Diagnosis and Treatment of Nasopharyngeal Carcinoma in Children and Adolescents - Recommendations of the GPOH-NPC Study Group.

Nasopharyngeal carcinoma (NPC) is a rare malignant tumor arising from epithelial cells of the nasopharynx. Its incidence is highest in Southeast Asia. Age distribution of NPC is bimodal, with one peak in young adolescents and another in patients 55-59 years of age. EBV appears to be the primary etiologic agent in the pathogenesis, environmental factors such as nitrosamines and genetic factors are contributory. NPC is most commonly diagnosed in locally advanced stages, with lymph node metastases occurring in up to 90% of patients. About 5-10% of patients present with distant metastases. Diagnosis of NPC is made histologically, supported by an abnormal anti-EBV-VCA IgA titer and elevated plasma EBV-DNA load. Superior results in children and adolescents with advanced locoregional NPC, with overall and event-free survival rates>90%, have been achieved by neoadjuvant chemotherapy with 5-fluoruracil and cisplatin, followed by synchronous radiochemotherapy and subsequent maintenance therapy with interferon-ß as demonstrated by the 2 prospective studies GPOH-NPC-91 and -2003. Response to therapy can be assessed by PET-imaging and in patients with complete remission after neoadjuvant chemotherapy, the radiation dose to the primary tumor can be safely reduced from 59.4 to 54.4 Gy. Since the majority of long term sequalae such as xerostomia, skin and tissue fibrosis are caused by high radiation dosages, radiotherapy modalities such as intensity-modulated radiotherapy should be used to efficiently spare non-tumorous tissue. For patients with metastatic disease and relapse, survival chances are low. New treatment strategies, such as the application of EBV-specific T-lymphocytes should be considered for these patients.

Evaluation of treatment response to enzyme replacement therapy with Velaglucerase alfa in patients with Gaucher disease using whole-body magnetic resonance imaging.

OBJECTIVE: This was a retrospective data analysis to evaluate the treatment response to enzyme replacement therapy (ERT) with Velaglucerase alfa using whole-body magnetic resonance imaging (MRI). MATERIALS AND METHODS: A baseline and follow-up MRI were performed on 18 Gaucher Type 1 patients at an interval of 11.6 months. The MRI score systems determined the Bone-Marrow-Burden (BMB) score, the Düsseldorf-Gaucher score (DGS), and the Vertebra-Disc-Ratio (VDR). The Severity Score Index Type 1 (GD-DS3) was also assessed. RESULTS: The baseline MRI medians were: BMB, 7.00; DGS, 3.00; and VDR: 1.70; while, the follow-up MRI medians were: BMB, 7.00; DGS, 3.00; and VDR: 1.73. The baseline GD-DS3 median was 2.40 (BMB excl.: 0.50) and the follow-up median was 2.00 (BMB excl.: 0.50). There was weak statistical significance with the Wilcoxon signed-rank test for the DGS (p=0.034) and GD-DS3 (p=0.047) between both MRIs. CONCLUSION: Velaglucerase alfa therapy is a effective long-term treatment for Gaucher Type 1 patients who are newly diagnosed or switching therapies. Measurements with whole-body MRI and an objective scoring system were reliable tools for detecting early stage bone marrow activity. Further research is needed to evaluate the "Booster-Effect" of Velaglucerase alfa therapy in Gaucher skeletal disease.

Evaluation of Bone Marrow Infiltration in Non-Neuropathic Gaucher Disease Patients with Use of Whole-Body MRI--A Retrospective Data Analysis.

PURPOSE: To evaluate whole-body magnetic resonance imaging (WB-MRI) for the assessment of bone marrow infiltration in patients with confirmed Gaucher disease type 1 under long-term enzyme replacement therapy (ERT). MATERIALS AND METHODS: This retrospective data analysis included 38 patients in two subgroups. Group A: 10 females, 9 males, 15-29 years, mean age 22 years and Group B: 11 females, 8 males, 29-77 years, mean age 49 years, all treated with alglucerase or imiglucerase for at least 12.5 years. Whole-body MRI was carried out in all patients using a standard MRI protocol. Two radiologists assessed all MR images retrospectively with the use of three different MRI score systems: The bone marrow burden (BMB) score, the Düsseldorf-Gaucher score (DGS) and the vertebra disc ratio (VDR). As a clinical component, severity score index type 1 (GD-DS3) was determined. RESULTS: In both groups the MR scores showed low to moderate pathologic levels but no statistically significant difference was found between both groups. The median scores in group A/group B were 7.00/9.00 for the BMB score (p=0.07), 4.00/3.00 for the DGS score (p=0.062) and 1.54/1.62 for the VDR score (p=0.267). The GD-DS3 score was statistically significantly different between both groups (1.6/3.9, p=0.000) and osseous Gaucher disease complications were only found in group B. CONCLUSION: Bone marrow involvement and typical clinical manifestations are reduced to a minimum, when ERT starts immediately after the confirmed diagnosis of Gaucher disease type 1. The applied MR scores are useful markers to control bone marrow infiltration under enzyme replacement therapy in older patients. Pathologic MR scores in young patients may reflect postponed fat conversion of the juvenile bone marrow. This issue has to be examined in further studies. KEY POINTS: Whole-body MRI is valuable for the staging of Gaucher disease type 1. Osseous complications are reduced to a minimum in early treated patients. MR score systems have to be adjusted in young Gaucher patients.

