to describe the opt-MAP, the autoregulation limits, and the time spent outside these limits in children within 48 h of cardiac surgery. Cerebral autoregulation was assessed using the correlation coefficient (COx) between cerebral oxygenation and MAP in children following cardiac surgery. Plots depicting the COx according to the MAP were used to determine the opt-MAP using weighted multiple time windows. For each patient, we estimated (1) the time spent with MAP outside the autoregulation limits and (2) the burden of deviation, defined as the area between the MAP curve and the autoregulation limits when the MAP was outside these limits. Fifty-one patients with a median age of 7.1 (IQR 0.7-52.0) months old were included. The opt-MAP was calculated for 94% (IQR 90-96) of the monitored time. The opt-MAP was significantly lower in neonates < 1 month old. The patients spent 24% (18-31) of the time outside of the autoregulation limits, with no significant differences between age groups. Continuous determination of the opt-MAP is feasible in children within the first 48 h following cardiac surgery.
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Pressão Arterial , Procedimentos Cirúrgicos Cardíacos , Criança , Recém-Nascido , Humanos , Lactente , Pré-Escolar , Pressão Arterial/fisiologia , Monitorização Intraoperatória , Estudos Prospectivos , Ponte Cardiopulmonar , Circulação Cerebrovascular/fisiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Homeostase , Pressão Sanguínea/fisiologiaRESUMO
Carboxyhemoglobin (COHb) is potentially a novel marker of hemolysis on extracorporeal membrane oxygenation (ECMO) and may be useful as an indicator for circuit-related complication in adults, but little is known about COHb levels in children. An observational single-center study was performed between January 2018 and December 2021. Fifty-eight children were included and COHb levels were obtained along with routine blood gas analysis before, during, and after ECMO support. From the 6th hour of ECMO support, the COHb level increased relative to the pre-ECMO level, with an adjusted mean difference of 0.44 (95% confidence interval [CI], 0.26-0.62; p < 0.001) and remained higher during ECMO run and within 6 hours after weaning ( p < 0.001). Among the 18 children (31%) who experienced at least one circuit-related complication leading to a circuit change, we observed a significant decrease in COHb levels within 24 hours after the circuit change, compared with the 24 hours before (adjusted mean difference, 0.54%; 95% CI, 0.27-0.80; p < 0.001). The maximal daily COHb level was able to predict circuit-related complications within 24 hours following COHb measurement with an area under the receiver operating characteristic (ROC) curve of 0.85 (95% CI, 0.77-0.92; p < 0.001).
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Carboxihemoglobina , Oxigenação por Membrana Extracorpórea , Adulto , Humanos , Criança , Carboxihemoglobina/análise , Oxigenação por Membrana Extracorpórea/efeitos adversos , Hemólise , Estudos RetrospectivosRESUMO
OBJECTIVES: To describe the distribution, consequences and potential determinants of time to antibiotics administration in children with community-onset severe bacterial infections (COSBIs). DESIGN: Secondary analysis of the available data from a prospective population-based study from 2009 to 2014. SETTING: An administrative area in western France accounting for 13% of the national pediatric population. PATIENTS: All children from 1 month to 16 years old admitted to a PICU or who died before admission and had a COSBI. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The time to antibiotics was divided into patient interval (from first signs of COSBI to the first medical consultation) and medical interval (from the first consultation to appropriate antibiotics administration). The association between the medical interval and child outcome was studied by a multinomial logistic regression model and the potential determinants of the patient and medical intervals were by a Cox proportional-hazards model. Of the 227 children included (median age 2.1 yr), 22 died (9.7%), and 21 (9.3%) had severe sequelae at PICU discharge. Median patient and medical intervals were 7.0 hours (interquartile range [IQR], 2.0-16.5 hr) and 3.3 hours (IQR, 1.1-12.2 hr), respectively. The last quartile of medical interval was not associated with death (adjusted odds ratio [aOR], 3.7; 95% CI, 0.8-17.5) or survival with severe sequelae (aOR, 1.3; 95% CI, 0.4-4.0) versus survival without severe sequelae. Patient interval was shorter in younger children (adjusted hazard ratio [aHR], 0.95; 95% CI, 0.92-0.99), and medical interval was reduced when the first consultation was conducted in a hospital (aHR, 1.5; 95% CI, 1.1-2.0) versus outpatient medicine. CONCLUSIONS: For children with COSBI, we found no significant association between medical interval and mortality or severe sequelae. An initial hospital referral could help reduce the time to antibiotics in COSBIs.
