New Anti-Hypoxic Metabolites from Co-Culture of Marine-Derived Fungi Aspergillus carneus KMM 4638 and Amphichorda sp. KMM 4639.

The KMM 4639 strain was identified as Amphichorda sp. based on two molecular genetic markers: ITS and ß-tubulin regions. Chemical investigation of co-culture marine-derived fungi Amphichorda sp. KMM 4639 and Aspergillus carneus KMM 4638 led to the identification of five new quinazolinone alkaloids felicarnezolines A-E (1-5), a new highly oxygenated chromene derivative oxirapentyn M (6) and five previously reported related compounds. Their structures were established using spectroscopic methods and by comparison with related known compounds. The isolated compounds showed low cytotoxicity against human prostate and breast cancer cells but felicarnezoline B (2) protected rat cardiomyocytes H9c2 and human neuroblastoma SH-SY5Y cells against CoCl2-induced damage.

Cytotoxic Drimane-Type Sesquiterpenes from Co-Culture of the Marine-Derived Fungi Aspergillus carneus KMM 4638 and Beauveria felina (=Isaria felina) KMM 4639.

Chemical investigation of a coculture of the marine-derived fungi Beauveria felina KMM 4639 and Aspergillus carneus KMM 4638 led to the identification of three new drimane-type sesquiterpenes, asperflavinoids B, D and E (2, 4, 5), and nine previously reported related compounds. The structures of these compounds were established using spectroscopic methods and by comparison with known analogues. We also investigated the cytotoxic activity of the isolated compounds against several cancer and normal cell lines. Asperflavinoid C (3) and ustusolate E (9) exerted a significant effect on human breast cancer MCF-7 cell viability, with IC50 values of 10 µM, and induced in caspase-dependent apoptosis and arrest of the MCF-7 cell cycle in the G2/M phase in these cells.

Historical Patterns of Diagnosis, Treatments, and Outcome of Epilepsy Associated With Tuberous Sclerosis Complex: Results From TOSCA Registry.

Background: Epilepsy is the most common neurological manifestation in individuals with tuberous sclerosis complex (TSC). However, real-world evidence on diagnosis and treatment patterns is limited. Here, we present data from TuberOus Sclerosis registry to increase disease Awareness (TOSCA) on changes in patterns of epilepsy diagnosis, treatments, and outcomes over time, and detailed epilepsy characteristics from the epilepsy substudy. Methods: TuberOus Sclerosis registry to increase disease Awareness (TOSCA) was a multicentre, international disease registry, consisting of a main study that collected data on overall diagnostic characteristics and associated clinical features, and six substudies focusing on specific TSC manifestations. The epilepsy substudy investigated detailed epilepsy characteristics and their correlation to genotype and intelligence quotient (IQ). Results: Epilepsy was reported in 85% of participants, more commonly in younger individuals (67.8% in 1970s to 91.8% in last decade), while rate of treatments was similar across ages (>93% for both infantile spasms and focal seizures, except prior to 1960). Vigabatrin (VGB) was the most commonly used antiepileptic drugs (AEDs). Individuals with infantile spasms showed a higher treatment response over time with lower usage of steroids. Individuals with focal seizures reported similar rates of drug resistance (32.5-43.3%). Use of vagus nerve stimulation (VNS), ketogenic diet, and surgery remained low. Discussion: The epilepsy substudy included 162 individuals from nine countries. At epilepsy onset, most individuals with infantile spasms (73.2%) and focal seizures (74.5%) received monotherapies. Vigabatrin was first-line treatment in 45% of individuals with infantile spasms. Changes in initial AEDs were commonly reported due to inadequate efficacy. TSC1 mutations were associated with less severe epilepsy phenotypes and more individuals with normal IQ. In individuals with TSC diagnosis before seizure onset, electroencephalogram (EEG) was performed prior to seizures in only 12.5 and 25% of subsequent infantile spasms and focal seizures, respectively. Conclusions: Our study confirms the high prevalence of epilepsy in TSC individuals and less severe phenotypes with TSC1 mutations. Vigabatrin improved the outcome of infantile spasms and should be used as first-line treatment. There is, however, still a need for improving therapies in focal seizures. Electroencephalogram follow-up prior to seizure-onset should be promoted for all infants with TSC in order to facilitate preventive or early treatment.

