123I-mIBG scintigraphy in neuroblastoma: development of a SIOPEN semi-quantitative reporting ,method by an international panel.

PURPOSE: A robust method is required to standardise objective reporting of diagnostic 123I-mIBG images in neuroblastoma. Prerequisites for an appropriate system are low inter- and intra-observer error and reproducibility across a broad disease spectrum. We present a new reporting method, developed and tested for SIOPEN by an international expert panel. METHOD: Patterns of abnormal skeletal 123I-mIBG uptake were defined and assigned numerical scores [0-6] based on disease extent within 12 body segments. Uptake intensity was excluded from the analysis. Data sets from 82 patients were scored independently by six experienced specialists as unblinded pairs (pre- and post-induction chemotherapy) and in random order as a blinded study. Response was defined as ≥50 % reduction in post induction score compared with baseline. RESULTS: In total, 1968 image sets were reviewed individually. Response rates of 88 % and 82 % were recorded for patients with baseline skeletal scores ≤23 and 24-48 respectively, compared with 44 % response in patients with skeletal scores >48 (p = 0.02). Reducing the number of segments or extension scale had a small but statistically negative impact upon the number of responses detected. Intraclass correlation coefficients [ICCs] calculated for the unblinded and blinded study were 0.95 at diagnosis and 0.98 and 0.99 post-induction chemotherapy, respectively. CONCLUSIONS: The SIOPEN mIBG score method is reproducible across the full spectrum of disease in high risk neuroblastoma. Numerical assessment of skeletal disease extent avoids subjective evaluation of uptake intensity. This robust approach provides a reliable means with which to examine the role of 123I mIBG scintigraphy as a prognostic indicator in neuroblastoma.

Hepatic involvement in congenital cytomegalovirus infection - infrequent yet significant.

Congenital cytomegalovirus (cCMV) infection can reside in many organ systems; however, the virus has a particular predilection towards inhabiting the reticuloendothelial system, especially the liver. Specific studies focusing only on hepatic involvement in infants with cCMV are lacking. We report our experience with a large cohort of infants treated in our hospital clinic due to cCMV and hepatic involvement. Hepatic involvement was defined either as hepatitis (elevated alanine transaminases (ALT) >80 units/L without cholestatic disease) or cholestatic disease (elevated ALT >80 units/L combined with direct bilirubin >2 mg/dL). During the study period, 198 infants were diagnosed with symptomatic cCMV in our clinic. Hepatic involvement was observed in 13 infants (6.6%); 7 (3.5%) with hepatitis and 6 (3%) with cholestatic disease. Maternal primary infection with cytomegalovirus during pregnancy was diagnosed in 7 (53.8%) of the 13 infants, nonprimary in 3 (23.1%) and unknown in 3 (23.1%). Among these 13 infants, central nervous system (CNS) involvement was observed in 11 (84.6%) and hearing impairment in 7 (53.8%). Treatment with an antiviral agent was initiated in all cases. Gradual improvement of hepatic enzymes and cholestasis was observed over a prolonged period. We found that the incidence of hepatic involvement in infants with cCMV is much less frequent than previously reported. The hepatic involvement in these infants may manifest in two different ways, and thus, a high index of suspicion and a stepwise approach will help in correctly diagnosing these infants. Antiviral treatment due to CNS involvement is warranted and prognosis is excellent.

Functional hyposplenism is an important and underdiagnosed immunodeficiency condition in children.

AIM: Few studies have focused on paediatric hyposplenism/asplenism, in which splenic phagocytic activity is diminished or absent in an anatomically present spleen. This study aimed to evaluate clinical findings, laboratory tests and prognosis of children with functional hyposplenism/asplenism. METHODS: The study group comprised 74 children who had liver/spleen technetium-99m sulphur colloid scintigraphy from 2002 to 2008. Information collected included demographic features, background diseases, blood smear findings, indications for scintigraphy and outcome. Children with functional hyposplenism were followed until 2012. RESULTS: We found that 34 patients had functional hyposplenism/asplenism. The main indications for scintigraphy in the hyposplenic patients were persistent thrombocytosis and recurrent infections. Associated conditions included immunodeficiencies, autoimmune diseases, malignancies and genetic disorders. Main infections were sinopulmonary infections, bacteraemia and sepsis. The major pathogens were Streptococcus pneumoniae and Haemophilus influenza group A. There was no correlation between the presence of Howell-Jolly bodies in blood smear with clinical disease severity or scintigraphic findings. Repeated scintigraphy showed spontaneous normalisation in 40% of patients. CONCLUSION: Functional hyposplenism is an important and underdiagnosed immunodeficiency condition in children, associated with various clinical conditions including prolonged unexplained thrombocytosis, immune deficiency and autoimmunity. Technetium-99m sulphur colloid scintigraphy is the method of choice for evaluating splenic function.