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Antibacterianos , Infecções Bacterianas , Humanos , Criança , Pré-Escolar , Estudos Prospectivos , Antibacterianos/uso terapêutico , Hospitalização , Modelos de Riscos Proporcionais , Infecções Bacterianas/tratamento farmacológicoRESUMO
OBJECTIVES: The antiarrhythmic effects of dexmedetomidine (DEX) have been suggested, but there are controversial reports on the effectiveness of intraoperative use of DEX to reduce the incidence of postoperative tachyarrhythmia (POT). METHODS: From a local European Congenital Heart Surgery Association database, we included patients operated for congenital heart diseases under cardiopulmonary bypass within a 5-year period (2017-2021), during which intraoperative use of high dose of DEX (1-1.4 µg/kg/h) was implemented. A doubly robust matching estimation of the causal effect of DEX on the incidence of POT was conducted. We combined a multimodal estimation model in patients not exposed to DEX (disease risk score) as well as a regression analysis in a matched cohort for patients exposured to DEX. RESULTS: From a cohort of 593 surgeries (514 patients) occurring during the study period, doubly matched analysis consisted of the analysis of 426 surgeries conducted under DEX or not (213 per group). The probability of developing POT in patients exposed to DEX was 6.6% (95% confidence interval 0.032-0.099) vs 14.5% (95% confidence interval 0.098-0.193) in the group of patients not exposed to DEX. The doubly robust matched estimation method showed a mean reduction of 8.8% (95% confidence interval -0.137 to -0.023) of POT when DEX is used for intraoperative anaesthesia. CONCLUSIONS: The use of high doses of DEX during anaesthesia for congenital heart surgery in neonates and infants is associated with a moderate but significant reduction of POT.
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Procedimentos Cirúrgicos Cardíacos , Dexmedetomidina , Cardiopatias Congênitas , Recém-Nascido , Humanos , Lactente , Dexmedetomidina/uso terapêutico , Incidência , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Taquicardia/epidemiologia , Taquicardia/prevenção & controle , Taquicardia/induzido quimicamente , Cardiopatias Congênitas/cirurgiaRESUMO
The primary objective was to investigate the association between partial pressure of carbon dioxide (PaCO 2 ) change after extracorporeal membrane oxygenation (ECMO) initiation and neurologic outcome in neonates treated for respiratory failure. A retrospective analysis of the Extracorporeal Life Support Organization (ELSO) database including newborns supported by ECMO for respiratory indication during 2015-2020. The closest Pre-ECMO (Pre-ECMO PaCO 2 ) and at 24 hours after ECMO initiation (H24 PaCO 2 ) PaCO 2 values allowed to calculate the relative change in PaCO 2 (Rel Δ PaCO 2 = [H24 PaCO 2 - Pre-ECMO PaCO 2 ]/Pre-ECMO PaCO 2 ). The primary outcome was the onset of any acute neurologic event (ANE), defined as cerebral bleeding, ischemic stroke, clinical or electrical seizure, or brain death during ECMO. We included 3,583 newborns (median age 1 day [interquartile range {IQR}, 1-3], median weight 3.2 kg [IQR, 2.8-3.6]) from 198 ELSO centers. The median Rel Δ PaCO 2 value was -29.9% [IQR, -46.2 to -8.5]. Six hundred nine (17%) of them had ANE (405 cerebral bleedings, 111 ischemic strokes, 225 seizures, and 6 brain deaths). Patients with a decrease of PaCO 2 > 50% were more likely to develop ANE than others (odds ratio [OR] 1.78, 95% confidence interval [CI], 1.31-2.42, p < 0.001). This was still observed after adjustment for all clinically relevant confounding factors (adjusted OR 1.94, 95% CI, 1.29-2.92, p = 0.001). A significant decrease in PaCO 2 after ECMO start is associated with ANE among neonates requiring ECMO for respiratory failure. Cautious PaCO 2 decrease should be considered after start of ECMO therapy.