Rare manifestations and malignancies in tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increAse disease awareness (TOSCA).

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant disorder caused by pathogenic variants in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existence of rare disease manifestations and to the potential association of TSC with malignant tumors. In this study we sought to characterize rare manifestations and malignancies using a large cohort of patients. METHODS: TuberOus SClerosis registry to increAse disease awareness (TOSCA) is a multicenter, international disease registry collecting clinical manifestations and characteristics of patients with TSC, both retrospectively and prospectively. We report rates and characteristics of rare manifestations and malignancies in patients with TSC who had enrolled in the TOSCA registry. We also examined these manifestations by age, sex, and genotype (TSC1 or TSC2). RESULTS: Overall, 2211 patients with TSC were enrolled in the study. Rare manifestations were reported in 382 (17.3%) study participants and malignancies in 65 (2.9%). Of these rare manifestations, the most frequent were bone sclerotic foci (39.5%), scoliosis (23%), thyroid adenoma (5.5%), adrenal angiomyolipoma (4.5%), hemihypertrophy and pancreatic neuroendocrine tumors (pNET; both 3.1%). These rare manifestations were more commonly observed in adults than children (66.2% vs. 22.7%), in females versus males (58.4% vs. 41.6%; except for scoliosis: 48.9% vs. 51.1%), and in those with TSC2 versus TSC1 (67.0% vs. 21.1%; except for thyroid adenoma: 42.9% vs. 57.1%). In the 65 individuals with reported malignancies, the most common were renal cell carcinoma (47.7%), followed by breast (10.8%) and thyroid cancer (9.2%). Although malignancies were more common in adult patients, 26.1% were reported in children and 63.1% in individuals < 40 years. TSC1 mutations were over-represented in individuals with malignancies compared to the overall TOSCA cohort (32.1% vs. 18.5%). CONCLUSION: Rare manifestations were observed in a significant proportion of individuals with TSC. We recommend further examination of rare manifestations in TSC. Collectively, malignancies were infrequent findings in our cohort. However, compared to the general population, malignant tumors occurred earlier in age and some tumor types were more common.

Russian Consensus on Exo- and Endocrine Pancreatic Insufficiency After Surgical Treatment.

The Russian consensus on exo- and endocrine pancreatic insufficiency after surgical treatment was prepared on the initiative of the Russian Pancreatic Club using the Delphi method. Its goal was to consolidate the opinions of national experts on the most relevant issues of diagnosis and treatment of exo- and endocrine insufficiency after surgical interventions on the pancreas. An interdisciplinary approach is ensured by the participation of leading gastroenterologists and surgeons.

TuberOus SClerosis registry to increAse disease awareness (TOSCA) Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis Complex.

This non-interventional post-authorisation safety study (PASS) assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) who participated in the TuberOus SClerosis registry to increase disease Awareness (TOSCA) clinical study and received everolimus for the licensed indications in the European Union. The rate of adverse events (AEs), AEs that led to dose adjustments or treatment discontinuation, AEs of potential clinical interest, treatment-related AEs (TRAEs), serious AEs (SAEs), and deaths were documented. One hundred seventy-nine patients were included in the first 5 years of observation; 118 of 179 patients had an AE of any grade, with the most common AEs being stomatitis (7.8%) and headache (7.3%). AEs caused dose adjustments in 56 patients (31.3%) and treatment discontinuation in nine patients (5%). AEs appeared to be more frequent and severe in children. On Tanner staging, all patients displayed signs of age-appropriate sexual maturation. Twenty-two of 106 female (20.8%) patients had menstrual cycle disorders. The most frequent TRAEs were stomatitis (6.7%) and aphthous mouth ulcer (5.6%). SAEs were reported in 54 patients (30.2%); the most frequent SAE was pneumonia (>3% patients; grade 2, 1.1%, and grade 3, 2.8%). Three deaths were reported, all in patients who had discontinued everolimus for more than 28 days, and none were thought to be related to everolimus according to the treating physicians. The PASS sub-study reflects the safety and tolerability of everolimus in the management of TSC in real-world routine clinical practice.