High prevalence of TSHR/Gsα mutation-negative clonal hot thyroid nodules (HNs) in a Turkish cohort.

Whereas the majority of hot thyroid nodules are caused by somatic TSH-receptor mutations, the percentage of TSH-receptor mutation negative clonal hot nodules (HN) and thus the percentage of hot nodules likely caused by other somatic mutations are still debated. This is especially the case for toxic multinodular goiter (TMNG). 35 HNs [12 solitary hot nodules (SHN), 23 TMNG] were screened for somatic TSHR mutations in the exons 9 and 10 and for Gsα mutations in the exons 7 and 8 using DGGE. Determination of X-chromosome inactivation was used for clonality analysis. Overall TSHR mutations were detected in 14 out of 35 (40%) HNs. A nonrandom X-chromosome inactivation pattern was detected in 18 out of 25 (72%) HNs suggesting a clonal origin. Of 15 TSHR or Gsα mutation negative cases 13 (86.6%) showed nonrandom X-chromosome inactivation, indicating clonal origin. The frequency of activating TSHR and/or Gsα mutations was higher in SHNs (9 of 12) than in TMNGs (6 of 23). There was no significant difference for the incidence of clonality for HNs between TMNGs or SHNs (p: 0.6396). Activating TSHR and/or Gsα mutations were more frequent in SHNs than in TMNG. However, the frequency of clonality is similar for SHN and TMNG and there is no significant difference for the presence or absence of TSHR and/or Gsα mutations of clonal or polyclonal HNs. The high percentage of clonal mutation-negative HNs in SHN and TMNG suggests alternative molecular aberrations leading to the development of TSHR mutation negative nodules.

Comparison of Color Flow Doppler Sonography (CFDS) and immunohistologic detection of microvessels for the assessment of the malignancy of thyroid nodules.

The assessment of tumor vascularization by color flow Doppler sonography (CFDS) has been suggested for the distinction between benign and malignant thyroid nodules. Our objective was to investigate if the CFDS results reflect the percentage of histologically determined microvessels in adenomas (As), adenomatous nodules (ANs), and papillary carcinomas (PCs). Tissue sections from 10 adenomas, 8 ANs and 13 PC and surrounding tissue of 10 PCs and 2 benign nodules were immunostained for CD34. A computerized image analysis was used to determine the microvessel density in four hot spots and ten systematically selected fields. Preoperatively CFDS was performed and classified according to Frates et al. We found a consistent percentage increase of CD34 stained microvessels in PCs (83 and 96%) as compared to adenomas and ANs (38 and 49%) determined by the hot spot analysis and systematic field analysis. A ROC analysis on the basis of the histologically determined number of microvessels demonstrated 70% microvessels as an optimal cut point for the diagnosis of PC with the highest sensitivity of 92% and highest specificity of 89%. The analysis of the CFDS-classification IV for the distinction between PCs and adenomas and ANs showed a sensitivity of 62% with a specificity of 100%. The lower sensitivity of the CFDS classification as compared with the immunohistologic determination of the microvessel density indicates that the CFDS classification detects the pathognomonic intranodular microvessels only incompletely. The higher CFDS specificity is most likely due to the detection of other vascular aspects of malignancy in addition to intranodular microvessels.

Increased percentage of microvessels but decreased density of large vessels in papillary carcinomas as compared to hot and cold thyroid nodules.

OBJECTIVE: For thyroid tumors increased as well as decreased vessel densities have been reported. Because of different morphometric methods and specificities of previously used antibodies for small and large vessels our objective was to investigate and compare the density of large vessels and microvessels by different morphometric methods and antibodies in hot nodules(HN), cold nodules (CN), papillary carcinoma (PC) and Graves' disease (GD) to try to clarify some of these discrepancies. DESIGN: Tissue sections from 29 HN, 22 CN, 19 PC and 8 GD thyroids were stained with the antibodies for CD34 and alpha-SMA. A computerized image analysis was used to calculate the mean area of endothelium (mEA) and the mean endothelium to tumor epithelial nucleus area ratio (mE/N) in four hot spots and ten systematically selected fields. MAIN OUTCOME: We found a consistent increase of the CD34 stained percentage of microvessels in PC as compared to HN and CN determined by the hot spot analysis and systematic field analysis. This increased microvessel density in PC is of a similar magnitude as in GD, which is characterised by a prominent increase of vascularisation during its active disease stage. Our SMA staining results reveal a kind of mirror image of the CD34 staining results with higher vessel counts in the normal surrounding tissues as compared to HN, CN and PC. CONCLUSIONS: The specific immunohistologic detection of microvessels with the CD34 antibody combined with their specific evaluation is able to clearly differentiate PCs from normal tissue, HN and CN.