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Oxigenação por Membrana Extracorpórea , Insuficiência Respiratória , Humanos , Recém-Nascido , Lactente , Estudos Retrospectivos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Dióxido de Carbono , Sistema de Registros , Insuficiência Respiratória/terapia , Morte EncefálicaRESUMO
BACKGROUND: Levosimendan (LVSMD) is a calcium-sensitizer inotropic and vasodilator agent whose use might have a beneficial effect on the weaning of venoarterial extracorporeal membrane oxygenation (VA-ECMO). In light of LVSMD pharmacological characteristics, we hypothesized that ECMO may induce major pharmacokinetic (PK) modifications for LVSMD and its metabolites. OBJECTIVE: The aim of this study was to investigate the PK of LVSMD and its metabolites, and to assess the effects of ECMO on PK parameters. METHODS: We conducted a multicentric, prospective study (NCT03681379). Twenty-seven infusions of LVSMD were performed, allowing for the collection of 255 blood samples. Non-linear mixed-effects modeling software (MONOLIX®) was used to develop a parent-metabolite PK model of LVSMD and its metabolites. RESULTS: Most patients received a 0.2 µg/kg/min infusion of LVSMD over 24 h. After elimination of non-reliable samples or concentrations below the limit of quantification, 166, 101 and 85 samples were considered for LVSMD, OR-1855 and OR-1896, respectively, of which 81, 53 and 41, respectively, were drawn under ECMO conditions. Parent-metabolite PK modeling revealed that a two-compartment model with first-order elimination best described LVSMD PK. Use of a transit compartment allowed for an explanation of the delayed appearance of circulating OR-1855 and OR-1896, with the latter following a first-order elimination. Patient weight influenced the central volume of distribution and elimination of LVSMD. ECMO support increased the elimination rate of LVSMD by 78%, and ECMO also slowed down the metabolite formation rate by 85% for OR-1855, which in turn is converted to the active metabolite OR-1896, 14% slower than without ECMO. Simulated data revealed that standard dosing may not be appropriate for patients under ECMO, with a decrease in the steady-state concentration of LVSMD and lower exposure to the active metabolite OR-1896. CONCLUSIONS: ECMO altered PK parameters for LVSMD and its metabolites. An infusion of LVSMD over 48 h, instead of 24 h, with a slightly higher dose may promote synthesis of the active metabolite OR-1896, which is responsible for the long-term efficacy of LVSMD. Further trials evaluating ECMO effects using a PK/pharmacodynamic approach may be of interest. REGISTRATION: ClinicalTrials.gov identifier number NCT03681379.