Renal Manifestations of Tuberous Sclerosis Complex: Key Findings From the Final Analysis of the TOSCA Study Focussing Mainly on Renal Angiomyolipomas.

Renal angiomyolipomas are one of the most common renal manifestations in patients with tuberous sclerosis complex (TSC), with potentially life-threatening complications and a poor prognosis. Despite the considerable progress in understanding TSC-associated renal angiomyolipomas, there are no large scale real-world data. The aim of our present study was to describe in detail the prevalence and outcome of renal angiomyolipomas in patients with TSC, enrolled into the TuberOus SClerosis registry to increase disease Awareness (TOSCA) from 170 sites across 31 countries worldwide. We also sought to evaluate the relationship of TSC-associated renal angiomyolipomas with age, gender and genotype. The potential risk factors for renal angiomyolipoma-related bleeding and chronic kidney disease (CKD) were studied in patients who participated in the TOSCA renal angiomyolipoma substudy. Of the 2,211 eligible patients, 1,062 (48%) reported a history of renal angiomyolipomas. The median age of TSC diagnosis for the all subjects (n = 2,211) was 1 year. The median age of diagnosis of renal angiomyolipoma in the 1,062 patients was 13 years. Renal angiomyolipomas were significantly more prevalent in female patients (p < 0.0001). Rates of angiomyolipomas >3 cm (p = 0.0119), growing lesions (p = 0.0439), and interventions for angiomyolipomas (p = 0.0058) were also higher in females than males. Pre-emptive intervention for renal angiomyolipomas with embolisation, surgery, or mammalian target of rapamycin (mTOR) inhibitor may have abolished the gender difference in impaired renal function, hypertension, and other complications. The rate of interventions for angiomyolipomas was less common in children than in adults, but interventions were reported in all age groups. In the substudy of 76 patients the complication rate was too low to be useful in predicting risk for more severe CKD. In addition, in this substudy no patient had a renal hemorrhage after commencing on an mTOR inhibitor. Our findings confirmed that renal angiomyolipomas in subjects with TSC1 mutations develop on average at the later age, are relatively smaller in size and less likely to be growing; however, by age 40 years, no difference was observed in the percentage of patients with TSC1 and TSC2 mutations needing intervention. The peak of appearance of new renal angiomyolipomas was observed in patients aged between 18 and 40 years, but, given that angiomyolipomas can occur later, lifelong surveillance is necessary. We found that pre-emptive intervention was dramatically successful in altering the outcome compared to historical controls; with high pre-emptive intervention rates but low rates of bleeding and other complications. This validates the policy of surveillance and pre-emptive intervention recommended by clinical guidelines.

Natural clusters of tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND): new findings from the TOSCA TAND research project.

BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have unique, individual patterns that pose significant challenges for diagnosis, psycho-education, and intervention planning. A recent study suggested that it may be feasible to use TAND Checklist data and data-driven methods to generate natural TAND clusters. However, the study had a small sample size and data from only two countries. Here, we investigated the replicability of identifying natural TAND clusters from a larger and more diverse sample from the TOSCA study. METHODS: As part of the TOSCA international TSC registry study, this embedded research project collected TAND Checklist data from individuals with TSC. Correlation coefficients were calculated for TAND variables to generate a correlation matrix. Hierarchical cluster and factor analysis methods were used for data reduction and identification of natural TAND clusters. RESULTS: A total of 85 individuals with TSC (female:male, 40:45) from 7 countries were enrolled. Cluster analysis grouped the TAND variables into 6 clusters: a scholastic cluster (reading, writing, spelling, mathematics, visuo-spatial difficulties, disorientation), a hyperactive/impulsive cluster (hyperactivity, impulsivity, self-injurious behavior), a mood/anxiety cluster (anxiety, depressed mood, sleep difficulties, shyness), a neuropsychological cluster (attention/concentration difficulties, memory, attention, dual/multi-tasking, executive skills deficits), a dysregulated behavior cluster (mood swings, aggressive outbursts, temper tantrums), and an autism spectrum disorder (ASD)-like cluster (delayed language, poor eye contact, repetitive behaviors, unusual use of language, inflexibility, difficulties associated with eating). The natural clusters mapped reasonably well onto the six-factor solution generated. Comparison between cluster and factor solutions from this study and the earlier feasibility study showed significant similarity, particularly in cluster solutions. CONCLUSIONS: Results from this TOSCA research project in an independent international data set showed that the combination of cluster analysis and factor analysis may be able to identify clinically meaningful natural TAND clusters. Findings were remarkably similar to those identified in the earlier feasibility study, supporting the potential robustness of these natural TAND clusters. Further steps should include examination of larger samples, investigation of internal consistency, and evaluation of the robustness of the proposed natural clusters.

