A Statistical Framework for Assessing the Relationship between Biomarkers and Clinical Endpoints in Alzheimer's Disease.

Changes in biomarker levels of Alzheimer's disease (AD) reflect underlying pathophysiological changes in the brain and can provide evidence of direct and downstream treatment effects linked to disease modification. Recent results from clinical trials of anti-amyloid ß (Aß) treatments have raised the question of how to best characterize the relationship between AD biomarkers and clinical endpoints. Consensus methodology for assessing such relationships is lacking, leading to inconsistent evaluation and reporting. In this review, we provide a statistical framework for reporting treatment effects on early and late accelerating AD biomarkers and assessing their relationship with clinical endpoints at the subject and group levels. Amyloid positron emission tomography (PET), plasma p-tau, and tau PET follow specific trajectories during AD and are used as exemplar cases to contrast biomarkers with early and late progression. Subject-level correlation was assessed using change from baseline in biomarkers versus change from baseline in clinical endpoints, and interpretation of the correlation is dependent on the biomarker and disease stage. Group-level correlation was assessed using the placebo-adjusted treatment effects on biomarkers versus those on clinical endpoints in each trial. This correlation leverages the fundamental advantages of randomized placebo-controlled trials and assesses the predictivity of a treatment effect on a biomarker or clinical benefit. Harmonization in the assessment of treatment effects on biomarkers and their relationship to clinical endpoints will provide a wealth of comparable data across clinical trials and may yield new insights for the treatment of AD.

Japanese Subgroup Analyses from EMERGE and ENGAGE, Phase 3 Clinical Trials of Aducanumab in Patients with Early Alzheimer's Disease.

BACKGROUND: Global prevalence and incidence of dementia continue to rise at a rapid rate. There is a need for new Alzheimer's disease (AD) treatments globally. Aducanumab is a human monoclonal antibody that selectively targets aggregated soluble amyloid beta oligomers and insoluble amyloid beta fibrils. In June 2021, aducanumab was approved by the US Food and Drug Administration for the treatment of AD under the accelerated approval pathway. OBJECTIVES: We evaluated the efficacy, safety, biomarker and pharmacokinetics (PK) of aducanumab in Japanese subgroups in EMERGE and ENGAGE studies. DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early AD (mild cognitive impairment due to AD or mild AD dementia). SETTING: These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants enrolled in Japan included 121 (7.4% of total 1638 in EMERGE) and 100 (6.1% of total 1647 in ENGAGE) patients (aged 50-85 years with confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to AD or mild AD dementia. INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (6 or 10 mg/kg target dose) or placebo via IV infusion once every 4 weeks over 76 weeks. MEASUREMENTS: The primary outcome measure was change from baseline to Week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; biomarker endpoints (amyloid PET and plasma p-tau181); serum PK profiles and immunogenicity. RESULTS: Results from the Japanese subgroup analyses were generally consistent with those of the overall study population across endpoints, while a lower mean body weight (kg) and a smaller proportion of ApoE ε4 carriers were observed in the Japanese subgroup population. A treatment effect was observed in favor of aducanumab on the primary and secondary efficacy endpoints at Week 78 in EMERGE, but not ENGAGE. The incidence and type of adverse events in the Japanese subgroups were generally comparable to those observed in the overall study population; amyloid related imaging abnormalities (ARIA) were common treatment-related adverse events that appeared to be related to the aducanumab dose. ARIA incidence was generally lower in the Japanese subgroup compared with the overall population. Consistent with the overall data set, a robust dose-dependent decrease in amyloid beta levels as assessed with amyloid-PET and plasma p-tau181 was observed. Serum PK profiles and immunogenicity of aducanumab in Japanese population were consistent with the non-Japanese population. CONCLUSION: Efficacy, safety, biomarker, and PK profiles of aducanumab were consistent between the Japanese subgroup and the overall population. A positive treatment effect of aducanumab on efficacy endpoints was observed in EMERGE, but not in ENGAGE.

