Neuropsychiatric Symptoms and Alzheimer Disease Biomarkers Independently Predict Progression to Incident Cognitive Impairment.

OBJECTIVES: To investigate the effect of neuropsychiatric symptoms and depression symptoms, respectively, and Alzheimer disease (AD) biomarkers (cerebrospinal fluid [CSF] or Positron Emission Tomography [PET] imaging) on the progression to incident cognitive impairment among cognitively normal older adults. DESIGN: Prospective, observation, longitudinal study. SETTING: Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine. PARTICIPANTS: Older adults aged 65 and above who participated in AD longitudinal studies (n = 286). MEASUREMENTS: CSF and PET biomarkers, Clinical Dementia Rating (CDR), Geriatric Depression Scale (GDS), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Participants had an average follow-up of eight years, and 31 progressed from CDR 0 to CDR >0. After adjusting for sex, age, and education in the Cox proportional hazards survival models, neuropsychiatric symptoms as a time-dependent covariate was statistically significant in the three CSF (Aß42/Aß40, t-Tau/Aß42, p-Tau/Aß42) PET imaging models (HR = 1.33-1.50). The biomarkers were also significant as main effects (HR = 2.00-4.04). Change in depression symptoms was not significant in any models. The interactions between biomarkers and neuropsychiatric symptoms and depression were not statistically significant. CONCLUSIONS: Changes in neuropsychiatric symptoms increase the risk of progression to cognitive impairment among healthy, cognitively normal adults, independent of AD biomarkers. Routine assessment of neuropsychiatric symptoms could provide valuable clinical information about cognitive functioning and preclinical disease state.

Real-world adjuvant chemotherapy patterns and outcomes among elderly patients with resected early non-small-cell lung cancer in the USA.

Background: This study investigated real-world treatment patterns and overall survival (OS) in early non-small-cell lung cancer patients and the association between OS and time-to-adjuvant-treatment. Materials & methods: This retrospective study using Surveillance, Epidemiology and End Results data linked with Medicare claims included resected early non-small-cell lung cancer patients between 2010 and 2015. Unadjusted OS analyses used Kaplan-Meier curves; adjusted OS analyses used extended Cox proportional hazards models. Results: Only 54-71% of stage II-IIIA patients received any adjuvant treatment. Adjusted risk of death was higher when starting treatment outside 6-8 weeks after surgery (p < 0.05). Conclusion: Improved systemic therapy in the adjuvant chemotherapy setting is needed.

Lung cancer is one of the deadliest cancers in the USA. Most lung cancers are a type called non-small-cell lung cancer (NSCLC). Patients with NSCLC that has not spread to other parts of the body generally have surgery and may receive treatment before surgery, after surgery or both to help fight the cancer. It is not clear how often people receive treatment before or after surgery. It is important to know how patients are being treated because it helps clinicians decide how to use the new treatments that are becoming available. This study used a large database of more than 7000 people aged 65 years and older with lung cancer in the USA to understand how they are treated. More than a third of patients had stage IA NSCLC (39%), followed by stage IB (24%), stage II (20%), stage IIIA (15%) and stage IIIB (2%). Most people had surgery (64%) and some received another treatment after surgery (27%). That treatment was most often about 2 months of chemotherapy, on average. The study also tried to understand how the timing of treatment may have been important for their survival. People who received treatment after surgery lived the longest if they received that treatment about 6­8 weeks after the surgery. Overall, the study showed that a substantial proportion of people do not receive treatment for their NSCLC after surgery, even though treatment after surgery is recommended by medical guidelines. There is a need for more effective treatments for these patients, and when those treatments are given may be important for their survival.

Exploration of sleep disturbances in children and adolescents with and without autism in a paediatric sample referred for polysomnography.