Burden of Illness and Quality of Life in Tuberous Sclerosis Complex: Findings From the TOSCA Study.

Research on tuberous sclerosis complex (TSC) to date has focused mainly on the physical manifestations of the disease. In contrast, the psychosocial impact of TSC has received far less attention. The aim of this study was therefore to examine the impact of TSC on health, quality of life (QoL), and psychosocial well-being of individuals with TSC and their families. Questionnaires with disease-specific questions on burden of illness (BOI) and validated QoL questionnaires were used. After completion of additional informed consent, we included 143 individuals who participated in the TOSCA (TuberOus SClerosis registry to increase disease Awareness) study. Our results highlighted the substantial burden of TSC on the personal lives of individuals with TSC and their families. Nearly half of the patients experienced negative progress in their education or career due to TSC (42.1%), as well as many of their caregivers (17.6% employed; 58.8% unemployed). Most caregivers (76.5%) indicated that TSC affected family life, and social and working relationships. Further, well-coordinated care was lacking: a smooth transition from pediatric to adult care was mentioned by only 36.8% of adult patients, and financial, social, and psychological support in 21.1, 0, and 7.9%, respectively. In addition, the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population.

Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders (TAND): New Findings on Age, Sex, and Genotype in Relation to Intellectual Phenotype.

Background: Knowledge is increasing about TSC-Associated Neuropsychiatric Disorders (TAND), but little is known about the potentially confounding effects of intellectual ability (IA) on the rates of TAND across age, sex, and genotype. We evaluated TAND in (a) children vs. adults, (b) males vs. females, and (c) TSC1 vs. TSC2 mutations, after stratification for levels of IA, in a large, international cohort. Methods: Individuals of any age with a documented visit for TSC in the 12 months prior to enrolment were included. Frequency and percentages of baseline TAND manifestations were presented by categories of IA (no intellectual disability [ID, intelligence quotient (IQ)>70]; mild ID [IQ 50-70]; moderate-to-profound ID [IQ<50]). Chi-square tests were used to test associations between ID and TAND manifestations. The association between TAND and age (children vs. adults), sex (male vs. female), and genotype (TSC1 vs. TSC2) stratified by IA levels were examined using the Cochran-Mantel-Haenszel tests. Results: Eight hundred and ninety four of the 2,211 participants had formal IQ assessments. There was a significant association (P < 0.05) between levels of IA and the majority of TAND manifestations, except impulsivity (P = 0.12), overactivity (P = 0.26), mood swings (P = 0.08), hallucinations (P = 0.20), psychosis (P = 0.06), depressive disorder (P = 0.23), and anxiety disorder (P = 0.65). Once controlled for IA, children had higher rates of overactivity, but most behavioral difficulties were higher in adults. At the psychiatric level, attention deficit hyperactivity disorder (ADHD) was seen at higher rates in children while anxiety and depressive disorders were observed at higher rates in adults. Compared to females, males showed significantly higher rates of impulsivity and overactivity, as well as autism spectrum disorder (ASD) and ADHD. No significant age or sex differences were observed for academic difficulties or neuropsychological deficits. After controlling for IA no genotype-TAND associations were observed, except for higher rates of self-injury in individuals with TSC2 mutations. Conclusions: Findings suggest IA as risk marker for most TAND manifestations. We provide the first evidence of male preponderance of ASD and ADHD in individuals with TSC. The study also confirms the association between TSC2 and IA but, once controlling for IA, disproves the previously reported TSC2 association with ASD and with most other TAND manifestations.

The use of 5-aminosalicylate for patients with Crohn's disease in a prospective European inception cohort with 5 years follow-up - an Epi-IBD study.