Risk of cancer incidence before the age of 15 years after exposure to ionising radiation from computed tomography: results from a German cohort study.

The aim of this cohort study was to assess the risk of developing cancer, specifically leukaemia, tumours of the central nervous system and lymphoma, before the age of 15 years in children previously exposed to computed tomography (CT) in Germany. Data for children with at least one CT between 1980 and 2010 were abstracted from 20 hospitals. Cancer cases occurring between 1980 and 2010 were identified by stochastic linkage with the German Childhood Cancer Registry (GCCR). For all cases and a sample of non-cases, radiology reports were reviewed to assess the underlying medical conditions at time of the CT. Cases were only included if diagnosis occurred at least 2 years after the first CT and no signs of cancer were recorded in the radiology reports. Standardised incidence ratios (SIR) using incidence rates from the general population were estimated. The cohort included information on 71,073 CT examinations in 44,584 children contributing 161,407 person-years at risk with 46 cases initially identified through linkage with the GCCR. Seven cases had to be excluded due to signs possibly suggestive of cancer at the time of first CT. Overall, more cancer cases were observed (O) than expected (E), but this was mainly driven by unexpected and possibly biased results for lymphomas. For leukaemia, the SIR (SIR = O/E) was 1.72 (95 % CI 0.89-3.01, O = 12), and for CNS tumours, the SIR was 1.35 (95 % CI 0.54-2.78, O = 7). Despite careful examination of the medical information, confounding by indication or reverse causation cannot be ruled out completely and may explain parts of the excess. Furthermore, the CT exposure may have been underestimated as only data from the participating clinics were available. This should be taken into account when interpreting risk estimates.

Morphologic assessment of thoracic deformities for the preoperative evaluation of pectus excavatum by magnetic resonance imaging.

OBJECTIVE: To assess whether MRI is a suitable modality for the preoperative assessment and quantification of pectus excavatum. METHODS: A total of 69 patients (57 male, 12 female; median age 15 years, range 5-35 years) with pectus excavatum were evaluated preoperatively using standardized MRI sequences on 1.5- and 3-Tesla systems (T2-HASTE/inspiration and expiration, T1-VIBE, T2-TRUFI free-breathing, T2-BLADE). The MR sequences were analysed for quality semiquantitatively. The Haller index, correction index, sternal rotation angle and asymmetry index were assessed; correlations between these indices and changes in inspiration and expiration were evaluated. RESULTS: T2-HASTE was the best sequence to assess pectus excavatum morphology, with a higher quality at 3 T than at 1.5 T. All indices could be assessed in every patient. A total of 37 patients had a symmetric deformity, 32 patients an asymmetric deformity. The Haller index correlated significantly (p < 0.001) with the correction index, both becoming higher in expiration. The asymmetry index correlated with the sternal rotation angle (p < 0.001) and did not change significantly in expiration (p = 0.28). CONCLUSIONS: Thoracic MRI is suitable for the preoperative evaluation of patients with pectus excavatum. An exact morphologic assessment is possible without radiation exposure as well as the determination of several indices to quantify the deformities.

Massive pulmonary embolism in a young boy with T-cell leukaemia. Successful thrombolytic therapy by recombinant tissue plasminogen activator (rtPA).

Acute pulmonary embolism (PE) is a serious complication in association with malignant diseases. We describe the successful treatment of PE applying a systemic thrombolytic therapy in a 4-year-old boy with acute lymphoblastic leukaemia. The thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) 0.1 mg/kg bodyweight per hour for six hours was continued for six days without important side effects. In particular no bleeding complications were observed. Computed tomography with contrast revealed a remarkable regression of the central PE. Without further delays the chemotherapy was resumed.

Disturbed Wnt Signalling due to a Mutation in CCDC88C Causes an Autosomal Recessive Non-Syndromic Hydrocephalus with Medial Diverticulum.

The etiology of non-syndromic hydrocephalus is poorly understood. Via positional cloning in a consanguineous family with autosomal recessive hydrocephalus we have now identified a homozygous splice site mutation in the CCDC88C gene as a novel cause of a complex hydrocephalic brain malformation. The only living patient showed normal psychomotor development at the age of 3 years and 3 months and her deceased aunt, who was assumed to suffer from the same condition, had mild mental retardation. The mutation in the affected patients, a homozygous substitution in the donor splice site of intron 29, resulted in a shorter transcript due to exclusion of exon 29 and loss of functional protein, as shown by Western blotting (p.S1591HfsX7). In normal human tissue panels, we found CCDC88C ubiquitously expressed, but most prominently in the fetal brain, especially in pons and cerebellum, while expression in the adult brain appeared to be restricted to cortex and medulla oblongata. CCDC88C encodes DAPLE (HkRP2), a Hook-related protein with a binding domain for the central Wnt signalling pathway protein Dishevelled. Targeted quantitative RT-PCR and expression profiling of 84 genes from the Wnt signalling pathway in peripheral blood from the index patient and her healthy mother revealed increased mRNA levels of CCDC88C indicating transcriptional upregulation. Due to loss of CCDC88C function ß-catenin (CTNNB1) and the downstream target LEF1 showed increased mRNA levels in the patient, but many genes from the Wnt pathway and transcriptional target genes showed reduced expression, which might be explained by a complex negative feedback loop. We have thus identified a further essential component of the Wnt signalling pathway in human brain development.

Strategies for dose-optimized imaging in pediatric cardiac dual source CT.

PURPOSE: As a result of rapid advances in CT technology, including dual source CT, cardiac CT exams at high heart rates are feasible, making pediatric cardiac CT in congenital heart disease possible. Dose concerns and patient size variability make general recommendations difficult. The aim of this study was to investigate which scanner settings are suitable for multiple weight groups to provide dose-optimized scanning. MATERIALS AND METHODS: All 12 patients underwent a contrast-enhanced gated dual source CT exam. A maximum of 2 ml/kg body weight or 60 ml contrast was applied. Scanner settings at 80 and 120 kV, as well as weight-adapted mAs settings were used in an iterative fashion. Datasets were assessed for image quality and dose-optimized scan parameters were established via class comparison. In a final step a table was created as a recommendation for cardiac CT in children corresponding to their body weight. Strategies for optimized contrast application with hand vs. manual injection were explored. RESULTS: In all children diagnostic image quality was obtained. In children < 60 kg, 80 kV can be used, in all others 100 kV is sufficient. The eff. mAs varied from 362 mAs to 30 mAs depending on body weight. Retrospectively a significant dose reduction would have been possible in 6 / 12 patients. Cardiac CT can be performed between 0.6 and 3.2 mSv in a pediatric population. CONCLUSION: The present study shows that dual source cardiac CT is a potential diagnostic alternative in children with congenital heart disease without excessive radiation exposure or contrast media application.

Infantile hypophosphatasia due to a new compound heterozygous TNSALP mutation - functional evidence for a hydrophobic side-chain?

BACKGROUND: Infantile hypophosphatasia (IH) is an inherited disorder characterized by defective bone mineralization and a deficiency of alkaline phosphatase activity. OBJECTIVE/DESIGN: The aim of the study was to evaluate a new compound heterozygous TNSALP mutation for its residual enzyme activity and localization of the comprised amino acid residues in a 3D-modeling. PATIENT: We report on a 4-week old girl with craniotabes, severe defects of ossification, and failure to thrive. Typical clinical features as low serum alkaline phosphatase, high serum calcium concentration, increased urinary calcium excretion, and nephrocalcinosis were observed. Vitamin D was withdrawn and the patient was started on calcitonin and hydrochlorothiazide. Nonetheless, the girl died at the age of 5 months from respiratory failure. RESULTS: Sequence analysis of the patient's TNSALP gene revealed two heterozygous mutations [c.653T>C (I201T), c.1171C>T (R374C)]. Transfection studies of the unique I201T variant in COS-7 cells yielded a mutant TNSALP protein with only a residual enzyme activity (3.7%) compared with wild-type, whereas the R374C variant was previously shown to reduce normal activity to 10.3%. 3D-modeling of the mutated enzyme showed that I201T resides in a region that does not belong to any known functional site. CONCLUSION: We note that I201, which has been conserved during evolution, is buried in a hydrophobic pocket and, therefore, the I>T-change should affect its functional properties. Residue R374C is located in the interface between monomers and it has been previously suggested that this mutation affects dimerization. These findings explain the patient's clinical picture and severe course.

Pediatric multidetector computed tomography using tube current modulation and a patient image gallery.

BACKGROUND: Dose reduction is crucial in pediatric multidetector computed tomography (MDCT). PURPOSE: To perform pediatric 16-slice MDCT using tube current modulations and to adjust prospectively the tube current using a patient image gallery (IG) providing simulated dose-reduced protocols; and to evaluate and compare the image quality of the IG and the clinical MDCT. MATERIAL AND METHODS: 30 examinations (thorax, n = 15; abdomen, n = 8; pelvis, n = 7) in 20 patients (nine male, age 8.05 +/- 7.33 years, weight 29.8 +/- 24.02 kg) were performed according to an IG on a 16-slice MDCT with additional use of online tube current modulation (CARE Dose). Three radiologists visually assessed image quality from the IG and actual 16-slice MDCT scans. For objective analysis, image noise was determined. RESULTS: Statistical analysis showed moderate concordance in objective (K = 0.68-0.78) and subjective (K = 0.33-0.64) image assessment between the IG and clinical 16-slice MDCT scans. Depending on the weight group and clinical question, no or only minor dose reductions in the chest, but moderate to considerable reductions in the abdominal/pelvic 16-slice MDCT scans compared to previously used pediatric protocols were achieved. Extra dose reduction was achieved due to additional use of CARE Dose depending on age group and scan region (mean 8.6-23.9%). CONCLUSION: The IG enabled us to prospectively reduce the tube current and adapt the required image quality to the clinical question. Additional dose reduction was achieved with application of CARE Dose; nevertheless, the images are comparable to the simulated images of the IG.

[Tolerance of magnetic resonance imaging in children and adolescents performed in a 1.5 Tesla MR scanner with an open design]. / Untersuchungstoleranz von Kindern und Adoleszenten in einem 1,5 Tesla MR-Tomografen mit offenem Magnetdesign.

PURPOSE: To investigate the tolerance of MR examinations in children and adolescents performed in a 1.5 Tesla MR scanner with an expanded bore diameter. METHOD AND MATERIALS: 163 patients, ages 4 to 25, underwent MR examinations in a 1.5 Tesla MR scanner with an open design (MAGNETOM Espree, Siemens, Erlangen, Germany), characterized by a compact length of 125 cm and an expanded 70 cm bore diameter. MR imaging of the brain was carried out in most cases (78.5 %), followed by examinations of the spinal canal (9.8 %), the extremities (9.2 %) and the neck (2.5 %). The patients were divided into four age groups and the success rate, motion artifacts and diagnostic quality of the MR examinations were assessed using a 3-grade scale. RESULTS: In 119 of 163 patients (73.0 %), MR examination was possible without any motion artifacts. With respect to the different age groups, 41.7 % of the 4 - 7-year-old children, 67.6 % of the 8 - 10-year-old children, 84.1 % of the 11 - 16-year-old children and 95.8 % of the patients older than 17 showed tolerance grade I without motion artifacts and excellent diagnostic image quality. In 39 of 163 children (23.9 %), the MR images showed moderate motion artifacts but had sufficient diagnostic quality. With regard to the different age groups, 52.8 % of the 4 - 7-year-old children, 26.5 % of the 8 - 10-year-old children, 15.9 % of the 11 - 16-year-old children and none of the patients older than 17 showed tolerance grade II with moderate motion artifacts and sufficient diagnostic image quality. In only 4 of 124 children < 10 years old and 1 child > 10 years old, the MR examination was not feasible and had to be repeated under sedation. CONCLUSION: Pediatric MR imaging using a 1.5 Tesla MR scanner with an open design can be conducted in children and adolescents with excellent acceptance. The failure rate of 3.0 % of cases for pediatric MR imaging is comparable to that of a conventional low-field open MR scanner.

Evaluation of femoral head vascularization in slipped capital femoral epiphysis before and after cannulated screw fixation with use of contrast-enhanced MRI: initial results.

In this study we used contrast-enhanced magnetic resonance imaging (MRI) to evaluate the vascularization of the femoral head in children with slipped capital femoral epiphysis (SCFE) before and after cannulated screw fixation. Eleven consecutive children with SCFE, seven boys and four girls, aged 10-15 years were included in the study. There were no preslips; four children had acute, three acute-on-chronic, and four chronic SCFE. The MRI examinations were performed in a 1.5 Tesla MR scanner with use of a coronal STIR sequence, a coronal contrast-enhanced T1-weighted spin-echo sequence, and a sagittal three-dimensional gradient-echo sequence. Morphology, signal intensities, and contrast-enhancement of the femoral head were assessed by two radiologists in consensus. Morphologic distortion of the physis, bone marrow edema within the metaphysis and epiphysis, and joint effusion were the preoperative MRI findings of SCFE in each child. In nine children, the vascularization of the femoral head before and after surgery was normal. In one child, a preoperative avascular zone in the superolateral aspect of the epiphysis revascularized completely after surgery. One child with severe SCFE developed avascular necrosis of the femoral head after open reduction of the slip. We conclude that MRI allows for accurate evaluation of the femoral head vascularization before and after surgery in children with SCFE.

[Ectopic ureter with urinary dribbling in childhood -- a diagnostic challenge: our own experience and review of the literature]. / Ureterektopie mit Harnträufeln im Kindesalter -- eine diagnostische Herausforderung : Eigene Erfahrungen und Literaturübersicht.

Based on the observations in four girls suffering from constant urinary dribbling we analyzed the special features and difficulties in making the diagnosis of an ectopic ureter. In all patients there was marked diagnostic delay. In one symptomatic case the abnormality was not detected before the age of 18 years. Failure to recognize the characteristic signs and symptoms played a crucial role in delaying the diagnosis. Moreover, imaging of ureteral ectopia represents a diagnostic challenge. The ectopic ureters were associated with dysplastic, poorly functioning renal moieties. Common diagnostic imaging procedures, such as ultrasound, intravenous pyelography, or voiding cystourethrography yielded incomplete diagnostic information and often failed to provide a definitive diagnosis. The latter could only be obtained with MR urography. We assessed the diagnostic value of the different examinations and compared our findings with those reported in the literature.

[Dose-reduced 16-slice multidetector-row spiral computed tomography in children with bronchoscopically suspected vascular tracheal stenosis -- initial results]. / Dosisreduzierte 16-Schicht-Multidetektor-Spiralcomputertomographie bei Säuglingen und Kleinkindern mit bronchoskopischem Verdacht auf vaskulär bedingte Trachealstenosen -- erste klinische Ergebnisse.

PURPOSE: To evaluate the diagnostic accuracy of contrast-enhanced dose-reduced 16-slice multidetector-row CT (MDCT) in newborns and infants with fiberoptic bronchoscopically suspected vascular-induced tracheal stenosis. MATERIALS AND METHODS: 12 children (4 days to 3 years, 1.2 - 13.5 kg body weight) were examined using i. v. contrast-enhanced 16-slice MDCT (SOMATOM Sensation 16, Forchheim, Germany) without breath-hold and under sedation (11/12). All MDCTs were performed with a dose reduction. The beam collimation was 16 x 0.75 mm, except in the case of one child. MPRs along the tracheal axis in the x-, y- and z-directions and volume-rendering-reconstructions (VRTs) were calculated based on a secondary raw data set in addition to conventional axial slices. 2 radiologists used a three-point grade scale to evaluate the image quality, motion, and contrast media artifacts as well as the usefulness of the 2D- and 3D-reconstructions for determining the diagnosis. Statistical analysis was performed on the basis of a Kappa test. RESULTS: In all cases the cause of the fiberoptic bronchoscopically suspected tracheal stenosis was revealed: compression due to the brachiocephalic trunk (n = 7), double aortic arch (n = 2), lusorian artery (n = 1), vascular compression of the left main bronchus (n = 2). In 3 patients further thoracic anomalies, such as tracheobronchial (n = 2), and vascular (n = 2) and vertebral (n = 1) anomalies were found. The attenuation in the anomalous vessels was 307 +/- 140 HU. The image noise was 9.8 +/- 1.9 HU. The mean dose reduction was 82.7 +/- 3.2 % compared to a standard adult thoracic CT. All examinations were rated as diagnostically good (median 1, range 1, k = 1). 3D images did not show any stair artifacts (median 2, range 1 - 2, k = 1). The image noise was minor to moderate and hardly any motion artifacts were seen (median 1, range 1 - 2, k = 0.8). Contrast media artifacts were rated zero to minor (median 1.5, range 1 - 2, k = 0.676). MPRs (median 1, range 1, k = 1) and VRTs (median 1, range 1, k = 1) were found to be useful for diagnosis. Subsequent vascular surgery was performed on 8 patients. CONCLUSION: Contrast-enhanced dose-reduced 16-slice MDCT is effective for demonstrating the cause of fiberoptic bronchoscopically suspected vascular-induced tracheal stenosis even in very small and severely ill children despite the small contrast media amount and free breathing.