AIMS: The purpose of the study was to increase the body of knowledge related to sleep in children with autism. The specific aims were to (i) identify the subgroup of children with autism, ages 3-17 years, referred for polysomnography and (ii) describe types and frequency of clinical encounters for sleep problems in a sample of children ages 3-17 with and without the diagnosis of autism. METHODS: The authors performed a secondary data analysis of the de-identified Nationwide Children's Hospital Sleep DataBank, a collection of encounters with children referred for polysomnography. The data were filtered for ages 3-17 years at the time of the participant's first sleep study, and further filtered for the presence of an autism diagnosis. RESULTS: In the sample, there were 2838 unique participants (M = 10.5 years) with a total of 172 167 encounters between 2017 and 2019. Of these, 198 (7%) were diagnosed with Autism Spectrum Disorder, Asperger's Syndrome, or Pervasive Developmental Disorder. Among all participants, the most common sleep problems were apnea, snoring, non-specified sleep disorders (including restless sleeper), circadian rhythm disorder (CRD), and insomnia. The subgroup of patients diagnosed with autism was noted to have higher frequency of several types of sleep problems, especially restless sleep, CRD and insomnia, compared to those without an autism diagnosis. CONCLUSIONS: Findings elucidate the increased presence of sleep problems in paediatric patients with autism, and the need for purposeful sleep evaluation and research given the potential impact on daytime function for these individuals and their families.

Adverse driving behaviors increase over time as a function of preclinical Alzheimer's disease biomarkers.

INTRODUCTION: We investigated the relationship between preclinical Alzheimer's disease (AD) biomarkers and adverse driving behaviors in a longitudinal analysis of naturalistic driving data. METHODS: Naturalistic driving data collected using in-vehicle dataloggers from 137 community-dwelling older adults (65+) were used to model driving behavior over time. Cerebrospinal fluid (CSF) biomarkers were used to identify individuals with preclinical AD. Additionally, hippocampal volume and cognitive biomarkers for AD were investigated in exploratory analyses. RESULTS: CSF biomarkers predicted the longitudinal trajectory of the incidence of adverse driving behavior. Abnormal amyloid beta (Aß42 /Aß40 ) ratio was associated with an increase in adverse driving behaviors over time compared to ratios in the normal/lower range. DISCUSSION: Preclinical AD is associated with increased adverse driving behavior over time that cannot be explained by cognitive changes. Driving behavior as a functional, neurobehavioral marker may serve as an early detection for decline in preclinical AD. Screening may also help prolong safe driving as older drivers age.

Pediatric Preanesthesia Anxiety and Factors of Family Satisfaction.

PURPOSE: Pediatric patients scheduled for procedures with anesthesia experience stress and feelings of anxiety, but frequently lack the opportunity to report their feelings. Pediatric patient anxiety may be related to internal (patient perceptions/emotions) or external (demographic/family knowledge/satisfaction) factors. The purpose of the study was to explore patient reports of anxiety in young school-age through adolescent ages, and factors of family satisfaction before a scheduled procedure with anesthesia. DESIGN: Cross-sectional, descriptive, and correlational. METHODS: A voluntary survey including family-report of patient age and past anesthesia, type of procedure, family satisfaction factors (knowledge of anesthesia; perioperative concerns), and patient-report of anxiety with a visual analog scale (0-10) was offered to eligible families at their preanesthesia clinic appointment. FINDINGS: Completed surveys from 80 families (mean age of patient = 12 years; range 7-17 years) showed legally authorized guardians (LAGs) felt the preanesthesia visit helped them understand anesthesia information, but they also had concerns, such as complications and pain. Patient anxiety ratings ranged from 0 to 10 (M = 3.3, SD = 3.1), and were slightly higher for patients 11 years and younger (M = 3.8; SD = 3.4). Anxiety ratings were not significantly correlated with other factors measured. CONCLUSIONS: Pediatric patients, ages 7-17, report preanesthesia anxiety levels ranging from "not at all" to "worst imaginable," unrelated to demographic or family factors. Family members have perioperative concerns that need to be addressed before scheduled procedures. There is an impetus for improvement in psychosocial assessment and health care team collaboration to meet needs in a family-centered preanesthesia care model.

Estimation of the Efficacy of Remineralizing Agents on the Microhardness of Deciduous Teeth Demineralized Using Pediatric Formulations.

