Christian Kunze

Pharmacokinetics and safety of gadobutrol-enhanced magnetic resonance imaging in pediatric patients.

Objectives:This clinical study investigated the pharmacokinetics and safety of gadobutrol, a magnetic resonance (MR) imaging extracellular contrast agent, in pediatric patients aged 2 to 17 years. Materials and Methods:In this open-label, multicenter study, patients scheduled for routine contrast-enhanced MR imaging of the brain, spine, liver or kidney, or MR angiography received a single intravenous injection of gadobutrol (0.1 mmol/kg/0.1 mL/kg). Patients were stratified by age groups (2–6, 7–11, and 12–17 years). Blood and urine samples were collected at prespecified time points and analyzed for gadolinium concentrations. Plasma data were evaluated by means of a nonlinear mixed effects model, and urine data were analyzed using descriptive statistics. In addition, the safety of gadobutrol was evaluated. Results:A total of 130 patients (2–6 years, n = 45; 7–11 years, n = 39; 12–17 years, n = 46) were included in the final population pharmacokinetic analysis. Gadobutrol pharmacokinetics in children aged 2 to 17 years were adequately described by an open 2-compartment model with elimination from the central compartment. The median estimates (2.5th percentile, 97.5th percentile) of body weight-normalized total body clearance (L/h/kg) per age group were 0.10 (0.05, 0.17) for all ages, 0.13 (0.09, 0.17) in the 2 to 6 year age group, 0.10 (0.05, 0.17) in the 7 to 11 year age group and 0.09 (0.05, 0.10) in the 12 to 17 year age group. The body weight-normalized median estimates of total volume of distribution (L/kg) were 0.20 (0.12, 0.28) for all ages, 0.24 (0.20, 0.28) in the 2 to 6 year age group, 0.19 (0.14, 0.23) in the 7 to 11 year age group and 0.18 (0.092, 0.23) in the 12 to 17 year age group. Median gadolinium plasma concentrations at 20 minutes postinjection were simulated using the population pharmacokinetic model and ranged from 414 (13 kg subject) to 518 &mgr;mol/L (65 kg subject). Body weight was identified as the major covariate influencing the pharmacokinetic parameters of total body clearance and central volume of distribution. Age was not found to be an additional independent parameter. The median amount of renally excreted gadolinium was 77.0% of the administered dose within 6 hours postinjection, indicating that gadobutrol was renally excreted in this pediatric population aged 2 to 17 years. Gadobutrol was well tolerated, with drug-related adverse events of mild intensity reported for 8 (5.8%) of 138 patients. Conclusions:Observed differences in pharmacokinetics were attributed to body weight, with no additional independent effect of age. Thus, no dose adjustment from the standard dose of gadobutrol in adults based on body weight (0.1 mmol/kg) is necessary in pediatric patients aged 2 to 17 years. Gadobutrol was safe and well tolerated in the pediatric population in this study.

Pharmacokinetics and Safety of Macrocyclic Gadobutrol in Children Aged Younger Than 2 Years Including Term Newborns in Comparison to Older Populations.

ObjectivesThis clinical study evaluated the pharmacokinetics (PK) and safety data of macrocyclic extracellular contrast agent gadobutrol in pediatric subjects aged younger than 2 years. Materials and MethodsPediatric subjects (term newborns to those aged younger than 2 years) with normal renal function undergoing magnetic resonance imaging with gadobutrol (0.1 mmol/kg body weight [BW]) were prospectively enrolled in this open-label, multicenter clinical trial to evaluate PK as a primary end point. Plasma PK was analyzed using a population-based PK approach. Safety and qualitative efficacy (evaluation of images) were secondary end points. Safety and tolerability were assessed throughout study participation (approximately 7 days). Imaging efficacy variables were assessed by investigators. ResultsForty-four subjects were evaluated for safety and efficacy; 43 subjects were eligible for PK evaluation including 9 term newborns and infants aged younger than 2 months. Gadobutrol PK in pediatric subjects aged younger than 2 years were adequately described by a linear 2-compartmental model with elimination from the central compartment. Total median systemic exposure (area under the curve) of gadobutrol was estimated at 776 &mgr;mol · h/L (range, 544–1470 &mgr;mol · h/L). Simulated median concentration at 20 minutes after injection of gadobutrol (C20) was 339 &mgr;mol/L (range, 230–456 &mgr;mol/L). Safety and tolerability profile were similar to older populations. In 1 subject (2.3%), vomiting was reported as a mild adverse event related to gadobutrol, and there were no reported serious adverse events. The evaluation of gadobutrol-enhanced images provided improved diagnosis, increased confidence in diagnosis, and contributed to subject clinical management. ConclusionsThe PK profile of gadobutrol in children aged younger than 2 years including newborns is similar to that in older children and adults. At the dose of 0.1 mmol/kg BW, gadobutrol had a favorable safety profile and was well tolerated with similar profile across the age range 0 to younger than 2 years and compared with older children and adults. Extrapolation of efficacy data from adults to the younger pediatric population, including term newborns, is justified. The recommended standard dose of gadobutrol (0.1 mmol/kg BW), as used in the population aged 2 years and older, is also appropriate in children aged younger than 2 years.

