Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening.

BACKGROUND: A next-generation multitarget stool DNA test, including assessments of DNA molecular markers and hemoglobin level, was developed to improve the performance of colorectal cancer screening, primarily with regard to specificity. METHODS: In a prospective study, we evaluated a next-generation multitarget stool DNA test in asymptomatic adults 40 years of age or older who were undergoing screening colonoscopy. The primary outcomes were sensitivity of the test for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions). Advanced precancerous lesions included one or more adenomas or sessile serrated lesions measuring at least 1 cm in the longest dimension, lesions with villous histologic features, and high-grade dysplasia. Secondary objectives included the quantification of sensitivity for advanced precancerous lesions and specificity for nonneoplastic findings or negative colonoscopy and comparison of sensitivities for colorectal cancer and advanced precancerous lesions between the multitarget stool DNA test and a commercially available fecal immunochemical test (FIT). RESULTS: Of 20,176 participants, 98 had colorectal cancer, 2144 had advanced precancerous lesions, 6973 had nonadvanced adenomas, and 10,961 had nonneoplastic findings or negative colonoscopy. With the next-generation test, sensitivity for colorectal cancer was 93.9% (95% confidence interval [CI], 87.1 to 97.7), and specificity for advanced neoplasia was 90.6% (95% CI, 90.1 to 91.0). Sensitivity for advanced precancerous lesions was 43.4% (95% CI, 41.3 to 45.6), and specificity for nonneoplastic findings or negative colonoscopy was 92.7% (95% CI, 92.2 to 93.1). With the FIT, sensitivity was 67.3% (95% CI, 57.1 to 76.5) for colorectal cancer and 23.3% (95% CI, 21.5 to 25.2) for advanced precancerous lesions; specificity was 94.8% (95% CI, 94.4 to 95.1) for advanced neoplasia and 95.7% (95% CI, 95.3 to 96.1) for nonneoplastic findings or negative colonoscopy. As compared with FIT, the next-generation test had superior sensitivity for colorectal cancer (P<0.001) and for advanced precancerous lesions (P<0.001) but had lower specificity for advanced neoplasia (P<0.001). No adverse events occurred. CONCLUSIONS: The next-generation multitarget stool DNA test showed higher sensitivity for colorectal cancer and advanced precancerous lesions than FIT but also showed lower specificity. (Funded by Exact Sciences; BLUE-C ClinicalTrials.gov number, NCT04144738.).

Screening for Speech and Language Delay and Disorders in Children: US Preventive Services Task Force Recommendation Statement.

Importance: Speech and language delays and disorders can pose significant problems for children and their families. Evidence suggests that school-aged children with speech or language delays may be at increased risk of learning and literacy disabilities, including difficulties with reading and writing. Objective: The US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate benefits and harms of screening for speech and language delay and disorders in children 5 years or younger. Population: Asymptomatic children 5 years or younger whose parents or clinicians do not have specific concerns about their speech, language, hearing, or development. Evidence Assessment: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for speech and language delay and disorders in children who do not present with signs or symptoms or parent/caregiver concerns. Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for speech and language delay and disorders in children 5 years or younger without signs or symptoms. (I statement).

Screening and Preventive Interventions for Oral Health in Children and Adolescents Aged 5 to 17 Years: US Preventive Services Task Force Recommendation Statement.

Importance: Oral health is fundamental to health and well-being across the lifespan. Oral health conditions affect the daily lives of school-age children and adolescents, leading to loss of more than 51 million school hours every year. Untreated oral health conditions in children can lead to serious infections and affect growth, development, and quality of life. Objective: The US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate screening and preventive interventions for oral health conditions in children and adolescents aged 5 to 17 years. Population: Asymptomatic children and adolescents aged 5 to 17 years. Evidence Assessment: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for oral health conditions (eg, dental caries) performed by primary care clinicians in asymptomatic children and adolescents aged 5 to 17 years. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of preventive interventions for oral health conditions (eg, dental caries) performed by primary care clinicians in asymptomatic children and adolescents aged 5 to 17 years. Recommendations: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of routine screening performed by primary care clinicians for oral health conditions, including dental caries, in children and adolescents aged 5 to 17 years. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of preventive interventions performed by primary care clinicians for oral health conditions, including dental caries, in children and adolescents aged 5 to 17 years. (I statement).