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Oxigenação por Membrana Extracorpórea , Recém-Nascido , Humanos , Criança , Simendana , Estudos Prospectivos , Estado Terminal/terapia , Antibacterianos/farmacocinéticaRESUMO
PURPOSE: Early prognostication of neurologic outcome in neonates and children supported with extra-corporeal membrane oxygenation (ECMO) is challenging. Amplitude-integrated EEG (aEEG) offers the advantages of continuous monitoring and 24-hours availability at the bedside for intensive care unit providers. The objective of this study was to describe the early electrophysiological background patterns of neonates and children undergoing ECMO and their association with neurologic outcomes. METHODS: This was a retrospective review of neonates and children undergoing ECMO and monitored with aEEG. Amplitude-integrated EEG was summarized as an aEEG background score determined within the first 24 hours of ECMO and divided in 3-hour periods. Screening for electrical seizures was performed throughout the full ECMO duration. Neurologic outcome was defined by the Pediatric Cerebral Performance Category score at hospital discharge. RESULTS: Seventy-three patients (median age 79 days [8-660], median weight 4.78 kg [3.24-10.02]) were included in the analysis. Thirty-two patients had a favorable neurologic outcome and 41 had an unfavorable neurologic outcome group at hospital discharge. A 24-hour aEEG background score >17 was associated with an unfavorable outcome with a sensitivity of 44%, a specificity of 97%, a positive predictive value of 95%, and a negative predictive value of 57%. In multivariate analysis, 24-hour aEEG background score was associated with unfavorable outcome (hazard ratio, 6.1; p = 0.001; 95% confidence interval, 2.31-16.24). The presence of seizures was not associated with neurologic outcome at hospital discharge. CONCLUSIONS: Continuous aEEG provides accurate neurologic prognostication in neonates and children supported with ECMO. Early aEEG monitoring may help intensive care unit providers to guide clinical care and family counseling.
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Oxigenação por Membrana Extracorpórea , Recém-Nascido , Humanos , Criança , Lactente , Estudos Retrospectivos , Valor Preditivo dos Testes , Eletroencefalografia , Unidades de Terapia IntensivaRESUMO
Heat shock proteins (HSPs) play oncogenic roles in human tumours. We reported a somatic inactivating mutation of HSP110 (HSP110DE9) in mismatch repair-deficient (dMMR) cancers displaying microsatellite instability (MSI) but did not assess its impact. We evaluated the impact of the Hsp110DE9 mutation on tumour development and the chemotherapy response in a dMMR knock-in mouse model (Hsp110DE9KIMsh2KO mice). The effect of the Hsp110DE9 mutation on tumorigenesis and survival was evaluated in Msh2KO mice that were null (Hsp110wt), heterozygous (Hsp110DE9KI/+), or homozygous (Hsp110DE9KI/KI) for the Hsp110DE9 mutation by assessing tumoral syndrome (organomegaly index, tumour staging) and survival (Kaplan-Meier curves). 5-Fluorouracil (5-FU), which is the backbone of chemotherapy regimens in gastrointestinal cancers and is commonly used in other tumour types but is not effective against dMMR cells in vivo, was administered to Hsp110DE9KI/KI, Hsp110DE9KI/+, and Hsp110wtMsh2KO mice. Hsp110, Ki67 (proliferation marker) and activated caspase-3 (apoptosis marker) expression were assessed in normal and tumour tissue samples by western blotting, immunophenotyping and cell sorting. Hsp110wt expression was drastically reduced or totally lost in tumours from Msh2KOHsp110DE9KI/+ and Msh2KOHsp110DE9KI/KI mice. The Hsp110DE9 mutation did not affect overall survival or tumoral syndrome in Msh2KOHsp110DE9KI/+ and Msh2KOHsp110DE9KI/KI mice but drastically improved the 5-FU response in all cohorts (Msh2KOHsp110DE9KI/KI: P5fu = 0.001; Msh2KOHsp110DE9KI/+: P5fu = 0.005; Msh2KOHsp110wt: P5fu = 0.335). Histopathological examination and cell sorting analyses confirmed major hypersensitization to 5-FU-induced death of both Hsp110DE9KI/KI and Hsp110DE9KI/+ dMMR cancer cells. This study highlights how dMMR tumour cells adapt to HSP110 inactivation but become hypersensitive to 5-FU, suggesting Hsp110DE9 as a predictive factor of 5-FU efficacy.
