Endocrine morbidity in neurofibromatosis 1: a nationwide, register-based cohort study.

OBJECTIVE: Previous studies have found that neurofibromatosis 1 (NF1) is associated with an increased risk for endocrine disorders, but no comprehensive overview of the risk for specific endocrine disorders has been published. We assessed endocrine morbidity in individuals with NF1 from information on hospital admissions, surgery for endocrine disorders, and relevant medication. DESIGN: A nationwide population registry-based cohort study. METHODS: We identified 2467 individuals with NF1 diagnosed between 1977 and 2013 from the Danish National Patient Register and the RAREDIS database and 20 132 randomly sampled age- and sex-matched population comparisons. Information on endocrine diseases was identified using registrations of discharge diagnoses, surgery, and medication prescriptions. The rates of endocrine disorders in individuals with NF1 were compared with those in the comparison cohort in Cox proportional hazard models. RESULTS: Individuals with NF1 had a higher rate than the comparison group of any endocrine discharge diagnosis (hazard ratio [HR] 1.72, 95% confidence interval [CI]: 1.58-1.87), endocrine-related surgery (2.03, 1.39-2.96), and prescribed medications (1.32, 1.23-1.42). Increased HRs were observed for diseases and surgical operations of several glands, including pheochromocytoma, and for osteoporosis, and osteoporotic fractures. Decreased rates were observed with drugs for type 2 diabetes. Women with NF1 had higher HRs for surgery of the ovaries, uterus, and sterilization, but lower rates of surgeries of cervix and prescriptions for birth control pills. CONCLUSIONS: Neurofibromatosis 1 is associated with a variety of endocrine disorders, surgery, and medication related to endocrine disease. Awareness of endocrine morbidity is important in the clinical follow-up of individuals with NF1.

Clinical Characteristics and Management of Children and Adults with Neurofibromatosis Type 1 and Plexiform Neurofibromas in Denmark: A Nationwide Study.

INTRODUCTION: Plexiform neurofibromas (PN) are benign nerve sheath tumours that are a frequent and potentially debilitating complication in patients with neurofibromatosis type 1 (NF1). The objective of this study was to describe the natural history of PN in children, adolescents and adults with NF1. METHODS: This was a nationwide, longitudinal cohort study of patients with NF1 under observation at the two national centres of NF1 expertise in Denmark between 2000 and 2020. Patient and clinical characteristics were documented from individual medical records. RESULTS: A total of 1099 patients with NF1 were included. Overall, 12% (35/296) of paediatric patients and 21% (172/803) of adult patients had ≥ 1 large PN (≥ 3 cm). Approximately half of patients with a large PN had ≥ 1 symptomatic PN. The most frequent symptoms were pain, neurological deficits, cosmetic issues, disfigurement, compression, increased psychosocial burden and vision loss. Clinical evaluations of PN size were available for 40 PN in 34 paediatric patients and 191 PN in 159 adult patients with large PN. Surgery (complete resection or debulking) was performed in 38% (15/40) of PN in paediatric patients and 45% (86/191) in adult patients. In addition, 35% of PN in paediatric patients and 33% in adult patients were inoperable. In a subgroup analysis, the overall PN size increased 1.06-fold per year. Malignant peripheral nerve sheath tumours (MPNST) were diagnosed in 21 patients (two paediatric and 19 adult patients). CONCLUSIONS: This study shows that PN are common, their size and prevalence increase with age, many are often inoperable and pain and other symptoms are frequently associated. The results highlight the severe sequelae and unmet need for alternatives to analgesia and surgery in patients with PN.

Cohort profile: life with neurofibromatosis 1 - the Danish NF1 cohort.

PURPOSE: The Danish neurofibromatosis 1 (NF1) cohort was initiated to study health-related, socioeconomic and psychological consequences of living with the monogenetic disorder NF1 using a nationwide and population-based approach. PARTICIPANTS: The cohort includes all 2467 individuals in Denmark who were hospitalised with or due to NF1 from 1977 to 2013 or registered in the RAREDIS Database (1995-2013), a national clinical database for rare diseases, or both. A comparison cohort matched to individuals with NF1 on sex and date of birth was identified in the Civil Registration System (n=20 132). FINDINGS TO DATE: All cohort members were linked to the unique Danish registries to obtain information on hospital contacts, birth outcomes, education and partnership. A questionnaire was completed by 244 of the 629 adult cohort members with NF1 registered in the RAREDIS Database to evaluate the psychosocial and emotional burden. Further, neuropsychological tests were performed on 103 adult cohort members with NF1 and 38 adult population comparisons. To date, six studies have been published. Individuals with NF1 had an increased risk for (1) hospitalisation for disorders affecting all organ systems of the body throughout all decades of life, (2) psychiatric disorders, (3) attaining a short or medium long education and (4) not forming a life partner. Women with NF1 had an increased risk for spontaneous abortions and stillbirths. Finally, adults with NF1 had an impaired quality of life and a high need for professional support for physical, psychological and work-related problems, which was partly associated with disease severity and visibility. FUTURE PLANS: The cohort will regularly be updated with newly diagnosed patients in the RAREDIS Database as well as with outcome information in the Danish registries. New studies are in progress to assess other medical and socioeconomic dimensions of living with NF1.