Disentangling age, gender, and racial/ethnic disparities in multiple myeloma burden: a modeling study.

Multiple myeloma (MM) is a hematological malignancy that is consistently preceded by an asymptomatic condition, monoclonal gammopathy of undetermined significance (MGUS). Disparities by age, gender, and race/ethnicity in both MGUS and MM are well-established. However, it remains unclear whether these disparities can be explained by increased incidence of MGUS and/or accelerated progression from MGUS to MM. Here, we fit a mathematical model to nationally representative data from the United States and showed that the difference in MM incidence can be explained by an increased incidence of MGUS among male and non-Hispanic Black populations. We did not find evidence showing differences in the rate of progression from MGUS to MM by either gender or race/ethnicity. Our results suggest that screening for MGUS among high-risk groups (e.g., non-Hispanic Black men) may hold promise as a strategy to reduce the burden and MM health disparities.

Screening for Lipid Disorders in Children and Adolescents: US Preventive Services Task Force Recommendation Statement.

Importance: Familial hypercholesterolemia and multifactorial dyslipidemia are 2 conditions that cause abnormally high lipid levels in children, which can lead to premature cardiovascular events (eg, myocardial infarction and stroke) and death in adulthood. Objective: The US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of screening for lipid disorders in asymptomatic children and adolescents. Population: Asymptomatic children and adolescents 20 years or younger without a known diagnosis of a lipid disorder. Evidence Assessment: The USPSTF concludes that the current evidence is insufficient and the balance of benefits and harms for screening for lipid disorders in asymptomatic children and adolescents 20 years or younger cannot be determined. Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for lipid disorders in children and adolescents 20 years or younger. (I statement).

Symptoms Contributing to the Diagnosis of Small Bowel Tumors.

INTRODUCTION: Small bowel tumors (SBTs) are difficult to diagnose because of limited opportunities and technical difficulties in evaluating the small bowel. Asymptomatic conditions or nonspecific symptoms make SBT diagnosis more challenging. In Asia, SBTs are reported to be more frequently malignant lymphoma (ML), adenocarcinoma, and gastrointestinal stromal tumor (GIST). In this study, we examined 66 patients diagnosed with SBTs and determined their clinical characteristics. METHODS: This retrospective study was conducted from January 2013 to July 2020 at Kurume University Hospital. The modalities used to detect SBTs were computed tomography (CT), positron emission tomography, magnetic resonance imaging, and ultrasonography. Endoscopy was also performed in some cases to confirm SBT diagnosis. The study included 66 patients. The medical data collected included presenting symptoms, tumor location, underlying condition, diagnostic modalities, pathologic diagnosis, and treatment. RESULTS: ML and adenocarcinoma were the most common tumors (22.7%), followed by GIST (21.2%) and metastatic SBT (18.2%). Symptoms that led to SBT detection were abdominal pain (44.5%), asymptomatic conditions (28.8%), hematochezia (12.1%), and anemia (10.6%). CT was the most used modality to detect SBTs. Nineteen patients were asymptomatic, and SBTs were incidentally detected in them. GISTs and benign tumors were more often asymptomatic than other malignant tumors. CONCLUSION: Abdominal pain was the main symptom for SBTs in particular adenocarcinoma, ML, and metastatic SBT. In addition, GIST, which was highly prevalent in Asia, had fewer symptoms. An understanding of these characteristics may be helpful in the clinical practice of SBTs.

An adjusted Asia-Pacific colorectal screening score system to predict advanced colorectal neoplasia in asymptomatic Chinese patients.

