Hydrocephalus and hypothalamic involvement in pediatric patients with craniopharyngioma or cysts of Rathke's pouch: impact on long-term prognosis.

OBJECTIVE: Pediatric patients with sellar masses such as craniopharyngioma (CP) or cyst of Rathke's pouch (CRP) frequently suffer disease- and treatment-related sequelae. We analyzed the impact and prognostic relevance of initial hydrocephalus (HY) and hypothalamic involvement (HI) on long-term survival and functional capacity (FC) in children with CP or CRP. SUBJECTS AND METHODS: Using retrospective analysis of patient records, presence of initial HY or HI was assessed in 177 pediatric patients (163 CP and 14 CRP). Twenty-year overall survival (OS) and progression-free survival (PFS), FC, and BMI were analyzed with regard to initial HY, degree of resection, or HI. RESULTS: Of the 177 patients, 105 patients (103/163 CP and 2/14 CRP) presented with initial HY and 96 presented with HI. HY at diagnosis was associated (P=0.000) with papilledema, neurological deficits, and higher BMI at diagnosis and during follow-up. OS, PFS, and FC were not affected by HY at initial diagnosis. HI at diagnosis (96/177) had major negative impact on long-term prognosis. Sellar masses with HI were associated with lower OS (0.84±0.04; P=0.021), lower FC (P=0.003), and higher BMI at diagnosis and last follow-up (P=0.000) when compared with sellar masses without HI (OS: 0.94±0.05). PFS was not affected by HI or degree of resection. CONCLUSIONS: Initial HY has no impact on outcome in patients with sellar masses. OS and FC are impaired in survivors presenting with initial HI. PFS is not affected by HY, HI, or degree of resection. Accordingly, gross-total resection is not recommended in sellar masses with initial HI to prevent further hypothalamic damage.

[Childhood craniopharyngioma with hypothalamic obesity - no long-term weight reduction due to rehabilitation programs]. / Kraniopharyngeom mit hypothalamischer Adipositas - Stationäre Rehabilitation ohne Einfluss auf die Gewichtszunahme bei Kindern und Jugendlichen.

BACKGROUND: Severe obesity due to hypothalamic involvement has major impact on prognosis in long-term survivors of childhood craniopharyngioma. The long-term effects of rehabilitation efforts on weight development and obesity in these patients are not analyzed up to now. PATIENTS AND METHODS: 108 patients with childhood craniopharyngioma recruited in HIT Endo before 2001 were included in the study. Long-term weight development (BMI SDS after >10 yrs follow-up) was analyzed in regard to rehabilitation, which was performed in 31 of 108 (29%) patients (one rehabilitation in 4 patients (13%), more than one in 21 patients (68%), 6 patients unknown) in 13 German rehabilitation -clinics. RESULTS: 84% of patients underwent rehabilitation in order to reduce hypothalamic obesity (BMI>+ 2 SD), whereas 12% of patients were normal weight. Childhood craniopharyngioma pa-tients with rehabilitation presented with higher BMI at diagnosis (median BMI: +1.32 SD; range: -1.08 to + 7.00 SD) and at last evaluation (median BMI: +4.93 SD; range: -0.20 to + 13.13 SD) when compared with patients without rehabilitation (median BMI at diagnosis: +0.24 SD; range: -2.67 to + 6.98 SD; BMI at evaluation: +2.09 SD; range: -1.48 to + 10.23 SD). A long-term weight reducing effect of rehabilitation was no detectable regardless of degree of obesity, frequency of rehabilitation, and hospital of rehabilitation. CONCLUSION: Treatment options for hypothalamic obesity in terms of rehabilitation are limited. Accordingly, strategies for prevention of hypothalamic lesions and psychosocial effects of rehabilitation are currently in focus for improvement of prognosis in childhood craniopharyngioma patients.

Childhood craniopharyngioma - changes of treatment strategies in the trials KRANIOPHARYNGEOM 2000/2007.