AIM: This study aimed to evaluate the demineralizing effect of commonly used pediatric syrup formulations on primary teeth and the efficacy of two readily available remineralizing agents in treating this effect. MATERIALS AND METHODS: Ninety primary teeth were used for sample preparation and divided into three groups: antibiotic syrup (group A), cough syrup (group B), and control (group C) groups. These groups were further categorized into intragroups according to the treatment with remineralizing agents: groups A1, B1, and C1 received GC Tooth Mousse (casein phosphopeptide-amorphous calcium phosphate, CPP-ACP paste) and groups A2, B2, and C2 received Clinpro Tooth Crème. The samples were subjected to a series of demineralization cycles for 14 days, and remineralization cycles until 30 days were performed using two remineralizing agents, that is, GC Tooth Mousse (CPP-ACP paste) and Clinpro Tooth Crème and were evaluated using Vicker's microhardness test. RESULTS: Antibiotic syrup (group A) and cough syrup (group B) showed a significant decrease in surface microhardness compared with control (group C). All intragroups showed an increase in surface microhardness after treatment with remineralizing agents, which was significantly higher in intragroups A1, B1, and C1 treated with GC Tooth Mousse (CPP-ACP paste). CONCLUSIONS: Oral liquid medications showed definite demineralization potential. CPP-ACP paste was found to be better than Clinpro Tooth Crème for demineralized teeth. CLINICAL SIGNIFICANCE: The use of over-the-counter drugs has increased among the average Indian population, especially for the treatment of fever, cold, and cough. Unwise use of medications by the present population without proper medical guidance will lead to irreparable changes in future generations.

Global Disability Trajectories Over the First Decade Following Combat Concussion.

OBJECTIVE: To examine global disability trajectories in US military with and without traumatic brain injury (TBI) over the first decade following deployment to identify risk profiles for better intervention stratification, hopefully reducing long-term cost. SETTING: Patients and participants were enrolled in combat or directly following medical evacuation at the time of injury and followed up every 6 months for 10 years. PARTICIPANTS: There are 4 main groups (n = 475), 2 primary and 2 exploratory: (1) combat-deployed controls without a history of blast exposure "non-blast- control" (n = 143), (2) concussive blast TBI "'blast-TBI" (n = 236) (primary), (3) combat-deployed controls with a history of blast exposure "blast-control" (n = 54), and (4) patients sustaining a combat concussion not from blast "non-blast-TBI" (n = 42) (exploratory). DESIGN: Prospective, observational, longitudinal study. MAIN MEASURES: Combat concussion, blast exposure, and subsequent head injury exposure over the first decade post-deployment. Global disability measured by the Glasgow Outcome Scale Extended (GOSE). RESULTS: Latent class growth analysis identified 4 main trajectories of global outcome, with service members sustaining combat concussion 37 to 49 times more likely to be in the worse disability trajectories than non-blast-controls (blast-TBI: odds ratio [OR] = 49.33; CI, 19.77-123.11; P < .001; non-blast-TBI: OR = 37.50; CI, 10.01-140.50; P < .001). Even blast-exposed-controls were 5 times more likely to be in these worse disability categories compared with non-blast-controls (OR = 5.00; CI, 1.59-15.99; P = .007). Adjustment for demographic factors and subsequent head injury exposure did not substantially alter these odds ratios. CONCLUSIONS: Very high odds of poor long-term outcome trajectory were identified for those who sustained a concussion in combat, were younger at the time of injury, had lower education, and enlisted in the Army above the risk of deployment alone. These findings help identify a risk profile that could be used to target early intervention and screen for poor long-term outcome to aid in reducing the high public health cost and enhance the long-term quality of life for these service members following deployment.

The complex relationship between depression and progression to incident cognitive impairment across race and ethnicity.

INTRODUCTION: We examined baseline differences in depression and antidepressant use among cognitively normal older adults in five ethnoracial groups and assessed whether depression predicted a faster progression to incident cognitive impairment across groups. METHODS: Data from the National Alzheimer's Coordinating Center (n = 8168) were used to examine differences between non-Hispanic Whites (nHW), African Americans (AA), Hispanics, Asians, and American Indian and Alaskan Natives in cross-sectional and longitudinal models. RESULTS: AA had a lower risk of depression compared to nHW at baseline. No statistical interactions were noted between ethnoracial groups and depression. However, depression independently predicted a faster progression to incident cognitive impairment. Hispanics and Asian participants had a higher hazard for progression compared to nHW. DISCUSSION: Previously established risk factors between depression and dementia were not found among AA and nHW participants. The relationship between depression and ethnoracial groups is complex and suggests differential effects on progression from cognitive normality to impairment.