BACKGROUND: The lack of scientific evidence regarding the effectiveness of 5-aminosalicylate in patients with Crohn's disease is in sharp contrast to its widespread use in clinical practice. AIMS: The aim of the study was to investigate the use of 5-aminosalicylate in patients with Crohn's disease as well as the disease course of a subgroup of patients who were treated with 5-aminosalicylate as maintenance monotherapy during the first year of disease. METHODS: In a European community-based inception cohort, 488 patients with Crohn's disease were followed from the time of their diagnosis. Information on clinical data, demographics, disease activity, medical therapy and rates of surgery, cancers and deaths was collected prospectively. Patient management was left to the discretion of the treating gastroenterologists. RESULTS: Overall, 292 (60%) patients with Crohn's disease received 5-aminosalicylate period during follow-up for a median duration of 28 months (interquartile range 6-60). Of these, 78 (16%) patients received 5-aminosalicylate monotherapy during the first year following diagnosis. Patients who received monotherapy with 5-aminosalicylate experienced a mild disease course with only nine (12%) who required hospitalization, surgery, or developed stricturing or penetrating disease, and most never needed more intensive therapy. The remaining 214 patients were treated with 5-aminosalicylate as the first maintenance drug although most eventually needed to step up to other treatments including immunomodulators (75 (35%)), biological therapy (49 (23%)) or surgery (38 (18%)). CONCLUSION: In this European community-based inception cohort of unselected Crohn's disease patients, 5-aminosalicylate was commonly used. A substantial group of these patients experienced a quiescent disease course without need of additional treatment during follow-up. Therefore, despite the controversy regarding the efficacy of 5-aminosalicylate in Crohn's disease, its use seems to result in a satisfying disease course for both patients and physicians.

Health-care costs of inflammatory bowel disease in a pan-European, community-based, inception cohort during 5 years of follow-up: a population-based study.

BACKGROUND: Inflammatory bowel disease (IBD) places a significant burden on health-care systems because of its chronicity and need for expensive therapies and surgery. With increasing use of biological therapies, contemporary data on IBD health-care costs are important for those responsible for allocating resources in Europe. To our knowledge, no prospective long-term analysis of the health-care costs of patients with IBD in the era of biologicals has been done in Europe. We aimed to investigate cost profiles of a pan-European, community-based inception cohort during 5 years of follow-up. METHODS: The Epi-IBD cohort is a community-based, prospective inception cohort of unselected patients with IBD diagnosed in 2010 at centres in 20 European countries plus Israel. Incident patients who were diagnosed with IBD according to the Copenhagen Diagnostic Criteria between Jan 1, and Dec 31, 2010, and were aged 15 years or older the time of diagnosis were prospectively included. Data on clinical characteristics and direct costs (investigations and outpatient visits, blood tests, treatments, hospitalisations, and surgeries) were collected prospectively using electronic case-report forms. Patient-level costs incorporated procedures leading to the initial diagnosis of IBD and costs of IBD management during the 5-year follow-up period. Costs incurred by comorbidities and unrelated to IBD were excluded. We grouped direct costs into the following five categories: investigations (including outpatient visits and blood tests), conventional medical treatment, biological therapy, hospitalisation, and surgery. FINDINGS: The study population consisted of 1289 patients with IBD, with 1073 (83%) patients from western Europe and 216 (17%) from eastern Europe. 488 (38%) patients had Crohn's disease, 717 (56%) had ulcerative colitis, and 84 (6%) had IBD unclassified. The mean cost per patient-year during follow-up for patients with IBD was €2609 (SD 7389; median €446 [IQR 164-1849]). The mean cost per patient-year during follow-up was €3542 (8058; median €717 [214-3512]) for patients with Crohn's disease, €2088 (7058; median €408 [133-1161]) for patients with ulcerative colitis, and €1609 (5010; median €415 [92-1228]) for patients with IBD unclassified (p<0·0001). Costs were highest in the first year and then decreased significantly during follow-up. Hospitalisations and diagnostic procedures accounted for more than 50% of costs during the first year. However, in subsequent years there was a steady increase in expenditure on biologicals, which accounted for 73% of costs in Crohn's disease and 48% in ulcerative colitis, in year 5. The mean annual cost per patient-year for biologicals was €866 (SD 3056). The mean yearly costs of biological therapy were higher in patients with Crohn's disease (€1782 [SD 4370]) than in patients with ulcerative colitis (€286 [1427]) or IBD unclassified (€521 [2807]; p<0·0001). INTERPRETATION: Overall direct expenditure on health care decreased over a 5-year follow-up period. This period was characterised by increasing expenditure on biologicals and decreasing expenditure on conventional medical treatments, hospitalisations, and surgeries. In light of the expenditures associated with biological therapy, cost-effective treatment strategies are needed to reduce the economic burden of inflammatory bowel disease. FUNDING: Kirsten og Freddy Johansens Fond and Nordsjællands Hospital Forskningsråd.