Glucocorticosteroid and Silicone Gel During Patch Application Without Clinical Scar Improvement After Central Venous Catheter Removal: A Randomized Trial.

INTRODUCTION: We studied whether glucocorticosteroid during patch occlusion has a beneficial effect on scar outcome in children and adolescents treated for cancer. METHODS: A double-blinded placebo-controlled randomized clinical trial was performed. The main outcome was the Vancouver Scar Scale. Secondary outcomes were scar width and scar quality measured using the Patient and Observer Scar Assessment Scale. The patients were divided into an intervention groups and a control group. The intervention group was randomized into active and placebo group. The active treatment consisted of cream with glucocorticosteroid and fusidic acid. The placebo treatment consisted of cream with fusidic acid. Both groups received silicone gel patch after central venous catheter removal. The control group received no specific skin care. RESULTS: Assessment at 12 months showed that the intervention group had a significantly lower Vancouver Scar Scale and a smaller scar (0,1 cm) compared with the control group ( P =0.00, P =0.02) but no benefit of glucocorticosteroid. The Patient and Observer Scar Assessment Scale showed no significant difference between the intervention and control groups ( P =0.84, P =0.36). CONCLUSIONS: Silicone gel sheet alone or in combination with application of glucocorticosteroid during sheet occlusion does not clinically improve scar outcome after removal of central venous catheter in children treated for neoplastic diseases.

Optic pathway glioma and the sex association in neurofibromatosis type 1: a single-center study.

BACKGROUND: Low-grade optic pathway glioma (OPG) develops in 15-20% of children with neurofibromatosis type 1 (NF1). OPGs are symptomatic in 30-50% and one-third of these require treatment. A few studies have suggested female sex as a risk factor for visual impairment associated with NF1-OPG. This descriptive study investigated the correlation between NF1-OPG growth, sex and visual impairment. METHOD: We based our cross-sectional study on a systematic, retrospective data collection in a NF1 cohort of children and adolescents below 21 years of age followed at Center for Rare Diseases, Aarhus University Hospital, Denmark. For each patient with OPG a medical chart review was performed including demographics, ophthalmological examinations and magnetic resonance imaging (MRI) of OPG. RESULTS: Of 176 patients with NF1 (85 females, 91 males), we identified 21 patients with OPG (11.9%) with a preponderance of females, p = 0.184. Eight females (62%) and one male (13%) had visual impairment at the last ophthalmological evaluation. Five out of 21 children with OPG (24%) underwent diagnostic MRI because of clinical findings at the ophthalmological screening. Nine children (43%) had symptoms suggestive of OPG and seven (33%) experienced no OPG-related symptoms before the diagnostic MRI. Of eight children diagnosed with OPG ≤ two years of age, one had visual impairment. Of 13 children diagnosed > two years of age, eight had visual impairment; in each group, four of the children were treated with chemotherapy. The study suggested no correlation between NF1-OPG growth and sex. CONCLUSION: Our data suggest sex as a risk factor for visual impairment, while an OPG diagnose ≤ two years of age was a protective factor for visual impairment. Females with NF1-OPG had a higher prevalence of visual impairment outcome compared to males. Interestingly, our data also suggest a better response to treatment in children with OPG diagnosed ≤ two years of age compared to older children. The findings in our study suggest sex as a potential prognostic factor for visual impairment.

[Diagnosis, monitoring and treatment of tuberous sclerosis complex].

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with highly varying disease manifestations, many of which cause extensive morbidity. There are international consensus criteria for the diagnosis, monitoring and treatment of TSC, and approved medical treatment for some of the most serious disease manifestations. However, organisation of a rational and coordinated care of TSC patients involves many different medical specialities and is only sparsely described. This review describes the interdisciplinary care of TSC patients at Aarhus University Hospital, Denmark.

