Clinical characteristics of subsequent histologically confirmed meningiomas in long-term childhood cancer survivors:A Dutch LATER study

Background: Meningiomas are the most frequent brain tumours occurring after pediatric cranial radiotherapy (CrRT). Data on course of disease, to inform clinical management of meningiomas, are sparse. This study reports the clinical characteristics of histologically confirmed meningiomas in childhood cancer survivors (CCS) in the Netherlands.& nbsp; Methods: In total, 6015 CCS from the Dutch Long-Term Effects After Childhood Cancer (LATER) cohort were eligible, including 1551 with prior CrRT. These CCS were diagnosed with cancer ag

Colorectal cancer surveillance in Hodgkin lymphoma survivors at increased risk of therapy-related colorectal cancer: Study design

Background: Second primary malignancies are a major cause of excess morbidity and mortality in cancer survivors. Hodgkin lymphoma survivors who were treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine have an increased risk to develop colorectal cancer. Colonoscopy surveillance plays an important role in colorectal cancer prevention by removal of the precursor lesions (adenomas) and early detection of cancer, resulting in improved survival rates. Therefore, Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy and/or high-dose procarbazine could benefit from colonoscopy, or other surveillance modalities, which are expected to reduce colorectal cancer incidence and mortality. Current knowledge on clinicopathological and molecular characteristics of therapy-related colorectal cancer is limited. The pathogenesis of such colorectal cancers might be different from the pathogenesis in the general population and therefore these patients might require a different clinical approach. We designed a study with the primary aim to assess the diagnostic yield of a first surveillance colonoscopy among Hodgkin lymphoma survivors at increased risk of colorectal cancer and to compare these results with different screening modalities in the general population. Secondary aims include assessment of the test characteristics of stool tests and evaluation of burden, acceptance and satisfaction of CRC surveillance through two questionnaires. Methods/Design: This prospective multicenter cohort study will include Hodgkin lymphoma survivors who survived =8years after treatment with infradiaphragmatic radiotherapy and/or procarbazine (planned inclusion of 259 participants). Study procedures will consist of a surveillance colonoscopy with removal of precursor lesions (adenomas) and 6-8 normal colonic tissue biopsies, a fecal immunochemical test and a stool DNA test. All neoplastic lesions encountered will be classified using relevant histomorphological, immunohistochemical and molecular analyses in order to obtain more insight into colorectal carcinogenesis in Hodgkin lymphoma survivors. The Miscan-model will be used for cost-effectiveness analyses. Discussion: Evaluation of the diagnostic performance, patient acceptance and burden of colorectal cancer surveillance is necessary for future implementation of an individualized colorectal cancer surveillance program for Hodgkin lymphoma survivors. In addition, more insight into treatment-induced colorectal carcinogenesis will provide the first step towards prevention and personalized treatment. This information may be extrapolated to other groups of cancer survivors. Trial registration: Registered at the Dutch Trial Registry (NTR): NTR4961

High prevalence of advanced colorectal neoplasia and serrated polyposis syndrome in Hodgkin lymphoma survivors

Background: Hodgkin lymphoma (HL) survivors treated with abdominal radiotherapy and/or alkylating chemotherapy have an increased risk of colorectal cancer (CRC). This study was aimed at evaluating the prevalence of colorectal neoplasia in HL survivors. Methods: This multicenter cohort study assessed the diagnostic yield of advanced colorectal neoplasia detected by a first surveillance colonoscopy among HL survivors treated with abdominal radiotherapy and/or procarbazine. Advanced colorectal neoplasia included advanced adenomas (high-grade dysplasia, ≥25% villous component, or ≥10-mm diameter), advanced serrated lesions (dysplasia or ≥10-mm diameter), and CRC. The results were compared with those for a Dutch general population cohort that underwent a primary screening colonoscopy (1426 asymptomatic individuals 50-75 years old). This study demonstrated the results of a predefined interim analysis. Results: A colonoscopy was performed in 101 HL survivors, who were significantly younger (median, 51 years; interquartile range [IQR], 45-57 years) than the general population controls (median, 60 years; IQR, 55-65 years; P <.001). The prevalence of advanced neoplasia was higher in HL survivors than controls (25 of 101 [25%] vs 171 of 1426 [12%]; P <.001). Advanced adenomas were detected in 14 of 101 HL survivors (14%) and in 124 of 1426 controls (9%; P =.08). The prevalence of advanced serrated lesions was higher in HL survivors than controls (12 of 101 [12%] vs 55 of 1426 [4%]; P <.001). Serrated polyposis syndrome was present in 6% of HL survivors and absent in controls (P <.001). Conclusions: HL survivors treated with abdominal radiotherapy and/or procarbazine have a high prevalence of advanced colorectal neoplasia. The implementation of a colonoscopy surveillance program should be considered