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Fluoruracila , Proteínas de Choque Térmico HSP110 , Neoplasias , Animais , Carcinogênese/genética , Fluoruracila/uso terapêutico , Proteínas de Choque Térmico HSP110/genética , Camundongos , Instabilidade de Microssatélites , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
Importance: Assessment of the quality of initial care is necessary to target priority actions that can reduce the still high morbidity and mortality due to community-onset severe bacterial infections (COSBIs) among children. Objective: To study the prevalence, characteristics, and determinants of suboptimal care in the initial management of COSBIs. Design, Setting, and Participants: This prospective, population-based, cohort study and confidential enquiry was conducted between August 2009 and January 2014 in western France, a region accounting for 15% of the French pediatric population (1â¯968â¯474 children aged 1 month to 16 years) and including 6 pediatric intensive care units (PICUs) and 35 emergency departments. Participants included all children aged 1 month to 16 years who died before PICU admission or were admitted to a PICU with a COSBI (ie, bacterial sepsis, including meningitis, purpura fulminans, and pulmonary, osteoarticular, intra-abdominal, cardiac, and soft-tissue severe infections). Data were analyzed from March to June 2020. Exposures: Suboptimal care determined according to evaluation of 8 types of care: (1) the delay in seeking care by family, (2) the physician's evaluation of severity, (3) the patient's referral at the first consultation with signs of severity, (4) the timing and (5) dosage of antibiotic treatment, (6) the timing and (7) volume of fluid bolus administration, and (8) the clinical reassessment after fluid bolus. Main Outcomes and Measures: Two experts assessed the quality of care before death or PICU admission as optimal, possibly suboptimal, or certainly suboptimal. The consequences and determinants of certainly suboptimal care were identified with multinomial logistic regression and generalized linear mixed models. Results: Of the 259 children included (median [IQR] age, 24 [6-66] months; 143 boys [55.2%]), 27 (10.4%) died, and 25 (9.6%) had severe sequelae at PICU discharge. The quality of care was certainly suboptimal in 89 cases (34.4%). Suboptimal care was more frequent in children with sequelae (adjusted odds ratio [aOR], 5.61; 95% CI, 1.19-26.36) and less frequent in children who died (aOR, 0.16; 95% CI, 0.04-0.65) vs those surviving without sequelae. Factors independently associated with suboptimal care were age younger than 5 years (aOR, 3.15; 95% CI, 1.25-7.90), diagnosis of sepsis with no source (aOR, 5.77; 95% CI, 1.64-20.30) or meningitis (aOR, 3.39; 95% CI, 1.15-9.96) vs other severe infections, and care by a primary care physician (aOR, 3.22; 95% CI, 1.17-8.88) vs a pediatric hospital service. Conclusions and Relevance: This study found that suboptimal care is frequent in the initial management of COSBI and is associated with severe sequelae. The paradoxical association with reduced risk of death may be explained by an insufficient adjustment on bacterial or host intrinsic factors. Management could be optimized by improving the quality of primary care, especially for young children.
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Infecções Bacterianas , Sepse , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Humanos , Masculino , Prevalência , Estudos Prospectivos , Sepse/diagnóstico , Sepse/epidemiologia , Sepse/terapia , Adulto JovemRESUMO
In the era of immune checkpoint inhibitors, understanding the metastatic microenvironment of proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC) is of paramount importance to both prognostication and the development of more effective novel therapies. In this study, primary and paired metastasis tissue samples were collected from patients with resectable metastatic CRC treated with adjuvant FOLFOX or peri-operative chemotherapy in the MIROX phase III prospective study. In total, 74 cancer tissues were stained for CD3, CD8, Forkhead box protein 3 (FOXP3), programmed cell death protein-1 (PD-1, invasive front, stromal, intra-epithelial compartments), and programmed death-ligand 1 (PD-L1, tumor, immune cells). The immune profiling of primary CRC had a limited value to predict the immune context of paired metastases for all markers but CD3+. The expression of CD8 and PD-L1 was higher in metastases after neoadjuvant FOLFOX. In metastases, both CD3 T cells at the invasive front and PD-L1 expressions on immune cells were predictive of better disease-free survival. These results show that the effect of FOLFOX on modifying the immune microenvironment in resected CRC metastases and measurement of PD-L1 expression and tumor-infiltrating CD8 T cells in pMMR/MSS metastatic tissue samples could improve treatment strategies of metastatic CRC patients.