Importance of blood cultures from peripheral veins in pediatric patients with cancer and a central venous line.

BACKGROUND: When an infection is suspected in a child with cancer and a central venous line (CVL), cultures are often only obtained from the CVL and not from a peripheral vein (PV). This study was undertaken to evaluate the importance of concomitant blood cultures from the CVL and a PV. PROCEDURE: Clinical data and the results of all cultures taken concomitantly from the CVL and a PV were registered prospectively in children admitted with fever from April 2008 to December 2012 at the Department of Pediatrics at Aarhus University Hospital Skejby. RESULTS: During the study period 654 paired cultures obtained from the CVL and from a PV within two hour of each other were included. A true bloodstream infection (BSI) was registered in 112 episodes. In 20 (17%) out of 112, true BSI growth of a microorganism was detected only in the culture from a PV including seven cases of Escherichia coli and three cases of Staphylococcus aureus. In 52 episodes the same microorganism was cultured from both the CVL and a PV. Twenty-four of these episodes were classified as catheter-related bloodstream infections (CRBSI) using differential time to positivity. In total, 64 (57%) of all true BSI were defined as CRBSI. CONCLUSIONS: Blood cultures should be obtained from a PV in addition to cultures from CVL at the onset of fever in pediatric patients with cancer in order to maximize the findings of true BSIs. The frequency of CRBSI may be over-estimated if blood cultures are drawn from CVL only.

Central venous catheters and catheter locks in children with cancer: a prospective randomized trial of taurolidine versus heparin.

BACKGROUND: To determine if the catheter lock taurolidine can reduce the number of catheter-related bloodstream infections (CRBSI) in pediatric cancer patients with tunneled central venous catheters (CVC). PROCEDURE: During a study period of 34 months, 129 newly placed tunneled CVCs in 112 patients were randomly assigned to standard lock with heparin solution or experimental lock with a taurolidine solution (ClinicalTrials.gov Identifier NCT00735813). RESULTS: Sixty-five CVCs were included in the standard group and 64 CVCs in the experimental group. The groups were comparable regarding patients' characteristics. A total number of 72 bloodstream infections of which 33 were CRBSIs were observed during 39,127 CVC-days. A lower rate of CRBSI (0.4 per 1,000 CVC-days) was observed in the experimental arm compared with the standard arm (1.4 per 1,000 CVC-days, incidence rate ratio (IRR) = 0.26; 95% confidence interval (CI) 0.09-0.61; P = 0.001). A lower rate of total bloodstream infections (1.2 per 1,000 CVC-days) was also observed in the experimental arm compared with the standard arm (2.5 per 1,000 CVC-days, IRR = 0.49; 95% CI 0.29-0.82; P = 0.004). Median interval from catheter insertion until first CRBSI was significantly lower in the standard group (156 days, range 12-602) compared with the experimental group (300 days, range 12-1,176; P = 0.02). Premature removal of the CVC due to infection and overall CVC survival were similar in the two study groups. CONCLUSION: Locking of long-term tunneled CVC with taurolidine significantly reduces catheter-related bloodstream infections in children with cancer.

High frequency of streptococcal bacteraemia during childhood AML therapy irrespective of dose of cytarabine.

BACKGROUND: High-dose cytarabine has been associated with a high frequency of viridans group streptococcal (VGS) bacteraemia. VGS bacteraemia causes considerable morbidity and mortality. The Nordic Society of Paediatric Haematology and Oncology (NOPHO)-AML protocols use higher cumulated doses of cytarabine and more chemotherapy series (n = 6) than other protocols with the potential increased risk of severe VGS infections. PROCEDURE: Medical records of all Danish children enrolled on the NOPHO-AML-2004 protocol between January 2004 and September 2011 (n = 45) were retrospectively reviewed and all febrile episodes were registered. RESULTS: Following 236 courses of chemotherapy, 112 positive blood cultures were registered. VGS were found in 38% of all positive blood cultures. Infectious episodes with VGS resulted in more days of fever and intravenous antibiotic therapy compared with infections caused by other microorganisms. VGS were involved in 45% of all episodes categorized as sepsis (n = 51) and in 67% of life-threatening bloodstream infections (n = 9). Penicillin resistance was found in 40% of the VGS strains. No significant difference was observed in the proportion of VGS isolated following courses with low-dose cytarabine versus courses with high-dose cytarabine. CONCLUSIONS: VGS were the most commonly isolated pathogens causing the most severe infections and the majority of life-threatening infections. A substantial proportion of the strains were resistant to penicillin. The high rate of VGS seemed independent of high-dose cytarabine but was more likely caused by the intensive chemotherapy treatment leading to severe mucositis and neutropenia.