Caracterización de lesiones duodenales y su sobrevida / Characterization of duodenal lesions and their survival

Resumen Introducción: Las lesiones duodenales son infrecuentes. Objetivo: Caracterizar a los pacientes con lesiones duodenales observados entre enero de 2008 y diciembre de 2013 en el Servicio de Salud Metropolitano Sur, en Santiago de Chile. Materiales y Método: Se obtuvieron los datos de los registros del Hospital Barros Luco Trudeau y Hospital El Pino. Los pacientes incluidos fueron los observados entre enero de 2008 y diciembre de 2013. Se analizaron edad, género, características clínicas, localización, métodos diagnósticos, hallazgos anatomopatológicos y tratamiento. El 24 de abril de 2019 se obtuvo la fecha de fallecimiento de todos los pacientes del Registro Civil. El análisis estadístico se realizó con el software STATA 15.1. Resultados: Se encontraron 157 pacientes con lesiones duodenales, 65 presentaron adenocarcinoma duodenal y 71 pacientes pólipos duodenales, 25 de ellos fueron adenomas. Análisis univariado de sobrevida evidenció que los pacientes con pólipos asociado a carcinoma y los adenocarcinomas duodenales, presentaron una sobrevida inferior (p = 0,013, HR 6,584 y p < 0,001, HR 7,604, respectivamente). En los pacientes con adenocarcinoma duodenal, aquellos que se sometieron a una cirugía con intención curativa, y aquellos que recibieron quimioterapia tuvieron una sobrevida global mejor que aquellos que no recibieron terapia (p < 0,001, HR 0,351 y p = 0,001, HR 0,276, respectivamente. Discusión: La incidencia estimada del adenocarcinoma duodenal en nuestra población es de 1,1 por cada 100.000 habitantes, la que es más alta que otras publicadas. Proponemos estudio endoscópico en poblaciones de riesgo y tratamiento con intención curativa para los pacientes con adenocarcinoma duodenal sin metástasis a distancia.

Introduction: Duodenal lesions are infrequent. Aim: To characterize patients with duodenal lesions observed between January 2008 and December 2013 at the Southern Metropolitan Health Service, in Santiago, Chile. Materials and Method: Data were obtained from the Barros Luco Trudeau Hospital and El Pino Hospital records. The patients included were those observed between January 2008 and December 2013. Age, gender, clinical characteristics, location, diagnostic methods, anatomopathological findings and treatment were analyzed. On April 24th 2019 was obtained the date of death of all patients at the National Civil Registry. The statistical analysis was performed with the software STATA 15.1. Results: 157 patients with duodenal lesions were found, 65 presented duodenal adenocarcinoma and 71 patients had duodenal polyps, 25 of them were adenomas. Univariate analysis of survival showed that patients with polyps associated with carcinoma and duodenal adenocarcinomas had a lower survival rate (p = 0.013, HR 6.584 y p < 0.001, HR 7.604, respectively). In patients with duodenal adenocarcinoma, those who underwent surgery with curative intent, and those who receive chemotherapy had a better overall survival than those who did not received therapy (p < 0.001, HR 0.351 y p = 0.001, HR 0.276, respectively). Discussion: We propose endoscopic study in at-risk populations and treatment with curative intent for patients with duodenal adenocarcinoma without distant metastases. The estimated incidence of duodenal adenocarcinoma in our population is 1.1 per 100,000 inhabitants and seem to be higher than other published.

Machine Learning Algorithm Helps Identify Non-Diagnosed Prodromal Alzheimer's Disease Patients in the General Population.