The TOSCA Registry for Tuberous Sclerosis-Lessons Learnt for Future Registry Development in Rare and Complex Diseases.

Introduction: The TuberOus SClerosis registry to increase disease Awareness (TOSCA) is an international disease registry designed to provide insights into the clinical characteristics of patients with Tuberous Sclerosis Complex (TSC). The aims of this study were to identify issues that arose during the design, execution, and publication phases of TOSCA, and to reflect on lessons learnt that may guide future registries in rare and complex diseases. Methods: A questionnaire was designed to identify the strengths, weaknesses, and issues that arose at any stage of development and implementation of the TOSCA registry. The questionnaire contained 225 questions distributed in 7 sections (identification of issues during registry planning, during the operation of the registry, during data analysis, during the publication of the results, other issues, assessment of lessons learnt, and additional comments), and was sent by e-mail to 511 people involved in the registry, including 28 members of the Scientific Advisory Board (SAB), 162 principal investigators (PIs), and 321 employees of the sponsor belonging to the medical department or that were clinical research associate (CRA). Questionnaires received within the 2 months from the initial mailing were included in the analysis. Results: A total of 53 (10.4%) questionnaires were received (64.3% for SAB members, 12.3% for PIs and 4.7% for employees of the sponsor), and the overall completeness rate for closed questions was 87.6%. The most common issues identified were the limited duration of the registry (38%) and issues related to handling of missing data (32%). In addition, 25% of the respondents commented that biases might have compromised the validity of the results. More than 80% of the respondents reported that the registry improved the knowledge on the natural history and manifestations of TSC, increased disease awareness and helped to identify relevant information for clinical research in TSC. Conclusions: This analysis shows the importance of registries as a powerful tool to increase disease awareness, to produce real-world evidence, and to generate questions for future research. However, there is a need to implement strategies to ensure patient retention and long-term sustainability of patient registries, to improve data quality, and to reduce biases.

Treatment Patterns and Use of Resources in Patients With Tuberous Sclerosis Complex: Insights From the TOSCA Registry.

Tuberous Sclerosis Complex (TSC) is a rare autosomal-dominant disorder caused by mutations in the TSC1 or TSC2 genes. Patients with TSC may suffer from a wide range of clinical manifestations; however, the burden of TSC and its impact on healthcare resources needed for its management remain unknown. Besides, the use of resources might vary across countries depending on the country-specific clinical practice. The aim of this paper is to describe the use of TSC-related resources and treatment patterns within the TOSCA registry. A total of 2,214 patients with TSC from 31 countries were enrolled and had a follow-up of up to 5 years. A search was conducted to identify the variables containing both medical and non-medical resource use information within TOSCA. This search was performed both at the level of the core project as well as at the level of the research projects on epilepsy, subependymal giant cell astrocytoma (SEGA), lymphangioleiomyomatosis (LAM), and renal angiomyolipoma (rAML) taking into account the timepoints of the study, age groups, and countries. Data from the quality of life (QoL) research project were analyzed by type of visit and age at enrollment. Treatments varied greatly depending on the clinical manifestation, timepoint in the study, and age groups. GAB Aergics were the most prescribed drugs for epilepsy, and mTOR inhibitors are dramatically replacing surgery in patients with SEGA, despite current recommendations proposing both treatment options. mTOR inhibitors are also becoming common treatments in rAML and LAM patients. Forty-two out of the 143 patients (29.4%) who participated in the QoL research project reported inpatient stays over the last year. Data from non-medical resource use showed the critical impact of TSC on job status and capacity. Disability allowances were more common in children than adults (51.1% vs 38.2%). Psychological counseling, social services and social worker services were needed by <15% of the patients, regardless of age. The long-term nature, together with the variability in its clinical manifestations, makes TSC a complex and resource-demanding disease. The present study shows a comprehensive picture of the resource use implications of TSC.