Biofilm formation in long-term central venous catheters in children with cancer: a randomized controlled open-labelled trial of taurolidine versus heparin.

Taurolidine has demonstrated inhibition of biofilm formation in vitro. The aim of this study was to compare the effect of catheter locking with taurolidine vs heparin in biofilm formation in central venous catheters. Forty-eight children with cancer were randomized to catheter locking by heparin (n = 22) or taurolidine (n = 26), respectively. After removal, catheters were examined by standardized scanning electron microscopy to assess quantitative biofilm formation. Biofilm was present if morphologically typical structures and bacterial cells were identified. Quantitative and semi-quantitative cultures were also performed. Biofilm was identified in 23 of 26 catheters from the taurolidine group and 21 of 22 catheters from the heparin group. A positive culture was made of six of the catheters locked with taurolidine and heparin, respectively (p = 0.78). The rate of catheter-related bloodstream infections (CRBSI) was 0.1 per 1000 catheter-days using taurolidine and 0.9 per 1000 catheter-days using heparin (p = 0.03). This randomized trial confirmed that the use of taurolidine as catheter-lock compared with heparin reduced the rate of CRBSIs; this reduction was not related to a reduction in the intraluminal biofilm formation and the rate of bacterial colonization detected by scanning electron microscopy in the two groups.

[Infections related to central venous catheters in children affected from malignant diseases]. / Infektioner relateret til centralt venekateter hos børn med maligne lidelser.

Central venous catheters (CVC) are an essential part of the treatment of children with haematological and oncological diseases. Unfortunately, CVC also represent a major risk factor of bloodstream infections. Catheter-related bloodstream infections (CRBSI) in children are often diagnosed based on blood cultures from the CVC only. Most CRBSI can be treated without catheter removal. On suspicion of CRBSI empirical antibiotic treatment with piperacillin-tazobactam, meropenem or ampicillin in combination with gentamicin is recommended. The systemic treatment can be combined with catheter-lock therapy.

Placing of tunneled central venous catheters prior to induction chemotherapy in children with acute lymphoblastic leukemia.

BACKGROUND: Tunneled central venous catheters (CVCs) are inevitable in children with acute lymphoid leukemia (ALL). The aim of this study was to evaluate the risk of CVC-related complications in children with ALL in relation to timing of catheter placement and type of catheter. PROCEDURE: All children hospitalized from January 2000 to March 2008 with newly diagnosed ALL and with double-lumen total implantable devices (TIDs) or tunneled external catheters (TEs) were included retrospectively. We only used data related to the patient's first catheter. RESULTS: We included 98 children; 35 received a TID and the remaining 63 received a TE. A total number of 29,566 catheter days and 93 catheter-associated blood stream infections (CABSI) was identified. We found a CABSI rate of 3.1/1,000 catheter days (5.4/1,000 catheter days for TEs and 1.4/1,000 catheter days for TIDs, incidence rate ratio (IRR) 3.82 (95% CI 2.37-6.35) P = 0.0001). No difference was found in CABSI between neither early versus later placed TIDs (IRR = 0.99 (95% CI 0.41-2.45) P = 0.98) nor early versus later placed TEs (IRR = 0.81 (95% CI 0.40-1.86) P = 0.54). We found no difference between early and later placed catheters regarding non-elective removal (RR = 0.86 (95% CI 0.72-1.03) P = 0.09). TEs had a higher risk of non-elective removal compared with TIDs (RR = 3.95 (95% CI 1.88-8.29) P < 0.001). CONCLUSIONS: The study did not find that children with ALL and with early placed CVCs experienced significantly more complications compared with children with late placed catheters. This study found that children with ALL and TEs experienced more complications than children with TIDs.

[Rare brain tumour in 6-month-old girl]. / Sjaelden hjernetumor hos seks måneder gammel pige.

A six-month old girl presented with repetitive episodes of vomiting. Soon after admission to hospital she had convulsions. Computertomography showed a tumour in the third ventricle. She was non-radically operated. Histology showed an atypical teratoid/rhabdoid tumour (AT/RT). No active treatment was initiated, and the patient died three months later. AT/RT is a very rare tumor of the brain. It occurs primarily in early childhood. AT/RT is a very aggressive and rapidly progressing tumour.