Definitions, theories, and measurement of stress in children.

PROBLEM: Stress in children remains a complex concept to examine due to the inherent subjectivity and lack of specific manifestations, as well as the multiple ways stress can be defined and measured in children. Because stress is multifactorial,is experienced daily by children, and undergirds adolescent health and early mental illness, it is crucial to have a clear understanding of stress and the effects of stress in children from infancy through age twelve years. ELIGIBILITY CRITERIA: To be included in this review, literature must pertain to and highlight theories, definitions/classifications, and measurements of stress in children from infancy to 12 years of age. SAMPLE: The most pertinent articles identified through database searches (PubMed, Scopus, PsycINFO, CINAHL, Google Scholar), gray literature sources (e.g., child health websites), and reference lists of identified articles were included in this narrative overview. RESULTS: The results of this review are organized by themes and include: classifications and definitions of stress, stress-related theories, and tools to measure stress in children. CONCLUSIONS: Research addressing stressors and stress in children is limited, and there is wide variation in how researchers define and classify stress in children. Existing measures of stress in children younger than 12 address physiological, psychological, and observational components, but may be inconsistent and threaten validity of otherwise well-designed and well-executed studies. IMPLICATIONS: Improving the understanding and accurate measurement of stress in children enables researchers and clinicians to curtail undesirable health outcomes.

Lateral Meniscus Posterior Root Injury: MRI Findings in Children With Anterior Cruciate Ligament Tear.

BACKGROUND. Undiagnosed and unrepaired root tears are increasingly recognized as a preventable cause of accelerated osteoarthritis. Preoperative MRI findings of lateral meniscus posterior root tears in children with concomitant anterior cruciate ligament (ACL) injury are not well described. OBJECTIVE. The purpose of this study was to investigate the performance of preoperative MRI for identifying concomitant lateral meniscus posterior root injuries in pediatric patients with ACL tears with arthroscopy as the reference standard. METHODS. Consecutively registered children who underwent MRI within 90 days before arthroscopic primary ACL reconstruction between March 2017 and December 2019 were included. Two radiologists assessed MRI examinations for direct signs involving the root proper and for findings associated with lateral meniscus posterior root tears. Kappa coefficients for MRI findings were computed. Findings in patients with root tears and intact roots were compared by independent-samples t test, Mann-Whitney U test, chi-square test, Fisher exact test, and multivariable logistic regression analysis. RESULTS. At arthroscopy, 39 children (18 boys, 21 girls; mean age, 15.2 ± 1.4 years) had lateral meniscus posterior root tears; 51 (22 boys, 29 girls; mean age, 15.7 ± 1.8 years) had intact roots. Kappa coefficients ranged from 0.65 to 0.92, aside from tears involving the entheseal segment (κ = 0.55) or popliteomeniscal fascicles (κ = 0.45). MRI findings that were predictors of arthroscopically diagnosed root tear (p < .05) were lateral meniscus root tear in any segment (odds ratio [OR], 16.8; 95% CI, 5.6-50.1), degeneration in any segment (OR, 3.9; 95% CI, 1.6-9.6), coronal cleft sign (OR, 5.7; 95% CI, 2.0-16.7), sagittal ghost sign (OR, 4.8; 95% CI, 1.2-19.1), and axial radial defect sign (OR, 7.1; 95% CI, 2.4-20.5). Tear involving any segment of the root proper had the highest PPV, 82%, with 79% NPV. The coronal cleft, sagittal ghost, and axial radial defect signs had specificities of 88%, 94%, and 88% but sensitivities of 44%, 23%, and 49%. The only significant independent predictor on preoperative MRI was root tear in any segment (OR, 15.8; 95% CI, 2.7-137.5; p = .003). CONCLUSION. Among MRI findings evaluated for preoperative diagnosis of lateral meniscus posterior root tear, tear involving any segment of the root proper had the strongest performance; associated findings had high specificity but low sensitivity. CLINICAL IMPACT. Accurate identification of lateral meniscus posterior root tears on preoperative MRI can aid in operative planning and reduce treatment delay.