BACKGROUND: Recruiting patients for clinical trials of potential therapies for Alzheimer's disease (AD) remains a major challenge, with demand for trial participants at an all-time high. The AD treatment R and D pipeline includes around 112 agents. In the United States alone, 150 clinical trials are seeking 70,000 participants. Most people with early cognitive impairment consult primary care providers, who may lack time, diagnostic skills and awareness of local clinical trials. Machine learning and predictive analytics offer promise to boost enrollment by predicting which patients have prodromal AD, and which will go on to develop AD. OBJECTIVES: The authors set out to develop a machine learning predictive model that identifies prodromal AD patients in the general population, to aid early AD detection by primary care physicians and timely referral to expert sites for biomarker confirmation of diagnosis and clinical trial enrollment. DESIGN: The authors use a classification machine learning algorithm to extract patterns within healthcare claims and prescription data three years prior to AD diagnosis/AD drug initiation. SETTING: The study focused on subjects included within proprietary IQVIA US data assets (claims and prescription databases). Patient information was extracted from January 2010 to July 2018, for cohorts aged between 50 and 85 years. PARTICIPANTS: A total of 88,298,289 subjects aged between 50 and 85 years were identified. For the positive cohort, 667,288 subjects were identified who had 24 months of medical history and at least one record with AD or AD treatment. For the negative cohort, 3,670,254 patients were selected who had a similar length of medical history and who were matched to positive cohort subjects based on the prevalence rate. The scoring cohort was selected based on availability of recent medical data of 2-5 years and included 72,670,283 subjects between the ages of 50 and 85 years. Intervention (if any): None. MEASUREMENTS: A list of clinically-relevant and interpretable predictors was generated and extracted from the data sets for each subject, including pharmacological treatments (NDC/product), office/specialist visits (specialty), tests and procedures (HCPCS and CPT), and diagnosis (ICD). The positive cohort was defined as patients who have AD diagnosis/AD treatment with a 3 years offset as an estimate for prodromal AD diagnosis. Supervised ML techniques were used to develop algorithms to predict the occurrence of prodromal AD cases. The sample dataset was divided randomly into a training dataset and a test dataset. The classification models were trained and executed in the PySpark framework. Training and evaluation of LogisticRegression, DecisionTreeClassifier, RandomForestClassifier, and GBTClassifier were executed using PySpark's mllib module. The area under the precision-recall curve (AUCPR) was used to compare the results of the various models. RESULTS: The AUCPRs are 0.426, 0.157, 0.436, and 0.440 for LogisticRegression, DecisionTreeClassifier, RandomForestClassifier, and GBTClassifier, respectively, meaning that GBTClassifier (Gradient Boosted Tree) outperforms the other three classifiers. The GBT model identified 222,721 subjects in the prodromal AD stage with 80% precision. Some 76% of identified prodromal AD patients were in the primary care setting. CONCLUSIONS: Applying the developed predictive model to 72,670,283 U.S. residents, 222,721 prodromal AD patients were identified, the majority of whom were in the primary care setting. This could drive major advances in AD research by enabling more accurate and earlier prodromal AD diagnosis at the primary care physician level , which would facilitate timely referral to expert sites for in-depth assessment and potential enrolment in clinical trials.

Rol del endoscopista en la pancreatitis aguda y sus complicaciones / Role of the endoscopist in the management of acute pancreatitis and its complications

For a long time, the aim of the endoscopist in acute pancreatitis has been cleaning up obstructed biliary tract through endoscopic retrograde cholangiopancreatography (ERCP) at the precise momentum, so the main factor causing biliary pancreatitis is treated, decreasing possibilities of complications and modifying the prognosis. However, in the last two decades, the role of the endoscopist has acquired new dimensions so it is possible to treat complications like pseudocysts and walled-of pancreatic necrosis with minimally invasive procedures. This review is focused on technique, indications, follow-up and result of ERCP in acute pancreatitis, drainage of pancreatic pseudocyst and endoscopic necrosectomy.

El rol del endoscopista en la pancreatitis aguda por largo tiempo estuvo abocado fundamentalmente a la posibilidad de desobstruir y limpiar la vía biliar a través de la realización de colangiopancreatografia retrograda endoscópica (CPRE), eliminando así un importante factor ligado el efecto de la coledocolitiasis en la patogénesis, gravedad y complicaciones de la pancreatitis aguda de origen biliar. Sin embargo, en las últimas dos décadas, el papel del endoscopista ha adquirido nuevas dimensiones, ampliándose al tratamiento de ciertas complicaciones de la pancreatitis aguda en general, como son los pseudoquistes pancreáticos y, últimamente, los secuestros de necrosis pancreática. En este artículo se revisan las indicaciones de la CPRE en la pancreatitis aguda, del drenaje de pseudoquiste pancreático y la necrosectomia endoscópica, así como aspectos de la técnica, seguimiento y resultados.

Úlcera tuberculosa intestinal como causa de hemorragia digestiva baja masiva exanguinante / Intestinal tuberculosis causing a severe gastrointestinal bleeding: report of one case

We report a 27 years old woman presenting with hematochezia. An upper endoscopy and colonoscopy did not reveal the bleeding site. Due to persistence of bleeding, the patient was operated, finding a fibrinous secretion surrounding bowel loops and a hyper vascularized concentric papular lesion. The involved bowel loop was excised. The pathological study of the surgical piece revealed intestinal tuberculosis. The patient started treatment for extra pulmonary tuberculosis.

Reportamos el caso de una paciente de 27 años con tuberculosis extrapulmonar gastrointestinal que se manifestó clínicamente como una hemorragia digestiva baja masiva exanguinante requiriendo cirugía de urgencia, donde se realizó laparotomía exploradora con entero y colonoscopía intraoperatoria localizando lesión a nivel de intestino delgado, resecando segmento comprometido con anastomosis primaria, evolución satisfactoria sin complicaciones postoperatorias.