Complete Genome Sequence and Methylome Analysis of Sphaerotilus natans subsp. sulfidivorans D-507.

Sphaerotilus natans subsp. sulfidivorans D-507 is an environmental isolate from a sulfate spring in the northern Caucasus region of Russia. This heterotrophic bacterium is involved in the oxidation of reduced sulfur derivatives. This report includes the finished genome of this strain. In addition, we provide methylation data and the associated enzymes predicted to be responsible for each modified motif.

Newly Diagnosed and Growing Subependymal Giant Cell Astrocytoma in Adults With Tuberous Sclerosis Complex: Results From the International TOSCA Study.

The onset and growth of subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis complex (TSC) typically occurs in childhood. There is minimal information on SEGA evolution in adults with TSC. Of 2,211 patients enrolled in TOSCA, 220 of the 803 adults (27.4%) ever had a SEGA. Of 186 patients with SEGA still ongoing in adulthood, 153 (82.3%) remained asymptomatic, and 33 (17.7%) were reported to ever have developed symptoms related to SEGA growth. SEGA growth since the previous scan was reported in 39 of the 186 adults (21%) with ongoing SEGA. All but one patient with growing SEGA had mutations in TSC2. Fourteen adults (2.4%) were newly diagnosed with SEGA during follow-up, and majority had mutations in TSC2. Our findings suggest that surveillance for new or growing SEGA is warranted also in adulthood, particularly in patients with mutations in TSC2.

Clinical Characteristics of Subependymal Giant Cell Astrocytoma in Tuberous Sclerosis Complex.

Background: This study evaluated the characteristics of subependymal giant cell astrocytoma (SEGA) in patients with tuberous sclerosis complex (TSC) entered into the TuberOus SClerosis registry to increase disease Awareness (TOSCA). Methods: The study was conducted at 170 sites across 31 countries. Data from patients of any age with a documented clinical visit for TSC in the 12 months preceding enrollment or those newly diagnosed with TSC were entered. Results: SEGA were reported in 554 of 2,216 patients (25%). Median age at diagnosis of SEGA was 8 years (range, <1-51), with 18.1% diagnosed after age 18 years. SEGA growth occurred in 22.7% of patients aged ≤ 18 years and in 11.6% of patients aged > 18 years. SEGA were symptomatic in 42.1% of patients. Symptoms included increased seizure frequency (15.8%), behavioural disturbance (11.9%), and regression/loss of cognitive skills (9.9%), in addition to those typically associated with increased intracranial pressure. SEGA were significantly more frequent in patients with TSC2 compared to TSC1 variants (33.7 vs. 13.2 %, p < 0.0001). Main treatment modalities included surgery (59.6%) and mammalian target of rapamycin (mTOR) inhibitors (49%). Conclusions: Although SEGA diagnosis and growth typically occurs during childhood, SEGA can occur and grow in both infants and adults.

Epilepsy in tuberous sclerosis complex: Findings from the TOSCA Study.