PURPOSE: The Asia-Pacific Colorectal Screening (APCS) score and its derivatives have been used to predict advanced colorectal neoplasia (ACN). However, it remains unknown whether they apply to the current Chinese population in general clinical practice. Therefore, we aimed to update the APCS score system by applying data from two independent asymptomatic populations to predict the risk of ACN in China. METHODS: We developed an adjusted APCS (A-APCS) score by using the data of asymptomatic Chinese patients undergoing colonoscopies from January 2014 to December 2018. Furthermore, we validated this system in another cohort of 812 patients who underwent screening colonoscopy between January and December 2021. The discriminative calibration ability of the A-APCS and APCS scores was comparatively evaluated. RESULTS: Univariate and multivariate logistic regression were applied to assess the risk factors for ACN, and an adjusted scoring system of 0 to 6.5 points was schemed according to the results. Utilizing the developed score, 20.2%, 41.2%, and 38.6% of patients in the validation cohort were classified as average, moderate, and high risk, respectively. The corresponding ACN incidence rates were 1.2%, 6.0%, and 11.1%, respectively. In addition, the A-APCS score (c-statistics: 0.68 for the derivation and 0.80 for the validation cohort) showed better discriminative power than using predictors of APCS alone. CONCLUSIONS: The A-APCS score may be simple and useful in clinical applications for predicting ACN risk in China.

Predictive factors of delayed viral clearance of asymptomatic Omicron-related COVID-19 screened positive in patients with cancer receiving active anticancer treatment.

OBJECTIVES: We sought to identify the predictors of delayed viral clearance in patients with cancer with asymptomatic COVID-19 when the SARS-CoV-2 Omicron variants prevailed in Hong Kong. METHODS: All patients with cancer who were attending radiation therapy for head and neck malignancies or systemic anticancer therapy saved their deep throat saliva or nasopharyngeal swabs at least twice weekly for SARS-CoV-2 screening between January 1 and April 30, 2022. The multivariate analyses identified predictors of delayed viral clearance (or slow recovery), defined as >21 days for the cycle threshold values rising to ≥30 or undetectable in two consecutive samples saved within 72 hours. Three machine learning algorithms evaluated the prediction performance of the predictors. RESULTS: A total of 200 (15%) of 1309 patients tested positive for SARS-CoV-2. Age >65 years (P = 0.036), male sex (P = 0.003), high Charlson comorbidity index (P = 0.042), lung cancer (P = 0.018), immune checkpoint inhibitor (P = 0.036), and receipt of one or no dose of COVID-19 vaccine (P = 0.003) were significant predictors. The three machine learning algorithms revealed that the mean ± SD area-under-the-curve values predicting delayed viral clearance with the cut-off cycle threshold value ≥30 was 0.72 ± 0.11. CONCLUSION: We identified subgroups with delayed viral clearance that may benefit from targeted interventions.

Asymptomatic carotid stenosis and cognitive impairment.

INTRODUCTION: The aim of this review was to assess the evidence supporting an association between asymptomatic carotid stenosis (ACS) with impaired cognitive function due to chronic cerebral hypoperfusion and/or silent cerebral embolization. EVIDENCE ACQUISITION: PubMed/Medline, Embase and the Cochrane databases were searched up to December 1, 2022 to identify studies focusing on the association between ACS and cognitive function, as well as the mechanisms involved. EVIDENCE SYNTHESIS: A total of 49 studies were identified. The evidence supports an association between ACS and progressive cognitive deterioration. The mechanisms involved in the cognitive decline associated with ACS include cerebral hypoperfusion and silent cerebral embolization. Irrespective of the mechanism involved, severe ACS is associated with a progressive decline in several aspects of cognitive function, including global cognition, memory and executive function. CONCLUSIONS: Patients with ACS are at increased risk of developing a progressive decline in their cognitive function. The evidence from the present systematic review suggests that it may be inappropriate to consider ACS patients developing cognitive dysfunction as "asymptomatic". Besides stroke, myocardial infarction and death rates, future studies should include evaluation of cognitive function as part of their outcomes.

Discriminative capacity of guideline recommendations in the assessment of patients with asymptomatic microhematuria.