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Neoplasias do Colo , Neoplasias Colorretais , Antígeno B7-H1/genética , Estudos de Coortes , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Humanos , Linfócitos do Interstício Tumoral/patologia , Estudos Prospectivos , Microambiente TumoralRESUMO
The impact of cervical cannulation on neurologic outcome has not been yet studied among children receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) in the context of severe sepsis or septic shock. A retrospective cohort study was performed using the extracorporeal life support organization (ELSO) registry. A total of 559 children weighing less than 20 kg with a primary or secondary diagnosis of severe sepsis, septic shock or toxic shock syndrome were included between January 1, 2010, and December 31, 2019. Cervical cannulation was performed in 485 children (87%) and central cannulation in 74 children (13%). The prevalence of acute neurologic event (ANE) was 32%, including clinical and/or electroencephalographic seizures, cerebral infarction, cerebral hemorrhage, and/or brain death. In multivariable analysis, we did not find an association between cervical cannulation and greater/lesser odds of ANE during ECMO (adjusted odds ratio [aOR] = 1.39, 95% confidence interval [CI] 0.72-2.65; P = 0.326). Only pre-ECMO acidosis was independently associated with the development of ANE (pH < 6.99; aOR = 2.71, 95% CI 1.34-5.49; P = 0.006; pH 6.99 to <7.12; aOR = 2.57, 95% CI 1.37-4.82; P = 0.003). Thus, the site of cannulation appears not as a modifiable neurologic risk factor in this young septic population.
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Oxigenação por Membrana Extracorpórea , Sepse , Choque Séptico , Cateterismo/efeitos adversos , Criança , Oxigenação por Membrana Extracorpórea/efeitos adversos , Humanos , Estudos Retrospectivos , Sepse/epidemiologia , Sepse/etiologiaRESUMO
OBJECTIVES: Diaphragmatic paralysis following congenital cardiac surgery is associated with significant morbidity and mortality. Spontaneous recovery of diaphragmatic function has been described, contrasting with centres providing early diaphragmatic plication. We aimed to describe the outcomes of a conservative approach, as well as to identify factors associated with a failure of the strategy. METHODS: This is a retrospective study of patients admitted after cardiac surgery and suffering unilateral diaphragmatic paralysis within 2 French Paediatric Cardiac Surgery Centers. The conservative approach, defined by the prolonged use of ventilation until successful weaning from respiratory support, was the primary strategy adopted in both centres. In case of unsuccessful evolution, a diaphragmatic plication was scheduled. Total ventilation time included invasive and non-invasive ventilation. Diaphragm asymmetry was defined by the number of posterior rib segments counted between the 2 hemi-diaphragms on the chest X-ray after cardiac surgery. RESULTS: Fifty-one neonates and infants were included in the analysis. Patients' median age was 12.0 days at cardiac surgery (5.0-82.0), and median weight was 3.5 kg (2.8-4.9). The conservative approach was successful for 32/51 patients (63%), whereas 19/51 patients (37%) needed diaphragm plication. There was no difference in patients' characteristics between groups. Respiratory support prolonged for 21 days or more and diaphragm asymmetry more than 2 rib segments were independently associated with the failure of the conservative strategy [odds ratio (OR) 6.9 (1.29-37.3); P = 0.024 and OR 6.0 (1.4-24.7); P = 0.013, respectively]. CONCLUSIONS: The conservative approach was successful for 63% of the patients. We identified risk factors associated with the strategy's failure.