BACKGROUND: Prognosis in childhood cranio-pharyngioma, is frequently impaired due to sequelae. Radical surgery was the treatment of choice for decades. Even at experienced facilities radical surgery can result in hypothalamic disorders such as severe obesity. OBJECTIVE: We analyzed, whether treatment strategies for childhood craniopharyngioma patients recruited in GPOH studies have changed during the last 12 years. MATERIALS AND METHODS: We compared the grade of pre-surgical hypothalamic involvement, treatment, degree of resection and grade of surgical hypothalamic lesions between patients recruited in KRANIOPHARYNGEOM 2000 (n=120; 2001-2007) and KRANIOPHARYNGEOM 2007 (n=106; 2007-2012). RESULTS: The grade of initial hypothalamic involvement was similar in patients treated 2001-2007 and 2007-2012. The realized treatment was more radical (p=0.01) in patients recruited 2001-2007 (38%) when compared with patients treated 2007-2012 (18%). In patients with pre-surgical involvement of anterior/posterior hypothalamic areas, the rate of hypothalamus-sparing operations resulting in no (further) hypothalamic lesions was higher (p=0.005) in patients treated 2007-2012 (35%) in comparison with the 2001-2007 cohort (13%). Event-free-survival rates were similar in both cohorts. CONCLUSIONS: A trend towards less radical surgical approaches is observed, which was accompanied by a reduced rate of severe hypothalamic lesions. Radical surgery is not an appropriate treatment strategy in patients with hypothalamic involvement. Despite previous recommendations to centralize treatment at specialized centers, a trend towards further decentralization was seen.

Meningioma as second malignant neoplasm after oncological treatment during childhood.

A total of 38 patients (18 female/20 male) with childhood meningioma were recruited from the German registry HIT-Endo (1989-2009). In 5 cases meningioma occurred as second malignant neoplasm (SMN). Histologies were confirmed by reference assessment in all cases (SMN: 2 WHO I, 1 WHO II, 2 WHO III). The SMNs were diagnosed at a median age of 12.4 years with a median latency of 10.2 years after primary malignancy (PMN; 4 brain tumors, 1 lymphoblastic leukemia; median age at diagnosis 2.7 years). Meningioma occurred as SMN in the irradiated field of PMN (range 12-54 Gy). The outcome after treatment of SMN meningioma (surgery/irradiation) was favorable in terms of psychosocial status and functional capacity in 4 of 5 patients (1 death). We conclude that survivors of childhood cancer who were exposed to radiation therapy at young age harbor the risk of developing meningioma as a SMN at a particularly short latency period in case of high dose exposure.

First experiences with laparoscopic adjustable gastric banding (LAGB) in the treatment of patients with childhood craniopharyngioma and morbid obesity.

Craniopharyngiomas are embryogenic malformations which lead to eating disorders and morbid obesity due to hypothalamic involvement in about 50% of all patients with pediatric craniopharyngioma. The experience with laparoscopic adjustable gastric banding (LAGB) in obese craniopharyngioma patients is limited. We are reporting on four patients with childhood craniopharyngioma diagnosed at age 2, 11, 12, and 21 years. BMI-SDS at diagnosis was +0.9, +4.5, +4.7 and -0.1 SD. During follow-up, all patients developed morbid obesity (BMI-SDS: +13.9, +10.3, +11.4, +7.3) so that 11, 6, 9 and 3 years after diagnosis LAGB were performed. After a follow-up of 4.5, 1.5, 3.0 and 2.5 years BMI decreased or stabilized continuously in all patients (BMI-SDS at latest visit: +9.9, +9.7, +9.5, +5.9 SD). The eating behavior changed in all patients profoundly. The addiction to food and especially sweets significantly improved based on self-assessment. In two patients a dislocation of the LAGB occurred and resulted in weight gain. We conclude that LAGB could be effective in weight reduction of obese craniopharyngioma patients with hypothalamic syndrome. Close follow-up is necessary in order to analyze long-term effects and complications of LAGB in patients with childhood craniopharyngioma and morbid obesity.

Formation and thickness evolution of periodic twin domains in manganite films grown on SrTiO3(001) substrates.

We present an extended synchrotron x-ray scattering study of the structure of thin manganite films grown on SrTiO3(001) substrates and reveal a new kind of misfit strain relaxation process which exploits twinning to adjust lattice mismatch. We show that this relaxation mechanism emerges in thin films as one-dimensional twinning waves which freeze out into a twin domain pattern as the manganite film continues to grow. A quantitative microscopic model which uses a matrix formalism is able to reproduce all x-ray features and provides a detailed insight into this novel relaxation mechanism. We further demonstrate how this twin angle pattern affects the transport properties in these functional films.

Relapse pattern after complete resection and early progression after incomplete resection of childhood craniopharyngioma.