Inclusion of Effect Size Measures and Clinical Relevance in Research Papers.

BACKGROUND: There are multiple issues that arise when researchers focus on and only report "statistical significance" of study findings. An important element that is often not included in reports is a discussion of clinical relevance. OBJECTIVES: The authors address issues related to significance, the use of effect sizes, confidence or credible intervals, and the inclusion of clinical relevance in reports of research findings. METHODS: Measures of magnitude, precision, and relevance such as effect sizes, confidence intervals (CIs), and clinically relevant effects are described in detail. In addition, recommendations for reporting and evaluating effect sizes and CIs are included. Example scenarios are presented to illustrate the interplay of statistical significance and clinical relevance. RESULTS: There are several issues that may arise when significance is the focus of clinical research reporting. One issue is the lack of attention to nonsignificant findings in published works although findings show clinical relevance. Another issue is that significance is interpreted as clinical relevance. As well, clinically relevant results from small-sample studies are often not considered for publication, and thus, findings might not be available for meta-analysis. DISCUSSION: Findings in research reports should address effect sizes and clinical relevance and significance. Failure to publish clinically relevant effects and CIs may preclude the inclusion of clinically relevant studies in systematic reviews and meta-analyses, thereby limiting the advancement of evidence-based practice. Several accessible resources for researchers to generate, report, and evaluate measures of magnitude, precision, and relevance are included in this article.

Prognostic value of the nutmeg lung pattern/lymphangiectasia on fetal magnetic resonance imaging.

BACKGROUND: A nutmeg lung pattern on magnetic resonance imaging (MRI) is an imaging finding associated with pulmonary lymphangiectasia. However, the prognostic value of the nutmeg lung pattern is unknown. OBJECTIVE: To evaluate the clinical associations of nutmeg lung indicating lymphangiectasia on fetal lung MRI and its relationship with early mortality in fetuses with primary and secondary lymphangiectasia. MATERIALS AND METHODS: We retrospectively identified all pregnant patients with a fetal MRI performed for indication of evaluating for pulmonary lymphangiectasia from 2006 to 2019. Two readers evaluated the fetal MRIs and interobserver agreement was calculated. Multivariable logistic regression models were performed to estimate the association of the echocardiographic findings and the presence of nutmeg lung. Kaplan-Meier and Cox regression analyses were performed to evaluate association with mortality in the first 30 days of life. Survival analysis was defined as mortality or orthotopic heart transplant at 30 days of age. P<0.05 was considered significant. RESULTS: Our sample included 53 fetuses. Forty-seven (89%) had congenital heart disease (CHD) and 6 (11%) were diagnosed postnatally with primary lymphangiectasia. Interobserver agreement was 0.83. Pulmonary vein congestion on echocardiography was the strongest predictor of nutmeg lung (odds ratio [OR]=12.0, P=0.002). Ten fetuses reached the outcome of heart transplantation (n=1) or death (n=9) within the first 30 days of life. In fetuses with CHD, survival of those with nutmeg lung was significantly lower than in those without (P<0.001). Nutmeg lung was an independent risk factor for 30-day mortality (hazard ratio [HR]: 6.1, P=0.01). CONCLUSION: Nutmeg lung pattern on fetal MRI is an independent risk factor associated with 30-day mortality in fetuses with CHD.

Starting a pediatric contrast ultrasound service: made simple!

The addition of contrast US to an existing pediatric US service requires several preparatory steps. This overview provides a guide to simplify the process. Initially, it is important to communicate to all stakeholders the justifications for pediatric contrast US, including (1) its comparable or better diagnostic results relative to other modalities; (2) its reduction in procedural sedation or anesthesia by avoiding MRI or CT; (3) its reduction or elimination of radiation exposure by not having to perform fluoroscopy or CT; (4) the higher safety profile of US contrast agents (UCA) compared to other contrast agents; (5) the improved exam comfort and ease inherent to US, leading to better patient and family experience, including bedside US exams for children who cannot be transported; (6) the need for another diagnostic option in light of increasing demand by parents and providers; and (7) its status as an approved and reimbursable exam. It is necessary to have an UCA incorporated into the pharmacy formulary noting that only SonoVue/Lumason is currently approved for pediatric use. In the United States this UCA is approved for intravenous administration for cardiac and liver imaging and for vesicoureteric reflux detection with intravesical application. In Europe and China it is only approved for the intravesical use in children. All other applications are off-label. The US scanner needs to be equipped with contrast-specific software. The UCA has to be prepared just before the exam and it is important to strictly follow the steps as outlined in the packaging inserts in order to prevent premature destruction of the microbubbles. The initial training in contrast US is best focused on the frontline staff actually performing the US studies; these might be sonographers, pediatric or interventional radiologists, or trainees. It is important from the outset to educate the referring physicians about contrast US. It is helpful to participate in existing contrast US courses, particularly those with hands-on components.

Contrast-enhanced ultrasound: a comprehensive review of safety in children.

Contrast-enhanced ultrasound (CEUS) has been increasingly used in pediatric radiology practice worldwide. For nearly two decades, CEUS applications have been performed with the off-label use of gas-containing second-generation ultrasound contrast agents (UCAs). Since 2016, the United States Food and Drug Administration (FDA) has approved the UCA Lumason for three pediatric indications: the evaluation of focal liver lesions and echocardiography via intravenous administration and the assessment of vesicoureteral reflux via intravesical application (contrast-enhanced voiding urosonography, ceVUS). Prior to the FDA approval of Lumason, numerous studies with the use of second-generation UCAs had been conducted in adults and children. Comprehensive protocols for clinical safety evaluations have demonstrated the highly favorable safety profile of UCA for intravenous, intravesical and other intracavitary uses. The safety data on CEUS continue to accumulate as this imaging modality is increasingly utilized in clinical settings worldwide. As of August 2021, 57 pediatric-only original research studies encompassing a total of 4,518 children with 4,906 intravenous CEUS examinations had been published. As in adults, there were a few adverse events; the majority of these were non-serious, although very rarely serious anaphylactic reactions were reported. In the published pediatric-only intravenous CEUS studies included in our analysis, the overall incidence rate of serious adverse events was 0.22% (10/4,518) of children and 0.20% (10/4,906) of all CEUS examinations. Non-serious adverse events from the intravenous CEUS were observed in 1.20% (54/4,518) of children and 1.10% (54/4,906) of CEUS examinations. During the same time period, 31 studies with the intravesical use of UCA were conducted in 12,362 children. A few non-serious adverse events were encountered (0.31%; 38/12,362), but these were most likely attributable to the bladder catheterization rather than the UCA. Other developing clinical applications of UCA in children, including intracavitary and intralymphatic, are ongoing. To date, no serious adverse events have been reported with these applications. This article reviews the existing pediatric CEUS literature and provides an overview of safety-related information reported from UCA uses in children.

Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials.

BACKGROUND: Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials. METHODS: An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001). FINDINGS: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred. INTERPRETATION: Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours. FUNDING: Ignyta/F Hoffmann-La Roche.

Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials.

BACKGROUND: Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC. METHODS: We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0-2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001). FINDINGS: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64-88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4-20·2). Median duration of response was 24·6 months (95% CI 11·4-34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten [8%]) and neutropenia (five [4%]). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four [3%]) and cardiac disorders (three [2%]). No treatment-related deaths occurred. INTERPRETATION: Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC. FUNDING: Ignyta/F Hoffmann-La Roche.

Imaging of fetal tumors and other dysplastic lesions: A review with emphasis on MR imaging.

Fetal tumors and other dysplastic masses are relatively rare. They are usually the result of failure of differentiation and maturation during embryonic or fetal life; dysplastic lesions may be the consequence of an obstruction sequence. In this review, we present the most commonly encountered tumors and masses seen during fetal life. Imaging characteristics, tumoral organ of origin, and its effect on the surrounding organs and overall fetal hemodynamics are descriptors that must be relayed to the fetal surgeon and maternal fetal medicine expert, in order to institute most accurate parental counseling and appropriate perinatal treatment plan.

Extended-spectrum beta-lactamase (ESBL)-positive Escherichia coli presence in urban aquatic environments in Kanpur, India.

In India, high rates of antibiotic consumption and poor sanitation infrastructure combine to pose a significant risk to the public through the environmental transmission of antimicrobial resistance (AMR). The WHO has declared extended-spectrum beta-lactamase (ESBL)-positive Escherichia coli a key indicator for the surveillance of AMR worldwide. In the current study, we measured the prevalence of AMR bacteria in an urban aquatic environment in India by detecting metabolically active ESBL-positive E. coli. Water samples were collected in duplicate from 16 representative environmental water sources including open canals, drains, and rivers around Kanpur, Uttar Pradesh. We detected culturable E. coli in environmental water at 11 (69%) of the sites. Out of the 11 sites that were positive for culturable E. coli, ESBL-producing E. coli was observed at 7 (64%). The prevalence of ESBL-producing E. coli detected in the urban aquatic environment suggests a threat of AMR bacteria to this region.

How to read a fetal magnetic resonance image 101.

Accurate antenatal diagnosis is essential for planning appropriate pregnancy management and improving perinatal outcomes. The provision of information vital for prognostication is a crucial component of prenatal imaging, and this can be enhanced by the use of fetal MRI. Image acquisition, interpretation and reporting of a fetal MR study can be daunting to the individual who has encountered few or none of these examinations. This article provides the radiology trainee with a general approach to interpreting a fetal MRI. The authors review the added value of prenatal MRI in the overall assessment of fetal wellbeing, discuss MRI protocols and techniques, and review the normal appearance of maternal and fetal anatomy. The paper concludes with a sample template for structured reporting, to serve as a checklist and guideline for reporting radiologists.

Two's Company: Multiple Thoracic Lesions on Prenatal US and MRI.

BACKGROUND: Congenital pulmonary airway malformations (CPAM), bronchopulmonary sequestrations (BPS), and CPAM-BPS hybrid lesions are most commonly solitary; however, >1 lung congenital lung lesion may occur. OBJECTIVES: To assess the frequency of multiple congenital thoracic anomalies at a high-volume referral center; determine prenatal ultrasound (US) and magnetic resonance imaging (MRI) features of these multifocal congenital lung lesions that may allow prenatal detection; and determine the most common distribution or site of origin. METHODS: Database searches were performed from August 2008 to May 2019 for prenatally evaluated cases that had a final postnatal surgical diagnosis of >1 congenital lung lesion or a lung lesion associated with foregut duplication cyst (FDC). Lesion location, size, echotexture, and signal characteristics were assessed on prenatal imaging and correlated with postnatal computed tomographic angiography and surgical pathology. -Results: Of 539 neonates that underwent surgery for a thoracic lesion, 35 (6.5%) had >1 thoracic abnormality. Multiple discrete lung lesions were present in 19 cases, and a lung lesion associated with an FDC was present in 16. Multifocal lung lesions were bilateral in 3 cases; unilateral, multilobar in 12; and, unilobar multisegmental in 4. Median total CPAM volume/head circumference ratio for multifocal lung lesions on US was 0.66 (range, 0.16-1.80). Prenatal recognition of multifocal lung lesions occurred in 7/19 cases (36.8%). Lesion combinations were CPAM-CPAM in 10 cases, CPAM-BPS in 5, CPAM-hybrid in 2, hybrid-hybrid in 1, and hybrid-BPS in 1. Of 5 unilateral, multifocal lung lesions, multifocality was prenatally established through identification of a band of normal intervening lung or intrinsic differences in lesion imaging features. CONCLUSIONS: Although less common, multiple thoracic abnormalities can be detected prenatally. Of multifocal lung lesions, the most common combination was CPAM-CPAM, with a unilateral, multilobar distribution. Prenatal recognition is important for pregnancy counseling and postnatal surgical management.