Radiation-induced accelerated aging of the brain vasculature in young adult survivors of childhood brain tumors

Background. Cranial radiotherapy may damage the cerebral vasculature. The aim of this study was to understand the prevalence and risk factors of cerebrovascular disease (CVD) and white matter hyperintensities (WMHs) in childhood brain tumors (CBT) survivors treated with radiotherapy.Methods. Seventy CBT survivors who received radiotherapy were enrolled in a cross-sectional study at a median 20 years after radiotherapy cessation. The prevalence of and risk factors for CVD were investigated using MRI, MRA, and laboratory testing. Tumors, their treatment, and stroke-related data were retrieved from patients' files.Results. Forty-four individuals (63%) had CVD at a median age of 27 years (range, 16-43 years). The prevalence rates at 20 years for CVD, small-vessel disease, and large-vessel disease were 52%, 38%, and 16%, respectively. Ischemic infarcts were diagnosed in 6 survivors, and cerebral hemorrhage in 2. Lacunar infarcts were present in 7, periventricular or deep WMHs in 34 (49%), and mineralizing microangiopathy in 21 (30%) survivors. Multiple pathologies were detected in 44% of the participants, and most lesions were located in a high-dose radiation area. Higher blood pressure was associated with CVD and a presence of WMHs. Higher cholesterol levels increased the risk of ischemic infarcts and WMHs, and lower levels of high-density lipoprotein and higher waist circumference increased the risk of lacunar infarcts.Conclusions. Treating CBTs with radiotherapy increases the risk of early CVD and WMHs in young adult survivors. These results suggest an urgent need for investigating CVD prevention in CBT patients.</div

Gene-Expression Profiling Suggests Impaired Signaling via the Interferon Pathway in Cstb(-/-) Microglia

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1, OMIM254800) is an autosomal recessive neurodegenerative disorder characterized by stimulus-sensitive and action-activated myoclonus, tonic-clonic epileptic seizures, and ataxia. Loss-of-function mutations in the gene encoding the cysteine protease inhibitor cystatin B (CSTB) underlie EPM1. The deficiency of CSTB in mice (Cstb(-/-) mice) generates a phenotype resembling the symptoms of EPM1 patients and is accompanied by microglial activation at two weeks of age and an upregulation of immune system-associated genes in the cerebellum at one month of age. To shed light on molecular pathways and processes linked to CSTB deficiency in microglia we characterized the transcriptome of cultured Cstb(-/-) mouse microglia using microarray hybridization and RNA sequencing (RNA-seq). The gene expression profiles obtained with these two techniques were in good accordance and not polarized to either pro- or anti-inflammatory status. In Cstb(-/-) microglia, altogether 184 genes were differentially expressed. Of these, 33 genes were identified by both methods. Several interferon-regulated genes were weaker expressed in Cstb(-/-) microglia compared to control. This was confirmed by quantitative real-time PCR of the transcripts Irf7 and Stat1. Subsequently, we explored the biological context of CSTB deficiency in microglia more deeply by functional enrichment and canonical pathway analysis. This uncovered a potential role for CSTB in chemotaxis, antigen-presentation, and in immune-and defense response-associated processes by altering JAK-STAT pathway signaling. These data support and expand the previously suggested involvement of inflammatory processes to the disease pathogenesis of EPM1 and connect CSTB deficiency in microglia to altered expression of interferon-regulated genes.Peer reviewe

Interpretation of Tonsillectomy Outcome Inventory-14 scores:a prospective matched cohort study

Abstract Purpose: Knowledge of disease-specific instruments enables the evaluation of health- related quality-of-life (QoL) change associated with chronic and recurrent tonsillitis in adults. The main objective was to explore the interpretation of scores according to the throat-related QoL instrument, Tonsillectomy Outcome Inventory-14 (TOI-14), by determining the typical scores in healthy subjects and patients and define the minimum important change (MIC). Methods: We performed a prospective matched cohort study in a secondary care area of Oulu University Hospital. The surgical cohort consisted of 42 patients referred to tonsillectomy due to recurrent or chronic tonsillitis. The control cohort consisted of 42 age- and sex-matched healthy controls obtained from the escorts of patients in the same hospital. We translated and validated the Finnish TOI-14 instrument and collected TOI-14 scores at entry and at 6 months and compared results to the anchor question. Results: At entry, the mean TOI-14 scores were significantly higher in the surgical cohort than in the control cohort [mean (95% confidence interval)] 33.0 (27.0–39.1) vs. 5.0 (3.6–6.4), respectively. At 6 months follow-up, the mean TOI-14 scores had improved markedly after tonsillectomy to the level of the control cohort. In the healthy population, the score was in most cases under 15.0 points. In patients, a score of about 20.0 indicated mild symptoms, 30.0 moderate symptoms and 40.0 or higher intense symptoms. The MIC value was 10.0 points. Conclusions: These results enable the more accurate interpretation of the scores of the only disease-specific QoL instrument for adult throat-related diseases

Total or partial tonsillar resection (tonsillectomy or tonsillotomy) to change the quality of life for adults with recurrent or chronic tonsillitis: study protocol for a randomised controlled trial

Abstract Background Tonsillar surgery has been used for decades to treat recurrent and chronic tonsillitis in adults. Recurrent and chronic tonsillitis result in disturbing symptoms, treatment costs, sick leave, and impaired quality of life (QoL). Theoretically, removing all or part of the altered pathological palatal lymphoid tissue alleviates the symptoms and enhances the QoL. Whether this is true with total or partial tonsillar resection (tonsillectomy (TE) and tonsillotomy (TT), respectively) has not been reported in a randomised trial yet. Methods We conduct a multicentre, partly blinded, randomised, 6-month, parallel-group clinical study including 285 adult participants referred to surgical treatment for chronic or recurrent tonsillitis. The participants will either have TE, TT or watchful waiting (WW). The primary outcome will be the difference between the mean disease-specific Tonsillectomy Outcome Inventory-14 (QoL questionnaire) scores at 6 months. Comparison is made firstly between the combined TE+TT and WW groups (superiority analysis), and secondly between the TE and TT groups (non-inferiority analysis). Discussion This study will add significant new information to the effects and harms of TE and TT procedures in the treatment of adults with chronic or recurrent tonsillitis. Trial registration ClinicalTrials.gov: NCT0465754

Total or partial tonsillar resection (tonsillectomy or tonsillotomy) to change the quality of life for adults with recurrent or chronic tonsillitis:study protocol for a randomised controlled trial

Abstract Background: Tonsillar surgery has been used for decades to treat recurrent and chronic tonsillitis in adults. Recurrent and chronic tonsillitis result in disturbing symptoms, treatment costs, sick leave, and impaired quality of life (QoL). Theoretically, removing all or part of the altered pathological palatal lymphoid tissue alleviates the symptoms and enhances the QoL. Whether this is true with total or partial tonsillar resection (tonsillectomy (TE) and tonsillotomy (TT), respectively) has not been reported in a randomised trial yet. Methods: We conduct a multicentre, partly blinded, randomised, 6-month, parallel-group clinical study including 285 adult participants referred to surgical treatment for chronic or recurrent tonsillitis. The participants will either have TE, TT or watchful waiting (WW). The primary outcome will be the difference between the mean disease-specific Tonsillectomy Outcome Inventory-14 (QoL questionnaire) scores at 6 months. Comparison is made firstly between the combined TE+TT and WW groups (superiority analysis), and secondly between the TE and TT groups (non-inferiority analysis). Discussion: This study will add significant new information to the effects and harms of TE and TT procedures in the treatment of adults with chronic or recurrent tonsillitis. Trial registration: ClinicalTrials.gov: NCT04657549

Radiation-induced accelerated aging of the brain vasculature in young adult survivors of childhood brain tumors

Background. Cranial radiotherapy may damage the cerebral vasculature. The aim of this study was to understand the prevalence and risk factors of cerebrovascular disease (CVD) and white matter hyperintensities (WMHs) in childhood brain tumors (CBT) survivors treated with radiotherapy. Methods. Seventy CBT survivors who received radiotherapy were enrolled in a cross-sectional study at a median 20 years after radiotherapy cessation. The prevalence of and risk factors for CVD were investigated using MRI, MRA, and laboratory testing. Tumors, their treatment, and stroke-related data were retrieved from patients' files. Results. Forty-four individuals (63%) had CVD at a median age of 27 years (range, 16-43 years). The prevalence rates at 20 years for CVD, small-vessel disease, and large-vessel disease were 52%, 38%, and 16%, respectively. Ischemic infarcts were diagnosed in 6 survivors, and cerebral hemorrhage in 2. Lacunar infarcts were present in 7, periventricular or deep WMHs in 34 (49%), and mineralizing microangiopathy in 21 (30%) survivors. Multiple pathologies were detected in 44% of the participants, and most lesions were located in a high-dose radiation area. Higher blood pressure was associated with CVD and a presence of WMHs. Higher cholesterol levels increased the risk of ischemic infarcts and WMHs, and lower levels of high-density lipoprotein and higher waist circumference increased the risk of lacunar infarcts. Conclusions. Treating CBTs with radiotherapy increases the risk of early CVD and WMHs in young adult survivors. These results suggest an urgent need for investigating CVD prevention in CBT patients.Peer reviewe