Psychometric Properties of the Parent and Teacher Versions of the Strengths and Difficulties Questionnaire for 4- to 12-Year-Olds: A Review

Since its development, the Strengths and Difficulties Questionnaire (SDQ) has been widely used in both research and practice. The SDQ screens for positive and negative psychological attributes. This review aims to provide an overview of the psychometric properties of the SDQ for 4- to 12-year-olds. Results from 48 studies (N = 131,223) on reliability and validity of the parent and teacher SDQ are summarized quantitatively and descriptively. Internal consistency, test–retest reliability, and inter-rater agreement are satisfactory for the parent and teacher versions. At subscale level, the reliability of the teacher version seemed stronger compared to that of the parent version. Concerning validity, 15 out of 18 studies confirmed the five-factor structure. Correlations with other measures of psychopathology as well as the screening ability of the SDQ are sufficient. This review shows that the psychometric properties of the SDQ are strong, particularly for the teacher version. For practice, this implies that the use of the SDQ as a screening instrument should be continued. Longitudinal research studies should investigate predictive validity. For both practice and research, we emphasize the use of a multi-informant approach

Modeling tuberculous meningitis in zebrafish using Mycobacterium marinum

Tuberculous meningitis (TBM) is one of the most severe extrapulmonary manifestations of tuberculosis, with a high morbidity and mortality. Characteristic pathological features of TBM are Rich foci, i.e. brain- and spinal-cord-specific granulomas formed after hematogenous spread of pulmonary tuberculosis. Little is known about the early pathogenesis of TBM and the role of Rich foci. We have adapted the zebrafish model of Mycobacterium marinum infection (zebrafish-M. marinum model) to study TBM. First, we analyzed whether TBM occurs in adult zebrafish and showed that intraperitoneal infection resulted in granuloma formation in the meninges in 20% of the cases, with occasional brain parenchyma involvement. In zebrafish embryos, bacterial infiltration and clustering of infected phagocytes was observed after infection at three different inoculation sites: parenchyma, hindbrain ventricle and caudal vein. Infection via the bloodstream resulted in the formation of early granulomas in brain tissue in 70% of the cases. In these zebrafish embryos, infiltrates were located in the proximity of blood vessels. Interestingly, no differences were observed when embryos were infected before or after early formation of the blood-brain barrier (BBB), indicating that bacteria are able to cross this barrier with relatively high efficiency. In agreement with this observation, infected zebrafish larvae also showed infiltration of the brain tissue. Upon infection of embryos with an M. marinum ESX-1 mutant, only small clusters and scattered isolated phagocytes with high bacterial loads were present in the brain tissue. In conclusion, our adapted zebrafish-M. marinum infection model for studying granuloma formation in the brain will allow for the detailed analysis of both bacterial and host factors involved in TBM. It will help solve longstanding questions on the role of Rich foci and potentially contribute to the development of better diagnostic tools and therapeutics

Facilitators and barriers for implementing patient-reported outcome measures in clinical care: An academic center's initial experience

Objectives The aim of this study was to explore the perspectives of healthcare providers and researchers in a large academic hospital on facilitators and barriers for implementing patient-reported outcome measures (PROMs) in clinical care. Methods A customized web-based questionnaire was developed and disseminated to healthcare providers and researchers across multiple medical departments involved in a value-based health care initiative in the hospital. Questionnaire statements were rated using a 5-point Likert scale ranging from “strongly agree” to “strongly disagree”. In addition, 8 open-ended questions were included allowing respondents to mention additional facilitators and barriers for implementing PROMs. Descriptive statistics were used to summarize the results. Results In total, 61 participants from both surgical and non-surgical departments completed the survey. Most respondents (51%) were medical specialists and the median employment duration was 14 years. Frequently reported facilitators were the presence of a PROM coordinator in the (outpatient) clinic (85%), the integration of PROMs in the electronic health record (81%), and the intrinsic motivation of members involved in the implementation (N=9 open responses). Commonly reported barriers were language barriers (76%), IT issues (N=17 open responses), and time constraints (N=14 open responses). Conclusions For the successful implementation of PROMs in clinical practice, it is imperative that healthcare organizations consider supporting motivated healthcare professionals, involving PROMs coordinators, and investing in an adequate IT infrastructure, and removal of language barriers

EspH is a hypervirulence factor for Mycobacterium marinum and essential for the secretion of the ESX-1 substrates EspE and EspF

The pathogen Mycobacterium tuberculosis employs a range of ESX-1 substrates to manipulate the host and build a successful infection. Although the importance of ESX-1 secretion in virulence is well established, the characterization of its individual components and the role of individual substrates is far from complete. Here, we describe the functional characterization of the Mycobacterium marinum accessory ESX-1 proteins EccA1, EspG1 and EspH, i.e. proteins that are neither substrates nor structural components. Proteomic analysis revealed that EspG1 is crucial for ESX-1 secretion, since all detectable ESX-1 substrates were absent from the cell surface and culture supernatant in an espG1 mutant. Deletion of eccA1 resulted in minor secretion defects, but interestingly, the severity of these secretion defects was dependent on the culture conditions. Finally, espH deletion showed a partial secretion defect; whereas several ESX-1 substrates were secreted in normal amounts, secretion of EsxA and EsxB was diminished and secretion of EspE and EspF was fully blocked. Interaction studies showed that EspH binds EspE and therefore could function as a specific chaperone for this substrate. Despite the observed differences in secretion, hemolytic activity was lost in all M. marinum mutants, implying that hemolytic activity is not strictly correlated with EsxA secretion. Surprisingly, while EspH is essential for successful infection of phagocytic host cells, deletion of espH resulted in a significantly increased virulence phenotype in zebrafish larvae, linked to poor granuloma formation and extracellular outgrowth. Together, these data show that different sets of ESX-1 substrates play different roles at various steps of the infection cycle of M. marinum

Mycobacteria employ two different mechanisms to cross the blood-brain barrier

Central nervous system (CNS) infection by Mycobacterium tuberculosis is one of the most devastating complications of tuberculosis, in particular in early childhood. In order to induce CNS infection, M. tuberculosis needs to cross specialised barriers protecting the brain. How M. tuberculosis crosses the blood-brain barrier (BBB) and enters the CNS is not well understood. Here, we use transparent zebrafish larvae and the closely related pathogen Mycobacterium marinum to answer this question. We show that in the early stages of development, mycobacteria rapidly infect brain tissue, either as free mycobacteria or within circulating macrophages. After the formation of a functionally intact BBB, the infiltration of brain tissue by infected macrophages is delayed, but not blocked, suggesting that crossing the BBB via phagocytic cells is one of the mechanisms used by mycobacteria to invade the CNS. Interestingly, depletion of phagocytic cells did not prevent M. marinum from infecting the brain tissue, indicating that free mycobacteria can independently cause brain infection. Detailed analysis showed that mycobacteria are able to cause vasculitis by extracellular outgrowth in the smaller blood vessels and by infecting endothelial cells. Importantly, we could show that this second mechanism is an active process that depends on an intact ESX-1 secretion system, which extends the role of ESX-1 secretion beyond the macrophage infection cycle

Inorganic phosphate limitation modulates capsular polysaccharide composition in mycobacteria

Mycobacterium tuberculosis is protected by an unusual and highly impermeable cell envelope that is critically important for the successful colonization of the host. The outermost surface of this cell envelope is formed by capsular polysaccharides that play an important role in modulating the initial interactions once the bacillus enters the body. Although the bioenzymatic steps involved in the production of the capsular polysaccharides are emerging, information regarding the ability of the bacterium to modulate the composition of the capsule is still unknown. Here, we study the mechanisms involved in regulation of mycobacterial capsule biosynthesis using a high throughput screen for gene products involved in capsular α-glucan production. Utilizing this approach we identified a group of mutants that all carried mutations in the ATP-binding cassette phosphate transport locus pst. These mutants collectively exhibited a strong overproduction of capsular polysaccharides, including α-glucan and arabinomannan, suggestive of a role for inorganic phosphate (P(i)) metabolism in modulating capsular polysaccharide production. These findings were corroborated by the observation that growth under low P(i) conditions as well as chemical activation of the stringent response induces capsule production in a number of mycobacterial species. This induction is, in part, dependent on σ factor E. Finally, we show that Mycobacterium marinum, a model organism for M. tuberculosis, encounters P(i) stress during infection, which shows the relevance of our findings in vivo