In HIT Endo data on therapy and prognosis of 306 patients with childhood craniopharyngioma (CP) were analyzed. The 5 years-overall survival rate was 94 +/- 4 % in irradiated patients and 93 +/- 5 % in non-irradiated patients. Aims of the prospective study KRANIOPHARYNGEOM 2000 were to collect data on the incidence and time course of relapses after complete surgery and tumour progressions after incomplete resection. Furthermore, the impact of irradiation therapy (XRT) on tumour relapse and recurrence rates was analyzed. Since 2001 ninety-eight patients with CP were recruited at a median age at diagnosis of 9.9 years ranging from 1.8 to 18.0 years. Complete resection was achieved in 44 %, incomplete resection in 54 %. XRT was performed in 24 of 98 CP patients; in 10 early after incomplete resection, in 14 of 24 after progression of residual tumour or relapse, in 3 of 14 after second surgery of relapse. XRT was performed at a median age of 12.0 years ranging from 5.0 to 18.9 years and in median after an interval of 9 months after first diagnosis. The analysis of event-free survival rates (EFS) in patients with CP showed a high rate of early events in terms of tumour progression after incomplete resection (3y-EFS: 0.22 +/- 0.09) and relapses after complete resection (3y-EFS: 0.60 +/- 0.10) during the first three years of follow-up. A high rate of early events (1y-EFS: 0.78 +/- 0.10; 2y-EFS: 0.57 +/- 0.15) was also found for patients after XRT (3 cystic progressions, 3 progressions of solid tumour; in 24 patients after XRT). We conclude that tumour progression and relapse are frequent and early events even in irradiated patients. Monitoring of cerebral imaging and clinical status is recommended in follow-up of patients with childhood CP. In order to analyze the appropriate time point of XRT after incomplete resection, QoL, EFS and overall survival in patients (age > or = 5 years) will be analyzed in KRANIOPHARYNGEOM 2007 after stratified randomization of the time point of irradiation after incomplete resection (early irradiation versus irradiation at progression of residual tumour).

Prognosis and sequela in patients with childhood craniopharyngioma -- results of HIT-ENDO and update on KRANIOPHARYNGEOM 2000.

The overall survival rate of patients with craniopharyngioma, an embryogenic malformation, is high (0.92 +/- 0.03). However, there is considerable morbidity and impaired quality of life, even when the tumor can be completely resected. Aim of our study was to analyze risk factors for severe obesity (body mass index [BMI] > or = 7 SD) and the prognosis of severely obese survivors of childhood craniopharyngioma recruited in our cross-sectional study on 183 patients (HIT-ENDO) and in the prospective study KRANIOPHARYNGEOM 2000. Severe obesity (BMI > or = 7 SD) was present in 16 % of patients and associated with higher tumor volume (p < 0.05), more frequent neurosurgical interventions (p < 0.05) and a higher rate of hypothalamic involvement (p < 0.001). Self-assessed functional capacity (FMH) was lower (p < 0.001) in severely obese survivors (FMH: median 33, range: 4-64) when compared with normal weight patients (FMH: 50; 1-95). Overall survival (20 years) was lower (p = 0.034) in patients with severe obesity in comparison to patients with moderate obesity and normal weight. Cardiovascular morbidity and mortality was high in severely obese patients. Between 10/01 and 03/04 fifty-seven patients (27 female/30 male) were recruited in KRANIOPHARYNGEOM 2000 (www.kraniopharyngeom.com). The impact of tumor localization (3.2 % intrasellar, 22.6 % suprasellar, 74.2 % combined intra/suprasellar; 51.6 % hypothalamic involvement) and treatment (26 complete resections, 22 partial resections followed by irradiation in one case; primary irradiation after biopsy in one case) on quality of life, functional capacity and prognosis will be evaluated longitudinally and prospectively.

Functional capacity, obesity and hypothalamic involvement: cross-sectional study on 212 patients with childhood craniopharyngioma.

The aim of this study was to analyze the impact of hypothalamic involvement of craniopharyngioma on functional capacity (FC) and obesity in 212 patients with childhood craniopharyngioma. FC could be evaluated using an ability scale (Fertigkeitenskala Münster-Heidelberg [FMH]) in 174 patients with childhood craniopharyngioma. Obesity was quantified in 212 patients at the time of diagnosis and at the time of latest evaluation by body mass index SDS [BMI]. The influence of hypothalamic tumor involvement on FC and BMI was analyzed. Patients with hypothalamic involvement (n = 125) presented with higher BMI SDS at the time of diagnosis (p = 0.001) and at latest follow-up evaluation (p < 0.001). FC as measured by FMH percentiles was lower (p < 0.001) in patients with hypothalamic involvement when compared with patients without hypothalamic involvement. FC negatively correlated (p < 0.001) with BMI SDS (Spearman's Rho = -0.40) only in patients with hypothalamic involvement whereas no correlation between FC and BMI SDS was found in patients without hypothalamic involvement. We conclude that hypothalamic involvement of childhood craniopharyngioma had major impact on FC in survivors. Obesity resulted in impaired FC of patients with hypothalamic involvement. BMI at diagnosis was a sensitive parameter to identify patients at risk of severe obesity. Further analysis on this issue is performed in the prospective, multicenter surveillance study on children and adolescents with craniopharyngioma (KRANIOPHARYNGEOM 2000).

Perioperative dexamethasone treatment in childhood craniopharyngioma--influence on short-term and long-term weight gain.

The substitution of dexamethasone during and after surgery of childhood craniopharyngioma is necessary in order to treat and/or prevent brain edema and adrenal insufficiency. Early post-operative weight gain is a predictor for severe obesity during long-term follow-up. In a retrospective analysis of 60 patients with childhood craniopharyngioma we inquired whether dose and duration of perioperative dexamethasone therapy (n = 68) had influence on short-term post-operative weight gain and long-term development of severe obesity. The median follow-up period was 4.2 years, ranging from 1 to 9 years. 24 patients (14 f/10 m) developed severe obesity (BMI > 3 SD). 28 patients (10 f/18 m) retained normal weight (BMI < 2 SD). Eight patients presented with a BMI between 2 and 3 SD at the final visit. Differences in terms of age at surgery or follow-up period were non-detectable between the analyzed groups of craniopharyngioma patients. Duration and cumulative dexamethasone doses (mg/m2 BSA) for perioperative dexamethasone therapy were similar for severely obese patients (duration: 8.7 d; 4.5 - 17 d, cumulative dose: 74; 42 - 177 mg/m2 BSA) and normal weight patients (duration: 10.0 d; 1 - 41 d; dose: 76; 9 - 390 mg/m2 BSA). Whereas cumulative dexamethasone doses positively (p < 0.01; rho: 0.424) correlated with weight gain during the first year following surgery, long-term development of severe obesity was not influenced by dose and duration of perioperative dexamethasone treatment. Patients who developed severe obesity during follow-up had a higher (p < 0.001) BMI already at the time of diagnosis. We conclude that dose and duration of perioperative dexamethasone treatment had short-term effects on post-operative weight gain, but not on the development of long-term severe obesity. The results of our retrospective analysis are currently tested in a prospective surveillance study Kraniopharyngeom 2000 (www.kraniopharyngeom.com).

Volumetric bone mineral density in patients with childhood craniopharyngioma.

As the overall survival rate is high in patients with craniopharyngioma, the prognosis in survivors depends mainly on late effects. Late effects such as hypogonadism, growth hormone deficiency, glucocorticoid overreplacement and obesity have a strong impact on volumetric bone mineral density (vBMD). We analyzed vBMD and possible risk factors for reduced vBMD in 61 patients with childhood craniopharyngioma (29 f; 32 m) and in 14 weight, age, and sex-matched controls. VBMD was quantified by peripheral quantitative computed tomography (pQCT). Endocrine status, hormonal substitution therapy and calcium phosphate metabolism were evaluated. VBMD was in the lower normal range in 61 craniopharyngioma patients (total radial z-scores: median - 1.5; range - 3.1 to 1.4; trabecular z-scores: median - 0.4; - 2.4 to 2.3). 23 severely obese patients (body mass index [BMI] > 4 SD) had a higher total radial (p < 0.05) and trabecular (p < 0.05) vBMD when compared with 38 non-severely obese patients and 7 weight-matched controls. Although there was no gender difference in terms of obesity, endocrine substitution therapy or calcium phosphate metabolism, male patients had lower total radial (p < 0.01) and trabecular (p < 0.05) vBMD. Only in male patients' vBMD z-scores showed a positive correlation with BMI standard deviation score (SDS) (total radial z-score: Spearman r = 0.38, p = 0.03; trabecular z-score: Spearman r = 0.35, p = 0.04). We conclude that obesity has a major impact on vBMD in patients with craniopharyngioma. Lean male patients are at special risk for a lower vBMD, whereas female gender and severe obesity seem to have a protective effect regarding vBMD.

Hepatitis A virus-specific immunoglobulin A mediates infection of hepatocytes with hepatitis A virus via the asialoglycoprotein receptor.

The mechanisms underlying the hepatotropism of hepatitis A virus (HAV) and the relapsing courses of HAV infections are unknown. In this report, we show for a mouse hepatocyte model that HAV-specific immunoglobulin A (IgA) mediates infection of hepatocytes with HAV via the asialoglycoprotein receptor, which binds and internalizes IgA molecules. Proof of HAV infection was obtained by detection of HAV minus-strand RNA, which is indicative for virus replication, and quantification of infectious virions. We demonstrate that human hepatocytes also ingest HAV-anti-HAV IgA complexes by the same mechanism, resulting in infection of the cells, by using the HepG2 cell line and primary hepatocytes. The relevance of this surrogate receptor mechanism in HAV pathogenesis lies in the fact that HAV, IgA, and antigen-IgA complexes use the same pathway within the organism, leading from the gastrointestinal tract to the liver via blood and back to the gastrointestinal tract via bile fluid. Therefore, HAV-specific IgA antibodies produced by gastrointestinal mucosa-associated lymphoid tissue may serve as carrier and targeting molecules, enabling and supporting HAV infection of IgA receptor-positive hepatocytes and, in the case of relapsing courses, allowing reinfection of the liver in the presence of otherwise neutralizing antibodies, resulting in exacerbation of liver disease.

Variability of cerebral blood flow deficits in 99mTc-HMPAO SPECT in patients with Alzheimer's disease.

The purpose of this study was to analyse the frequency of the different pathological perfusion patterns in SPECT in a clinical, unselected population of patients with Alzheimer's disease. In 91 patients and 16 control subjects regional cerebral blood flow (rCBF) was measured with Single Photon Emission Computed Tomography (SPECT) using 99mTc-hexa-methyl-propyleneamine oxime (HMPAO). 95% confidence intervals obtained from the perfusion values of the control subjects were used to define normal perfusion ranges. The frequency of perfusion deficits in the left frontal, temporal, parietal and occipital lobes were 62.2%, 60.4%. 70.3% and 23.1%, respectively. In the right hemisphere the corresponding values were 60.4%, 58.2%, 63.7% and 9.9%. With the exception of the occipital lobes these frequencies were not significantly different. The analysis of the perfusion pattern of each patient revealed 35 different combinations of lobes with perfusion deficits. The temporo-parietal perfusion deficits were not more frequent than the temporofrontal perfusion deficits. These results suggest that in the clinical routine a high variety of heterogeneous rCBF patterns have to be expected.

Particulate contamination from siliconized rubber closures for freeze drying.

It can be shown that siliconized closures for freeze drying may cause the opalescence and turbidity observed in freeze-dried products after reconstitution. Closures of different rubber composition show different intensities of turbidity when treated identically with the same quantity and type of silicone oil. Clear solutions are obtained after reconstitution if ETFE-coated closures are used instead of siliconized closures. Samples stored at 4 degrees C for up to 6 months show no change in the intensity of turbidity, while the turbidity of samples manufactured with siliconized closures and stored at higher temperatures increase with time. Samples with ETFE-coated closures show clear solutions when stored at 25 degrees C and 37 degrees C for up to 6 months and at 45 degrees C for 3 months. After 6 months only a very weak opalescence could be observed in these samples.

The low affinity Fc gamma RIIa and Fc gamma RIIIb on polymorphonuclear neutrophils are differentially regulated by CD45 phosphatase.

Stimulation of human polymorphonuclear neutrophils through ligation and cross-linking of the low affinity Fc gamma RIIa and Fc gamma RIIIb using mAb Fab and F(ab')2 fragments led to transient intracellular calcium mobilization and activation of the respiratory burst. Fc gamma RIIIb engagement resulted in a different pattern of intracellular calcium flux, and induction of the respiratory burst was significantly more effective than in the case of Fc gamma RIIa. These data demonstrate that the capacity of Fc gamma RIIIb to transduce transmembrane signals itself contributes to full cell activation. Treatment with a mAb F(ab')2 fragment recognizing CD45 phosphatase suppressed Fc gamma R-induced calcium mobilization in a dose-dependent manner. An ongoing intracellular calcium mobilization was immediately terminated when activation was followed by co-cross-linking Fc gamma R and CD45. This suggests that the initial steps of Fc gamma R signal transduction pathways are influenced by the state of tyrosine phosphorylation. Combined cross-linking of both receptors, however, was hardly susceptible to CD45. Also, inhibition of respiratory burst by CD45 in the case of Fc gamma RIIIb was minimal compared with that for Fc gamma RIIa. Signal transduction pathways of low affinity Fc gamma RIIa and Fc gamma RIIIb are differentially regulated by CD45, underlining the essential function of Fc gamma R-mediated tyrosine phosphorylation in polymorphonuclear neutrophil activation.

Introduction of an automatic QT interval driven rate responsive pacemaker.

QT driven rate responsive pacemakers have been implanted since 1981. The more than 6 years experience and additional knowledge gained during several clinical studies have culminated in the design of an automatic rate responsive pacemaker. The adjustment of the rate responsive function to each individual patient is carried out automatically by the pacemaker, which therefore performs several measurements both at rest and during exercise. The results of these measurements are used to adapt the rate responsive parameters in order to optimize the rate response, even under changing circumstances.