SOX10 mutation with peripheral amyelination and developmental disturbance of axons

In this study we describe a case of a term infant with the neurological variant of Waardenburg syndrome type 4 (i.e., PCWH = peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease, as defined in OMIM #609136) due to a novel heterozygous base exchange (c.671C>G) in exon 4 of SOX10. Magnetic resonance imaging suggested central myelin deficiency with cerebral and cerebellar hypoplasia. Hirschsprung disease was confirmed by rectal biopsy. Sural nerve biopsy revealed hypoplasia due to amyelination (with the exception of a single, small myelinated fiber) and severe reduction in the number of axons. Muscle Nerve, 2012

Ectopic pancreas with pseudocyst and pseudoaneurysm formation

Ectopic pancreas is a rare congenital anomaly. It is usually asymptomatic, or presents with non specific gastrointestinal symptoms. We describe here a case of ectopic pancreas in the gastric antrum, with pseudocyst and pseudoaneurysm formation. This entity has not been reported previously in the literature.

Ovarian Borderline Tumors in Pre-menarche Girls

By reason of a new case of an ovarian mucinous borderline tumor (BOT) in a pre-menarche girl, a research of current literature was implemented. Low-grade malignant epithelial tumors are extremely rare in young children and, as far as we know, only a few case reports exist. The patients presented with vomiting, pain, and a swollen lower abdomen. Pre-operative diagnosis primarily consists of imaging techniques. At Stage Ia, the tumor is confined to the ovary without penetration of the capsule, no malignant ascites or peritoneal implants. Treatment consists of removal of the tumor combined with concurrent salpingo oophorectomy, appendectomy, omentectomy, and peritoneal lavage. Although the treatment recommendations are not uniform, basically, preservation of fertility is the main objective. The prognosis is very good, but recurrence is possible even after 10 years.

Inflammatory pseudotumor (IPT) and inflammatory myofibroblastic tumor (IMT): a representative literature review occasioned by a rare IMT of the transverse colon in a 9-year-old child

Aims and Background Inflammatory pseudotumor (IPT) and inflammatory myofibroblastic tumor (IMT) represent different entities. However, it is only in recent years that this has been taken into increasing consideration. Some authors still use both terms synonymously or interchangeably. Inflammatory myofibroblastic tumor is a real neoplasm because of the proliferation of myofibroblastic cells. Inflammatory pseudotumor is a more inflammatory reactive or regenerative entity and shows an overlapping with immunoglobulin G4-related disease. Methods and Study Design To analyze the current situation, 443 publications from the last 5 years (2009 to February 2014) were included. Reports involved 938 patients and 956 organ sites. The age distribution is twin peaked with one maximum in childhood and the other between 50 and 60 years of age. This distribution is questionable due to the more frequent occurrence of IPT in the liver and of IMT in the lung. Inflammatory pseudotumors mainly occur in older patients; IMTs in children and young adults. Results and Conclusions The liver and biliary tract were the most commonly affected of all body regions, at 32%. This was followed by the lung, including the respiratory tract, at 27%, and by the gastrointestinal tract, at 10%. Lesions of the large bowel, as in the present case of a 9-year-old boy, are very rare. There were organ-related as well as nonspecific clinical symptoms, such as fever, weight loss, and fatigue. Laboratory test results revealed anemia and elevated inflammation-dependent parameters. The patterns in medical imaging are variable and nonspecific. Morphology often suggests a malignant process. For this reason, therapy in most cases is surgical, but this is required more often in IMTs. Many IPTs could be treated conservatively.

Sonographische Bestimmung der Hodenmaße im Alter von 0 bis 18 Jahren

BACKGROUND Reference values are necessary in clinical practice in order to correctly evaluate testicular volume and detect disorders. OBJECTIVES The objective of this prospective cross-sectional study was to evaluate reference values for testicular volume dependent on age, height, and weight in boys aged 0-18 years. MATERIAL AND METHODS During their inpatient stay, the testes of 174 boys, who were free of disease or therapy that might influence testicular development, were examined by sonography. High resolution ultrasound transducers ranging from 7.5-14 MHz were used for evaluation. The testicular volume was calculated by the ellipsoid formula: length • width • height • (π/6). RESULTS The subject age ranged from 0-18 years (average 7.1 ± 5.3 years). At the age of 0-8 years, the left testicular volume (1.2 ml) was less than the right testicular volume (1.3 ml). At the age of 13 years, the testicular volume of all subjects was over 3 ml. Left testicular volume of boys aged 16.5-18 years ranged from 7 to 22 ml and the right testicular volume ranged from 6 to 22 ml. CONCLUSION Reference value tables of testicular volume dependent on age, and for the first time dependent on weight and height in boys aged from 0-18 years were compiled. Tables of testicular length, width, and height dependent on age are provided.

Patella Dislocation in Children and Adolescents

Introduction Patellar dislocation is one of the commonest knee injuries in adolescents. Although treatment usually leads to good results, the influence of anatomical and functional factors on therapeutic strategy has been underestimated, especially in cases of recurrence. Patients and Methods The course of treatment has been analysed in 88 patients with 136 patellar dislocations. The importance of anatomical conditions was studied using X-ray and MRI findings. The treatment results were critically evaluated in comparison with current recommendations. Results From 2000 to 2015, 109 patellar dislocations occurred in 88 patients; a further 27 previous dislocations were reported by the patients (mean age 14 years, 47 boys and 41 girls). About one-third of patients (35.2 %) suffered one or more recurrences. Almost half (48.6 %) of the dislocations occurred during physical exercise, particularly ball sports. Osteochondral flake fracture was found in 9 % of the patients, and a lesion of the medial patellofemoral ligament in 96 %. There was an anatomical predisposition to patellar dislocation in almost all cases. The sulcus angle, patellar and trochlear dysplasia, and patellar height were highly significantly different between the patient group and controls. The TT-TG distance was subsequently calculated, but had no impact on therapy. Seventy-seven patients were treated conservatively and 32 patients surgically. The conservative procedure included partial immobilisation for six weeks. Surgical reconstruction or tightening was performed in 27 cases; in five, in combination with other surgical procedures. Plasty of the medial patellofemoral ligament with a tendon graft was performed in five patients, and osteochondral or meniscal lesions were repaired in 10 patients. Recurrences occurred in 41.7 % of conservatively treated knees and in 29.6 % of surgically treated knees (without reconstruction with a tendon graft). No recurrence was seen after reconstruction of the medial patellofemoral ligament with a tendon graft. Fifty-four patients underwent a follow-up examination. Fourteen of these (25.9 %) had suffered a recurrence. The outcome 16 months after the end of treatment was mostly good, as were the results of self-assessment (Larson-Lauridsen Score). Conclusion An anatomical predisposition is detectable in almost all cases of patellar dislocation, but frequently occurs with an accident event, e.g. in ball sports. Primary patellar dislocations without serious concomitant injuries may be treated conservatively. In the event of recurrence, the indication for surgery is given, even in young patients and in any patient with an osteochondral flake fracture. Tightening reconstruction of the MPFL used to be frequently performed, but is associated with a high rate of recurrence.

Headache as the leading symptom in a case of cerebral tuberculosis

The advent of new and acute headaches poses a diagnostic challenge. The differential diagnosis comprises numerous diseases and syndromes, the prevalence of which varies depending on the geographical region. Due to increased magnitudes in international migration, the usual differential diagnostic spectrum has to be enlarged in individual cases. The presented case illustrates this dilemma and shows that, for example, tuberculosis deserves to be taken into consideration.

Sonographische Bestimmung der Hodenmaße im Alter von 0 bis 18 Jahren@@@Evaluation of testicular volume in 0- to 18-year-old boys by sonography

BACKGROUND Reference values are necessary in clinical practice in order to correctly evaluate testicular volume and detect disorders. OBJECTIVES The objective of this prospective cross-sectional study was to evaluate reference values for testicular volume dependent on age, height, and weight in boys aged 0-18 years. MATERIAL AND METHODS During their inpatient stay, the testes of 174 boys, who were free of disease or therapy that might influence testicular development, were examined by sonography. High resolution ultrasound transducers ranging from 7.5-14 MHz were used for evaluation. The testicular volume was calculated by the ellipsoid formula: length • width • height • (π/6). RESULTS The subject age ranged from 0-18 years (average 7.1 ± 5.3 years). At the age of 0-8 years, the left testicular volume (1.2 ml) was less than the right testicular volume (1.3 ml). At the age of 13 years, the testicular volume of all subjects was over 3 ml. Left testicular volume of boys aged 16.5-18 years ranged from 7 to 22 ml and the right testicular volume ranged from 6 to 22 ml. CONCLUSION Reference value tables of testicular volume dependent on age, and for the first time dependent on weight and height in boys aged from 0-18 years were compiled. Tables of testicular length, width, and height dependent on age are provided.