OBJECTIVE: To present the baseline data of the international TuberOus SClerosis registry to increase disease Awareness (TOSCA) with emphasis on the characteristics of epilepsies associated with tuberous sclerosis complex (TSC). METHODS: Retrospective and prospective patients' data on all aspects of TSC were collected from multiple countries worldwide. Epilepsy variables included seizure type, age at onset, type of treatment, and treatment outcomes and association with genotype, seizures control, and intellectual disability. As for noninterventional registries, the study protocol did not specify any particular clinical instruments, laboratory investigations, or intervention. Evaluations included those required for diagnosis and management following local best practice. RESULTS: Epilepsy was reported in 83.6% of patients (1852/2216) at baseline; 38.9% presented with infantile spasms and 67.5% with focal seizures. The mean age at diagnosis of infantile spasms was 0.4 year (median <1 year; range <1-30 years) and at diagnosis of focal seizures was 2.7 years (median 1 year; range <1-66 years). A total of 1469 patients (79.3%) were diagnosed with epilepsy <2 years. The rate of infantile spasms was higher in patients with a TSC 2 mutation than in patients with a TSC1 mutation (47.3% vs 23%). É£-aminobutyric acid (GABA)ergic drugs were the most common treatment modality for both infantile spasms (78.7%) and focal seizures (65.5%). Infantile spasms and focal seizures were controlled in 76.3% and 58.2% of patients, respectively. Control of seizures was associated with lower rates of intellectual disability in both groups. SIGNIFICANCE: This registry reports the largest international cohort of patients with TSC. Findings confirmed the typical onset pattern of infantile spasms and other focal seizures in the first 2 years of life, and the high rates of infantile spasms in patients with TSC2 mutation. Our results underscored the occurrence of focal seizures at all ages, including an onset that preceded emergence of infantile spasms. Seizure control was shown to be associated with lower rates of intellectual disability but did not preclude the presence of intellectual disability.

Nonhypervascular pancreatic neuroendocrine tumors: Spectrum of MDCT imaging findings and differentiation from pancreatic ductal adenocarcinoma.

PURPOSE: The purpose of our study was to determine contrast-enhanced MDCT features to differentiate nonhypervascular pancreatic neuroendocrine tumors (PNETs) from pancreatic ductal adenocarcinomas (PDACs). METHODS: and materials: We included 74 patients with PNETs and 80 patients with PDACs who underwent preoperative MDCT. Two radiologists evaluated the morphologic characteristic and enhancement patterns of the tumors. Quantitative and qualitative analysis was performed, including evaluation of tumor size, homogeneity, contrast enhancement pattern, presence of pancreatic duct dilatation and tumor invasion to the adjacent vessels and peripancreatic infiltration. Tumor-to-pancreas enhancement ratio was defined as the Hounsfield units (HU) value of the tumor divided by the HU value of the pancreas. the first group was hypervascular PNETs showing hyperenhancement on arterial phase images and nonhypervascular PNETs, showing iso- or hypoenhancement on arterial phase images. After that, two radiologists estimated the possibilities of PNET or PDAC were for nonhypervascular PNETs. RESULTS: On the basis of arterial enhancement, 43 PNETs were hypervascular and 31 were nonhypervascular. When compared to PDAC, nonhypervascular PNETs more frequently had well-defined tumor margins, intratumoral cystic components, calcifications and blood vessels and less frequently had main pancreatic duct dilatation, peripancreatic infiltration and vascular invasion (p < 0.01 for all). Nonhypervascular PNETs had higher tumor-to-pancreas enhancement ratio in venous phase (1.02 vs. 0.78, p = 0.012). Nonhypervascular PNETs more often had portal-venous hyperenhancement or persistent isoenhancement, while PDAC more often had persistent hypoenhancement or gradual delayed enhancement (p < 0.001). The absence of pancreatic duct dilatation and portal-venous hyperenhancement or persistent isoenhancement were the independent predictors for nonhypervascular PNETs. (The most accurate MDCT-findings to predict nonhypervascular PNET were the absence of pancreatic duct dilatation and peripancreatic infiltration (79% and 92% accuracy), portal-venous phase hyperenhancement or persistent isoenhancement (77%), the presence of intratumoral blood vessels (77%) and relative enhancement intensity in venous phase >0.9 (76%). Using these criteria, the area under curve for differentiation of PNET from PDAC was 0.906-0.846. CONCLUSION: Combined assessment of the enhancement and morphologic characteristics can improve the differentiation between nonhypervascular PNETs and PDAC at contrast-enhanced MDCT.

Natural disease course of Crohn's disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study.

OBJECTIVE: The Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn's disease (CD). DESIGN: Patients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis. RESULTS: In total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, P<0.01), while more Eastern European patients received 5-aminosalicylates (90% vs 56%, P<0.05). Treatment with immunomodulators reduced the risk of surgery (HR: 0.4, 95% CI 0.2 to 0.6) and hospitalisation (HR: 0.3, 95% CI 0.2 to 0.5). CONCLUSION: Despite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation.