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BACKGROUND: Various biomarkers are used to define peanut allergy (PA). We aimed to observe changes in PA resolution and persistence over time comparing biomarkers in PA and peanut sensitised but tolerant (PS) children in a population-based cohort. METHODS: Participants were recruited from the EAT and EAT-On studies, conducted across England and Wales, and were exclusively breastfeed babies recruited at 3 months old and followed up until 7-12 years old. Clinical characteristics, skin prick test (SPT), sIgE to peanut and peanut components and mast cell activation tests (MAT) were assessed at 12 months, 36 months and 7-12 years. PA status was determined at the 7-12 year time point. RESULTS: The prevalence of PA was 2.1% at 7-12 years. Between 3 and 7-12 year, two children developed PA and one outgrew PA. PA children had larger SPT, higher peanut-sIgE, Ara h 2-sIgE and MAT (all p < .001) compared to PS children from 12 months onwards. SPT, peanut-sIgE, Ara h 2-sIgE and MAT between children with persistent PA, new PA, outgrown PA and PS were statistically significant from 12 months onwards (p < .001). Those with persistent PA had SPT, peanut-sIgE and Ara h 2-sIgE that increased over time and MAT which was highest at 36 months. New PA children had increased SPT and peanut-sIgE from 36 months to 7-12 years, but MAT remained low. PS children had low biomarkers across time. CONCLUSIONS: In this cohort, few children outgrow or develop new PA between 36 months and 7-12 years. Children with persistent PA have raised SPT, peanut-sIgE, Ara h 2-sIgE and MAT evident from infancy that consistently increase over time.
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BACKGROUND: A randomized trial demonstrated consumption of peanut from infancy to age 5 years prevented the development of peanut allergy. An extension of that trial demonstrated the effect persisted after 1 year of peanut avoidance. This follow-up trial examined the durability of peanut tolerance at age 144 months after years of ad libitum peanut consumption. METHODS: Participants from a randomized peanut consumption trial were assessed for peanut allergy following an extended period of eating or avoiding peanuts as desired. The primary end point was the rate of peanut allergy at age 144 months. RESULTS: We enrolled 508 of the original 640 participants (79.4%); 497 had complete primary end point data. At age 144 months, peanut allergy remained significantly more prevalent in participants in the original peanut avoidance group than in the original peanut consumption group (15.4% [38 of 246 participants] vs. 4.4% [11 of 251 participants]; P<0.001). Participants in both groups reported avoiding peanuts for prolonged periods of time between 72 and 144 months. Participants at 144 months in the peanut consumption group had levels of Ara h2-specific immunoglobulin E (a peanut allergen associated with anaphylaxis) of 0.03 ± 3.42 kU/l and levels of peanut-specific immunoglobulin G4 of 535.5 ± 4.98 µg/l, whereas participants in the peanut avoidance group had levels of Ara h2-specific immunoglobulin E of 0.06 ± 11.21 kU/l and levels of peanut-specific immunoglobulin G4 of 209.3 ± 3.84 µg/l. Adverse events were uncommon, and the majority were related to the food challenge. CONCLUSIONS: Peanut consumption, starting in infancy and continuing to age 5 years, provided lasting tolerance to peanut into adolescence irrespective of subsequent peanut consumption, demonstrating that long-term prevention and tolerance can be achieved in food allergy. (Funded by the National Institute of Allergy and Infectious Diseases and others; ITN070AD, ClinicalTrials.gov number, NCT03546413.).
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Arachis , Hipersensibilidade a Amendoim , Humanos , Hipersensibilidade a Amendoim/prevenção & controle , Hipersensibilidade a Amendoim/imunologia , Hipersensibilidade a Amendoim/epidemiologia , Seguimentos , Arachis/imunologia , Feminino , Masculino , Pré-Escolar , Lactente , Adolescente , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Criança , Tolerância ImunológicaRESUMO
Studies of new therapies to preserve insulin secretion in early type 1 diabetes require several years to recruit eligible subjects and to see a treatment effect; thus, there is interest in alternative study designs to speed this process. Most people with longstanding type 1 diabetes no longer secrete insulin. However, studies from pancreata of those with longstanding T1D show that beta cells staining for insulin can persist for decades after diagnosis, and this is paralleled in work showing proinsulin secretion in individuals with longstanding disease; collectively this suggests that there is a reserve of alive but "sleeping" beta cells. Here, we designed a novel clinical trial platform to test whether a short course of therapy with an agent known to have effects in type 1 diabetes with residual endogenous insulin could transiently induce insulin secretion in those who no longer produce insulin. A therapy that transiently "wakes up" sleeping beta cells might be tested next in a fully powered trial in those with endogenous insulin secretion. In this three-arm non-randomized pilot study, we tested three therapies known to impact disease: two beta-cell supportive agents, liraglutide and verapamil, and an immunomodulatory agent, golimumab. The golimumab treated arm was not fully enrolled due to uncertainties about immunotherapy during the COVID-19 pandemic. Participants had mixed-meal tolerance test (MMTT)-stimulated C-peptide below the quantitation limit (<0.02 ng/mL) at enrollment and received 8 to 12 weeks of therapy. At the completion of therapy, none of the individuals achieved the primary outcome of MMTT-stimulated C-peptide ≥ 0.02 ng/mL. An exploratory outcome of the verapamil arm was MRI-assessed pancreas size, diffusion, and longitudinal relaxation time, which showed repeatability of these measures but no treatment effect. The liraglutide and golimumab arms were registered on clinicaltrials.gov under accession number NCT03632759 and the verapamil arm under accession number NCT05847413. Trail registration: Protocols are registered in ClinicalTrials.gov under accession numbers NCT03632759 and NCT05847413.
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Diabetes Mellitus Tipo 1 , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Peptídeo C , Liraglutida , Projetos Piloto , Pandemias , Insulina/uso terapêutico , VerapamilRESUMO
The use of a standardized outcome metric enhances clinical trial interpretation and cross-trial comparison. If a disease course is predictable, comparing modeled predictions with outcome data affords the precision and confidence needed to accelerate precision medicine. We demonstrate this approach in type 1 diabetes (T1D) trials aiming to preserve endogenous insulin secretion measured by C-peptide. C-peptide is predictable given an individual's age and baseline value; quantitative response (QR) adjusts for these variables and represents the difference between the observed and predicted outcome. Validated across 13 trials, the QR metric reduces each trial's variance and increases statistical power. As smaller studies are especially subject to random sampling variability, using QR as the outcome introduces alternative interpretations of previous clinical trial results. QR can provide model-based estimates that quantify whether individuals or groups did better or worse than expected. QR also provides a purer metric to associate with biomarker measurements. Using data from more than 1300 participants, we demonstrate the value of QR in advancing disease-modifying therapy in T1D. QR applies to any disease where outcome is predictable by pre-specified baseline covariates, rendering it useful for defining responders to therapy, comparing therapeutic efficacy, and understanding causal pathways in disease.
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Diabetes Mellitus Tipo 1 , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Peptídeo C/uso terapêutico , Ensaios Clínicos como Assunto , Secreção de Insulina , Medicina de PrecisãoRESUMO
INTRODUCTION: Peanut allergies cause serious health problems worldwide. A strong finding has shown that the early introduction of peanuts into the diet of infants at high risk of food allergy reduces the prevalence of peanut allergy. Allergies to peanuts, sesame and tree nuts have been shown to coexist in 60% of cases and vary according to geographical location and dietary habits. Insights into the prevalence of nut and seed allergies in societies with varying consumption levels are essential for developing population-specific weaning guidelines. Understanding the age at which peanut allergy develops is paramount for successful early introduction strategies. METHODS AND ANALYSIS: We will perform a cross-sectional study at two tertiary allergy centres in Warsaw and Bydgoszcz. Two hundred forty children aged 4-36 months with eczema or egg allergy will undergo an extensive assessment of their peanut, sesame and tree nut allergy status through skin testing, specific IgE measurements and oral food challenges. The primary outcome is the prevalence of peanut, sesame and tree nut allergies in Polish children at high risk of food allergy. Additionally, the timing of the development of peanut, sesame and tree nut allergies in the first 3 years of life in a high-risk population will be assessed. ETHICS AND DISSEMINATION: The Ethics Committee of the Medical University of Warsaw, Poland approved this protocol (KB/86/2021). The results of this study will be submitted to a peer-reviewed journal no later than 1 year after data collection. The abstract will be presented at relevant national and international conferences.Although the authors may be able to commit to journal submission no later than 1 year after data collection, publication dates remain beyond their control. TRIAL REGISTRATION NUMBER: NCT05662800.
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Hipersensibilidade Alimentar , Hipersensibilidade a Noz , Hipersensibilidade a Amendoim , Sesamum , Lactente , Criança , Humanos , Hipersensibilidade a Noz/epidemiologia , Hipersensibilidade a Amendoim/epidemiologia , Arachis , Estudos Transversais , Polônia/epidemiologia , Hipersensibilidade Alimentar/epidemiologia , Nozes , Alérgenos , PrevalênciaRESUMO
BACKGROUND: A precise diagnosis of peanut allergy is extremely important. We identified 4 Ara h 2 peptides that improved Ara h 2-specific IgE (sIgE) diagnostic accuracy. OBJECTIVE: To assess the diagnostic utility of sIgE to the mixture of these peptides and their role in mast cell response to peanut allergens. METHODS: sIgE to the peptide mix was determined using ImmunoCAP. Its diagnostic utility was compared with Ara h 2-sIgE and sIgE to the individual peptides. The functional relevance of the peptides was tested on the mast cell activation test using laboratory of allergic diseases 2 cell line and flow cytometry. RESULTS: A total of 52 peanut-allergic (PA), 36 peanut-sensitized but tolerant, and 9 nonsensitized nonallergic children were studied. Peptide mix-sIgE improved the diagnostic performance of Ara h 2-sIgE compared with Ara h 2-sIgE alone (area under the receiver operating characteristic curve .92 vs .89, respectively; P = .056). The sensitivity and specificity of Ara h 2-sIgE combined with the peptide mix were 85% and 96%, respectively. sIgE to individual peptides had the highest specificity (91%-96%) but the lowest sensitivity (10%-52%) compared with Ara h 2-sIgE (69% specificity and 87% sensitivity) or with peptide mix-sIgE (82% specificity and 63% sensitivity). Peptide 3 directly induced mast cell activation, and the peptide mix inhibited Ara h 2-induced activation of mast cells sensitized with plasma from Ara h 2-positive PA patients. CONCLUSIONS: sIgE to the peptide mix improved the diagnostic performance of Ara h 2-sIgE similarly to sIgE to individual peptides. The peptides interfered with Ara h 2-induced mast cell activation, confirming its relevance in peanut allergy.
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Hipersensibilidade a Amendoim , Criança , Humanos , Hipersensibilidade a Amendoim/diagnóstico , Mastócitos , Antígenos de Plantas , Imunoglobulina E , Albuminas 2S de Plantas , Arachis , Alérgenos , PeptídeosRESUMO
BACKGROUND: The incidence of diverticulitis in the United States is increasing, and hospitalization remains a surrogate for disease severity. State-level characterization of diverticulitis hospitalization is necessary to better understand the distribution of disease burden and target interventions. METHODS: A retrospective cohort of diverticulitis hospitalizations from 2008 through 2019 was created using Washington State's Comprehensive Hospital Abstract Reporting System. Hospitalizations were stratified by acuity, presence of complicated diverticulitis, and surgical intervention using ICD diagnosis and procedure codes. Patterns of regionalization were characterized by hospital case burden and distance travelled by patients. RESULTS: During the study period, 56,508 diverticulitis hospitalizations occurred across 100 hospitals. Most hospitalizations were emergent (77.2%). Of these, 17.5% were for complicated diverticulitis, and 6.6% required surgery. No single hospital received more than 5% (n = 235) of average annual hospitalizations. Surgeons operated in 26.5% of total hospitalizations (13.9% of emergent hospitalizations, and 69.2% of elective hospitalizations). Operations for complicated disease made up 40% of emergent surgery and 28.7% of elective surgery. Most patients traveled fewer than 20 miles for hospitalization, regardless of acuity (84% for emergent hospitalization and 77.5% for elective hospitalization). DISCUSSION: Hospitalizations for diverticulitis are primarily emergent, nonoperative, and broadly distributed across Washington State. Hospitalization and surgery occur close to patients' homes, regardless of acuity. This decentralization needs to be considered if improvement initiatives and research in diverticulitis are to have meaningful, population-level impact.
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Diverticulite , Humanos , Estados Unidos , Estudos Retrospectivos , Washington/epidemiologia , Diverticulite/terapia , Diverticulite/cirurgia , Hospitalização , Gravidade do PacienteRESUMO
BACKGROUND: The Learning Early About Peanut Allergy (LEAP) study team developed a protocol-specific algorithm using dietary history, peanut-specific IgE, and skin prick test (SPT) to determine peanut allergy status if the oral food challenge (OFC) could not be administered or did not provide a determinant result. OBJECTIVE: To investigate how well the algorithm determined allergy status in LEAP; to develop a new prediction model to determine peanut allergy status when OFC results are not available in LEAP Trio, a follow-up study of LEAP participants and their families; and to compare the new prediction model with the algorithm. METHODS: The algorithm was developed for the LEAP protocol before the analysis of the primary outcome. Subsequently, a prediction model was developed using logistic regression. RESULTS: Using the protocol-specified algorithm, 73% (453/617) of allergy determinations matched the OFC, 0.6% (4/617) were mismatched, and 26% (160/617) participants were nonevaluable. The prediction model included SPT, peanut-specific IgE, Ara h 1, Ara h 2, and Ara h 3. The model inaccurately predicted 1 of 266 participants as allergic who were not allergic by OFC and 8 of 57 participants as not allergic who were allergic by OFC. The overall error rate was 9 of 323 (2.8%) with an area under the curve of 0.99. The prediction model additionally performed well in an external validation cohort. CONCLUSION: The prediction model performed with high sensitivity and accuracy, eliminated the problem of nonevaluable outcomes, and can be used to estimate peanut allergy status in the LEAP Trio study when OFC is not available.
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Hipersensibilidade a Amendoim , Humanos , Hipersensibilidade a Amendoim/diagnóstico , Hipersensibilidade a Amendoim/epidemiologia , Arachis , Seguimentos , Alérgenos , Imunoglobulina E , Testes Cutâneos/métodos , Antígenos de PlantasRESUMO
Examining the genetics of peanut allergy (PA) in the context of clinical trial interventions and outcomes provides an opportunity to not only understand gene-environment interactions for PA risk but to also understand the benefit of allergen immunotherapy. A consistent theme in the genetics of food allergy is that in keeping with the dual allergen exposure hypothesis, barrier- and immune-related genes are most commonly implicated in food allergy and tolerance. With a focus on PA, we review how genetic risk factors across 3 genes (FLG, MALT1, and HLA-DQA1) have helped delineate distinct allergic characteristics and outcomes in the context of environmental interventions in the Learning Early about Peanut Allergy (LEAP) study and other clinical trials. We specifically consider and present a framework for genetic risk prediction for the development of PA and discuss how genetics, age, and oral consumption intertwine to predict PA outcome. Although there is some promise in this proposed framework, a better understanding of the mechanistic pathways by which PA develops and persists is needed to develop targeted therapeutics for established disease. Only by understanding the mechanisms by which PA develops, persists, and resolves can we identify adjuvants to oral immunotherapy to make older children and adults immunologically similar to their younger, more malleable counterparts and thus more likely to achieve long-term tolerance.
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Hipersensibilidade Alimentar , Hipersensibilidade a Amendoim , Criança , Adulto , Humanos , Adolescente , Hipersensibilidade a Amendoim/genética , Hipersensibilidade a Amendoim/terapia , Alérgenos , Fatores de Risco , Hipersensibilidade Alimentar/etiologia , Dessensibilização Imunológica/efeitos adversos , Arachis/genéticaRESUMO
BACKGROUND: Deleterious variation in the epidermal differentiation complex (EDC) on chromosome 1 is a well-known genetic determinant of atopic dermatitis (AD) and has been associated with risk of peanut allergy (PA) in population-based studies. OBJECTIVE: Our aim was to determine the effect of genetic variation in the EDC on AD trajectory and risk of PA in early life. METHODS: Genome sequencing was used to measure genetic variation in the EDC in the Learning Early about Peanut Allergy (LEAP) study participants. Association tests were done to identify gene- and variant-level predicted deleterious variation associated with AD severity by using the Scoring Atopic Dermatitis (SCORAD) tool (n = 559) at baseline and each follow-up visit, as well as PA and food allergy in peanut avoiders (n = 275). Predicted deleterious variants included missense variants that were frameshift insertions, frameshift deletions, stop-gain mutations, or stop-loss mutations. Associations between variant load, SCORAD score, and PA were tested by using linear and generalized linear regression models. RESULTS: The genes FLG, FLG2, HRNR, and TCHH1 harbored the most predicted deleterious variation (30, 6, 3, and 1 variant, respectively). FLG variants were associated with SCORAD score at all time points; 4 variants (R1798X, R501X, S126X, and S761fs) drove the association with SCORAD score at each time point, and higher variant load was associated with greater AD severity over time. There was an association between these variants and PA, which remained significant independent of baseline AD severity (odds ratio = 2.63 [95% CI = 1.11-6.01] [P = .02]). CONCLUSIONS: Variation in FLG predicted to be deleterious is associated with AD severity at baseline and longitudinally and has an association with PA independent of baseline severity.
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Dermatite Atópica , Hipersensibilidade a Amendoim , Humanos , Hipersensibilidade a Amendoim/genética , Dermatite Atópica/genética , Mutação da Fase de Leitura , Mutação , Arachis/genéticaRESUMO
BACKGROUND: Peanut allergy affects 1% to 2% of European children. Early introduction of peanut into the diet reduces allergy in high-risk infants. OBJECTIVE: We aimed to determine the optimal target populations and timing of introduction of peanut products to prevent peanut allergy in the general population. METHODS: Data from the Enquiring About Tolerance (EAT; n = 1303; normal risk; 3-year follow-up; ISRCTN14254740) and Learning Early About Peanut Allergy study (LEAP; n = 640; high risk; 5-year follow-up; NCT00329784) randomized controlled trials plus the Peanut Allergy Sensitization (PAS; n = 194; low and very high risk; 5-year follow-up) observational study were used to model the intervention in a general population. Peanut allergy was defined by blinded peanut challenge or diagnostic skin prick test result. RESULTS: Targeting only the highest-risk infants with severe eczema reduced the population disease burden by only 4.6%. Greatest reductions in peanut allergy were seen when the intervention was targeted only to the larger but lower-risk groups. A 77% reduction in peanut allergy was estimated when peanut was introduced to the diet of all infants, at 4 months with eczema, and at 6 months without eczema. The estimated reduction in peanut allergy diminished with every month of delayed introduction. If introduction was delayed to 12 months, peanut allergy was only reduced by 33%. CONCLUSIONS: The preventive benefit of early introduction of peanut products into the diet decreases as age at introduction increases. In countries where peanut allergy is a public health concern, health care professionals should help parents introduce peanut products into their infants' diet at 4 to 6 months of life.
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Eczema , Hipersensibilidade a Amendoim , Lactente , Criança , Humanos , Hipersensibilidade a Amendoim/epidemiologia , Hipersensibilidade a Amendoim/prevenção & controle , Hipersensibilidade a Amendoim/diagnóstico , Risco , Dieta , Arachis , Alérgenos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
CONTEXT: The presence of islet autoimmunity identifies individuals likely to progress to clinical type 1 diabetes (T1D). In clinical research studies, autoantibody screening followed by regular metabolic monitoring every 6 months reduces incidence of diabetic ketoacidosis (DKA) at diagnosis. OBJECTIVE: We hypothesized that DKA reduction can be achieved on a population basis with a reduced frequency of metabolic monitoring visits. We reasoned that prolonged time between the development of T1D and the time of clinical diagnosis ("undiagnosed time") would more commonly result in DKA and thus that limiting undiagnosed time would decrease DKA. METHODS: An analysis was conducted of data from TrialNet's Pathway to Prevention (PTP), a cross-sectional longitudinal study that identifies and follows at-risk relatives of people with T1D. PTP is a population-based study enrolling across multiple countries. A total of 6193 autoantibody (AAB)-positive individuals participated in PTP from March 2004 to April 2019. We developed models of progression to clinical diagnosis for pediatric and adult populations with single or multiple AAB, and summarized results using estimated hazard rate. An optimal monitoring visit schedule was determined for each model to achieve a minimum average level of undiagnosed time for each population. RESULTS: Halving the number of monitoring visits usually conducted in research studies is likely to substantially lower the population incidence of DKA at diagnosis of T1D. CONCLUSION: Our study has clinical implications for the metabolic monitoring of at-risk individuals. Fewer monitoring visits would reduce the clinical burden, suggesting a path toward transitioning monitoring beyond the research setting.
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Diabetes Mellitus Tipo 1 , Cetoacidose Diabética , Adulto , Criança , Humanos , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/complicações , Cetoacidose Diabética/diagnóstico , Cetoacidose Diabética/epidemiologia , Cetoacidose Diabética/etiologia , Autoanticorpos , Estudos Transversais , Estudos LongitudinaisRESUMO
BACKGROUND: The Learning Early About Peanut allergy (LEAP) study has shown the effectiveness of early peanut introduction in prevention of peanut allergy (PA). In the Enquiring About Tolerance (EAT) study, a statistically significant reduction in PA was present only in per-protocol (PP) analyses, which can be subject to bias. OBJECTIVE: The aim of this study was to combine individual-level data from the LEAP and EAT trials and provide robust evidence on the bias-corrected, causal effect of early peanut introduction. METHOD: As part of the European Union-funded iFAAM project, this pooled analysis of individual pediatric patient data combines and compares effectiveness and efficacy estimates of oral tolerance induction among different risk strata and analysis methods. RESULTS: An intention-to-treat (ITT) analysis of pooled data showed a 75% reduction in PA (p < .0001) among children randomized to consume peanut from early infancy. A protective effect was present across all eczema severity groups, irrespective of enrollment sensitization to peanut, and across different ethnicities. Earlier age of introduction was associated with improved effectiveness of the intervention. In the pooled PP analysis, peanut consumption reduced the risk of PA by 98% (p < .0001). A causal inference analysis confirmed the strong PP effect (89% average treatment effect relative risk reduction p < .0001). A multivariable causal inference analysis approach estimated a large (100%) reduction in PA in children without eczema (p = .004). CONCLUSION: We demonstrate a significant reduction in PA with early peanut introduction in a large group of pooled, randomized participants. This significant reduction was demonstrated across all risk subgroups, including children with no eczema. Furthermore, our results point to increased efficacy of the intervention with earlier age of introduction.
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Eczema , Hipersensibilidade a Amendoim , Humanos , Criança , Lactente , Hipersensibilidade a Amendoim/epidemiologia , Hipersensibilidade a Amendoim/prevenção & controle , Arachis , Alérgenos , Fatores de RiscoRESUMO
Rationale: Previous studies identified an interaction between HLA and oral peanut exposure. HLA-DQA1*01:02 had a protective role with the induction of Ara h 2 epitope-specific IgG4 associated with peanut consumption during the LEAP clinical trial for prevention of peanut allergy, while it was a risk allele for peanut allergy in the peanut avoidance group. We have now evaluated this gene-environment interaction in two subsequent peanut oral immunotherapy (OIT) trials - IMPACT and POISED - to better understand the potential for the HLA-DQA1*01:02 allele as an indicator of higher likelihood of desensitization, sustained unresponsiveness, and peanut allergy remission. Methods: We determined HLA-DQA1*01:02 carrier status using genome sequencing from POISED (N=118, age: 7-55yr) and IMPACT (N=126, age: 12-<48mo). We tested for association with remission, sustained unresponsiveness (SU), and desensitization in the OIT groups, as well as peanut component specific IgG4 (psIgG4) using generalized linear models and adjusting for relevant covariates and ancestry. Results: While not quite statistically significant, a higher proportion of HLA-DQA1*01:02 carriers receiving OIT in IMPACT were desensitized (93%) compared to non-carriers (78%); odds ratio (OR)=5.74 (p=0.06). In this sample we also observed that a higher proportion of carriers achieved remission (35%) compared to non-carriers (22%); OR=1.26 (p=0.80). In POISED, carriers more frequently attained continued desensitization (80% versus 61% among non-carriers; OR=1.28, p=0.86) and achieved SU (52% versus 31%; OR=2.32, p=0.19). psIgG4 associations with HLA-DQA1*01:02 in the OIT arm of IMPACT which included younger study subjects recapitulated patterns noted in LEAP, but no associations of note were observed in the older POISED study subjects. Conclusions: Findings across three clinical trials show a pattern of a gene environment interaction between HLA and oral peanut exposure. Age, and prior sensitization contribute additional determinants of outcomes, consistent with a mechanism of restricted antigen recognition fundamental to driving protective immune responses to OIT.
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Arachis , Hipersensibilidade a Amendoim , Adolescente , Adulto , Criança , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Imunoglobulina G , Fatores Imunológicos , Imunoterapia , Hipersensibilidade a Amendoim/genética , Hipersensibilidade a Amendoim/terapia , Ensaios Clínicos como AssuntoRESUMO
BACKGROUND: Contemporary treatment of stage II/III rectal cancer combines chemotherapy, chemoradiation, and surgery, though the sequence of surgery with neoadjuvant treatments and benefits of minimally-invasive surgery (MIS) is debated. AIM: To describe patterns of surgical approach for stage II/III rectal cancer in relation to neoadjuvant therapies. METHODS: A retrospective cohort was created using the National Cancer Database. Primary outcome was rate of sphincter-sparing surgery after neoadjuvant therapy. Secondary outcomes were surgical approach (open, laparoscopic, or robotic), surgical quality (R0 resection and 12+ lymph nodes), and overall survival. RESULTS: A total of 38927 patients with clinical stage II or III rectal adenocarcinoma underwent surgical resection from 2010-2016. Clinical stage II patients had neoadjuvant chemoradiation less frequently compared to stage III (75.8% vs 84.7%, P < 0.001), but had similar rates of total neoadjuvant therapy (TNT) (27.0% vs 27.2%, P = 0.697). Overall rates of total mesorectal excision without sphincter preservation were similar between clinical stage II and III (30.0% vs 30.3%) and similar if preoperative treatment was chemoradiation (31.3%) or TNT (30.2%). Over the study period, proportion of cases approached laparoscopically increased from 24.9% to 32.5% and robotically 5.6% to 30.7% (P < 0.001). This cohort showed improved survival for MIS approaches compared to open surgery (laparoscopy HR 0.85, 95%CI 0.78-0.93, and robotic HR 0.82, 95%CI 0.73-0.92). CONCLUSION: Sphincter preservation rates are similar across stage II and III rectal cancer, regardless of delivery of preoperative chemotherapy, chemoradiation, or both. At a national level, there is a shift to predominantly MIS approaches for rectal cancer, regardless of whether sphincter sparing procedure is performed.
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Importance: This study quantifies the trends in trimodality therapy use and its association with pathologic stage and overall survival of patients with rectal cancer at the population level. Objective: To describe changes between 2006 and 2016 in the sequence and use of chemotherapy/radiation therapy (C/RT), multiagent (MA) chemotherapy, and total neoadjuvant therapy (TNT) for patients with stage 2/3 rectal cancer and identify associations with pathologic stage and survival over time. Design, Setting, and Participants: This retrospective cohort analysis included patient records from the National Cancer Database between 2006 and 2016. Of 110â¯372 patient records, 77â¯905 were excluded owing to not receiving trimodality therapy and other predefined exclusion criteria. The final analytic cohort comprised 32â¯467 patients records treated with trimodality therapy, with 24â¯297 considered in the survival analysis. Data analysis was performed between June 2020 and December 2021. Exposures: Trimodality therapy was defined as including all of the following: definitive surgery; radiation therapy (RT), alone or in combination with chemotherapy; and neoadjuvant/adjuvant single-agent (SA) or multiagent (MA) chemotherapy independent of RT. Main Outcomes and Measures: Using Cox multivariable survival analyses across demographics, surgery type, stage, year of diagnosis, and facility type, treatment groups were allocated as the following: group A: TNT (n = 8883 [27%]); group B: preoperative C/RT plus postoperative SA chemotherapy (n = 5967 [18%]); group C: preoperative C/RT plus postoperative MA chemotherapy (n = 12â¯926 [40%]); and group D: postoperative C/RT plus MA chemotherapy (n = 4689 [14%]). Results: The final analytic cohort comprised 32â¯467 patients (mean [SD] age at diagnosis, 57.6 [11.6] years; 12â¯549 [38.7%] women and 19â¯918 [61.3%] men). Comparing 2016 with 2006, treatment shifted to fewer patients receiving postoperative C/RT (group D) (28% vs 8%; P < .001), and more preoperative C/RT and postoperative MA chemotherapy (group C) (24% vs 45%; P < .001) being used. While clinical stage 2 and 3 distribution remained unchanged, pathologic downstaging was observed to stages 0, 1, 2, and 3: 0.60%, 10%, 31%, and 57% vs 2.8%, 22%, 29%, and 45%, from 2006 to 2015, respectively (P < .001). More recent year of diagnosis was associated with an adjusted hazard ratio of 0.77 (95% CI, 0.67-0.87) for mortality within 36 months after diagnosis (2015 vs 2006). Conclusions and Relevance: In this cohort study, the shift toward preoperative C/RT and lower pathologic stage was associated with improved overall survival in stage 2/3 rectal cancers.
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Neoplasias Retais , Humanos , Masculino , Feminino , Criança , Estudos Retrospectivos , Estudos de Coortes , Neoplasias Retais/patologia , Terapia Neoadjuvante , Modelos de Riscos Proporcionais , Estadiamento de Neoplasias , Quimioterapia AdjuvanteRESUMO
The coinhibitory receptor lymphocyte activation gene 3 (LAG-3) is an immune checkpoint molecule that negatively regulates T cell activation, proliferation, and homeostasis. Blockade or deletion of LAG-3 in autoimmune-prone backgrounds or induced-disease models has been shown to exacerbate disease. We observed significantly fewer LAG-3+ CD4 and CD8 T cells from subjects with relapsing-remitting multiple sclerosis (RRMS) and type 1 diabetes. Low LAG-3 protein expression was linked to alterations in mRNA expression and not cell surface cleavage. Functional studies inhibiting LAG-3 suggest that in subjects with RRMS, LAG-3 retains its ability to suppress T cell proliferation. However, LAG-3 expression was associated with the expression of markers of apoptosis, indicating a role for low LAG-3 in T cell resistance to cell death. In T cells from subjects with RRMS, we observed a global dysregulation of LAG-3 expression stemming from decreased transcription and persisting after T cell stimulation. These findings further support the potential clinical benefits of a LAG-3 agonist in the treatment of human autoimmunity.