BACKGROUND & OBJECTIVE: Asymptomatic microhematuria (aMh) remains a diagnostic challenge in urological practice: while aMh is a risk factor of urothelial carcinoma (UC), prevalence of aMh is high. Guidelines were developed to permit risk stratification and reduce diagnostic workload. This study investigates the efficacy of several recommendations. MATERIAL & METHODS: Sixty hundred eight patients with newly diagnosed aMh without previous UC from an academic referral center (A; n = 320) and a private outpatient clinic (B; n = 288) were included. All patients underwent clinical workup including medical history, urine cytology, upper tract imaging and cystoscopy. Eleven former and current guidelines were applied to each patient individually; every patient was classified as either low risk (no further workup recommended) or high risk. Furthermore, a recently developed nomogram for hematuria assessment was included. RESULTS: The cohort comprised 142 females and 466 males (mean age 62 [range 18-92] years). Sixty-one patients (10.0%) were diagnosed with UC. Excluding the Swedish and recent NICE guideline generally advising against urologic workup, application of 9 other recommendations would have diagnosed all UCs and saved 1.6% to 16.1% of patients from workup. For the 2020 US guideline, solely applied to cohort B, 10.6% of patients were classified as low risk. The use of the nomogram would have saved 17.1% to 25% of patients from workup. CONCLUSIONS: Practical relevance of current guidelines is limited as they do not sufficiently identify patients not requiring clinical work up. Thus, guideline adherence may trigger overdiagnosis and even overtreatment. New ways of risk stratification are needed to improve aMh assessment.

Why do guidelines recommend screening for abdominal aortic aneurysms, but not for asymptomatic carotid stenosis? A plea for a randomized controlled trial.

BACKGROUND: Current guidelines do not recommend screening for asymptomatic carotid artery stenosis (AsxCS). The rationale behind this recommendation is that detection of AsxCS may lead to an unnecessary carotid intervention. In contrast, screening for abdominal aortic aneurysms is strongly recommended. METHODS: A critical analysis of the literature was performed to evaluate the implications of detecting AsxCS. RESULTS: Patients with AsxCS are at high risk for future stroke, myocardial infarction and vascular death. Population-wide screening for AsxCS should not be recommended. Additionally, screening of high-risk individuals for AsxCS with the purpose of identifying candidates for a carotid intervention is inappropriate. Instead, selective screening for AsxCS should be considered and should be viewed as an opportunity to identify individuals at high risk for atherosclerotic cardiovascular disease and future cardiovascular events for the timely initiation of intensive medical therapy and risk factor modification. CONCLUSIONS: Although mass screening should not be recommended, there are several arguments suggesting that selective screening for AsxCS should be considered. The rationale supporting such selective screening is to optimize risk factor control and to initiate intensive medical therapy for prevention of future cardiovascular events, rather than to identify candidates for an intervention.

[DIAGNOSIS OF GENETIC VARIANT CARRIERS IN A PATIENT WITH ASYMPTOMATIC BIRT-HOGG-DUBÉ SYNDROME: A CASE REPORT].

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN). It is characterized by skin tumors, multiple lung cysts, and renal tumors. Active genetic testing and appropriate periodic examinations of family lines of patients with BHD syndrome have not been widely performed. In this report, we present our experience regarding the diagnosis of asymptomatic family members with BHD syndrome. The proband was a 65-year-old female with a family history of colorectal cancer and spontaneous pneumothorax that affected her father. Computed tomography revealed an approximately 10 cm-sized tumor protruding from the upper pole of the left kidney, a buried tumor approximately 1.5 cm in length in the right kidney, and multiple pulmonary cysts. The patient underwent laparoscopic radical left nephrectomy. Pathological examination indicated that the resected tumor was a chromophobe renal cell carcinoma. After the surgery, there was no evidence of local recurrence or metastasis. The size of the tumor in the right kidney was monitored, but it did not increase. On FLCN genetic examination, targeted next generation sequencing revealed a partial deletion of exon 14, thus confirming the diagnosis of the patient to be BHD syndrome that caused the previously unreported pathogenic variant. Three years after the surgery, we conducted genetic counseling for the proposita and her three children. Genetic examination, performed at the request of the second daughter, confirmed that she carried the same genetic variant as her mother. This diagnosis prompted the second daughter to begin managing her health via periodic imaging tests.

Enfermedades asintomáticas o diagnósticos incipientes / Asymptomatic diseases or early diagnoses

RESUMEN Introducción: Constituye hecho relevante en el ejercicio de la medicina, individual o poblacional, conocer precozmente la instauración de las enfermedades, y por ello se tratan de realizar los diagnósticos clínicos precozmente. Sin embargo, un grupo de enfermedades, infecciosas o no infecciosas, agudas o crónicas, se caracterizan por escasas manifestaciones clínicas, por lo que el conocimiento de su existencia es de vital importancia, por ejemplo, la hipertensión arterial o la diabetes mellitus, cuyas expresiones sintomáticas pueden aparecer tardíamente. En igual medida, la actual pandemia por SARS-CoV-2, ha proliferado rápidamente debido al gran número de personas infectadas que no expresan síntomas. Objetivo: Caracterizar aspectos clínicos relevantes sobre las enfermedades asintomáticas y la importancia de los diagnósticos clínicos o biotecnológicos incipientes, individuales y poblacionales. Métodos: Se realizaron búsquedas bibliográficas de los últimos cinco años en libros clásicos de Medicina Interna, se analizaron artículos publicados en revistas nacionales e internacionales, específicamente en revistas de alto impacto como Lancet y The New England Journal of Medicine. Se consideraron bases de datos de la Organización Mundial de la Salud, así como lo expuesto en Infomed; además se utilizó Google Académico, con los descriptores de interés al respecto. Conclusiones: Por el momento siempre serán parciales, pues se enfatiza en las recomendaciones de la Organización Mundial de la Salud sobre la actual pandemia, para la identificación y control del SARS-CoV-2; se acentúa en la importancia de los métodos clínicos y epidemiológicos, así como en el desarrollo de la biotecnología para el conocimiento de las enfermedades.

ABSTRACT Introduction: early detection of the onset of diseases constitutes a relevant fact in the practice of individual or population medicine that is why early clinical diagnoses are tried to be made. However, a group of infectious or non-infectious, acute or chronic clinical diseases are characterized by few clinical manifestations, for which knowledge of their existence is of vital importance, for example, arterial hypertension or diabetes mellitus, whose symptomatic expressions may appear late. To the same extent, the current SARS-CoV-2 pandemic has proliferated rapidly due to the large number of infected people who do not express symptoms. Objective: to characterize relevant clinical aspects of asymptomatic diseases and the importance of incipient, individual and population clinical or biotechnological diagnoses. Methods: bibliographic searches of the last five years were carried out in classic books on Internal Medicine, articles published in national and international journals were analyzed, specifically in high-impact journals such as the Lancet and The New England Journal of Medicine. Databases of the World Health Organization were considered, as well as what was exposed in Infomed; in addition, Google Scholar was used, with the descriptors of interest in this regard. Conclusions: conclusions will always be partial for the moment, since the recommendations of the World Health Organization for the identification and control of SARS-CoV-2 are emphasized; the importance of clinical and epidemiological methods is highlighted, as well as the development of biotechnology for the knowledge of diseases.

Gantenerumab: an anti-amyloid monoclonal antibody with potential disease-modifying effects in early Alzheimer's disease.

BACKGROUND: This review describes the research and development process of gantenerumab, a fully human anti-amyloid monoclonal antibody in development to treat early symptomatic and asymptomatic Alzheimer's disease (AD). Anti-amyloid monoclonal antibodies can substantially reverse amyloid plaque pathology and may modify the course of the disease by slowing or stopping its clinical progression. Several molecules targeting amyloid have failed in clinical development due to drug-related factors (e.g., treatment-limiting adverse events, low potency, poor brain penetration), study design/methodological issues (e.g., disease stage, lack of AD pathology confirmation), and other factors. The US Food and Drug Administration's approval of aducanumab, an anti-amyloid monoclonal antibody as the first potential disease-modifying therapy for AD, signaled the value of more than 20 years of drug development, adding to the available therapies the first nominal success since cholinesterase inhibitors and memantine were approved. BODY: Here, we review over 2 decades of gantenerumab development in the context of scientific discoveries in the broader AD field. Key learnings from the field were incorporated into the gantenerumab phase 3 program, including confirmed amyloid positivity as an entry criterion, an enriched clinical trial population to ensure measurable clinical decline, data-driven exposure-response models to inform a safe and efficacious dosing regimen, and the use of several blood-based biomarkers. Subcutaneous formulation for more pragmatic implementation was prioritized as a key feature from the beginning of the gantenerumab development program. CONCLUSION: The results from the gantenerumab phase 3 programs are expected by the end of 2022 and will add critical information to the collective knowledge on the search for effective AD treatments.