Streptococcus acidominimus infection in a child causing Gradenigo syndrome.

UNLABELLED: Gradenigo syndrome is a rare presentation of acute petrositis. The clinical triad of Gradenigo syndrome consists of acute suppurative otitis media, severe unilateral headache and abducens nerve palsy. We report the first case of Gradenigo syndrome caused by Streptococcus acidominimus, a Gram-positive coccus of the Streptococcus viridans group, which rarely causes deep-seated infection in humans. CONCLUSION: Gradenigo syndrome may complicate acute otitis media and should be suspected in case of unilateral headache and abducens nerve palsy. Conservative medical treatment without surgery may be considered in some patients.

Radial osteomyelitis as a complication of venous cannulation.

Venepuncture of the superficial veins in the forearm is considered a relatively safe procedure. We report two patients who presented with osteomyelitis of the proximal radius following venous cannulation of the median cubital vein, and one patient who developed osteomyelitis of the distal radius after cannulation of the cephalic vein. Osteomyelitis developing in proximity to a venepuncture site should raise the suspicion that a pathogen causing superficial thrombophlebitis has spread through the deep veins of the arm into the adjacent bone, thus causing osteomyelitis.

Scintigraphic evaluation of calcinosis in juvenile dermatomyositis with Tc-99m MDP.

Two children with juvenile dermatomyositis and extensive, debilitating soft tissue calcifications are described. Whole-body bone scans with Tc-99m MDP were performed in both cases before and during specific treatment for the calcinosis. Baseline studies showed marked tracer localization in the soft tissues and provided an objective baseline assessment of the extent of the soft tissue calcifications. Follow-up studies showed gradual clearance of the extraskeletal uptake and were useful in monitoring the therapeutic response. These cases show that skeletal scintigraphy can function as a useful auxiliary tool to evaluate calcinosis in children with juvenile dermatomyositis.

The prognostic value of perfusion lung scintigraphy in patients who underwent single-lung transplantation for emphysema and pulmonary fibrosis.

UNLABELLED: The objective of this study was to evaluate the role of quantitative perfusion lung scintigraphy (QPLS) in predicting the development of chronic rejection in patients who underwent single-lung transplantation. METHODS: Eighteen patients (15 men, 3 women; age range, 41-60 y; mean age, 54.6+/-6.0 y) who underwent single-lung transplantation for emphysema (n = 14) or pulmonary fibrosis (n = 4) were studied. Patients were evaluated using QPLS and pulmonary function tests before surgery and at 1-3 mo and 1-3 y after transplantation. Relative perfusion of the transplanted lung was calculated from standard perfusion lung scintigrams. Values for forced expiratory volume in the first second (FEV1) were obtained from lung function tests at the same time points. The maximal and minimal relative perfusion and FEV1 values in the early (1-3 mo) and late (1-3 y) follow-up periods were identified for each patient. Receiver operating curve (ROC) analysis was performed on all parameters. RESULTS: In total, 82 lung scans were performed (mean, 4.8+/-1.55 per patient) and 484 FEV1 test determinations were obtained (mean, 30.0+/-15.6 per patient) during a follow-up period ranging from 8 to 84 mo (mean, 39.6+/-19.3 mo). In 7 of the 18 patients, chronic rejection developed, whereas 11 patients had a favorable outcome. No significant difference was found in the number of complications (acute rejection and infection episodes) between patients with a favorable outcome and patients with chronic rejection, up to 1 y after transplantation. At 1-3 mo, minimal relative perfusion values were 67.1%+/-12.2% in the favorable outcome group and 50.8%+/-9.6% in the chronic rejection group (P = 0.02). Before surgery and at 1-3 y, minimal relative perfusion was not significantly different between the 2 groups. The difference in maximal relative perfusion at 1-3 y was marginally significant, with 76.5%+/-8.9% in the favorable group and 64.3%+/-15.0% in the chronic rejection group (P = 0.051). FEV1 values were not significantly different preoperatively and 1-3 mo after surgery between the chronic rejection and the favorable outcome groups. Late in the follow-up period (1-3 y), FEV1 values in the chronic rejection and favorable outcome groups were 35.6%+/-7.9% and 56.9%+/-13.6%, respectively (P = 0.002). ROC analysis of minimal relative perfusion at 1-3 mo identified a threshold of 57% under which the sensitivity and specificity for chronic rejection were 83% and 88%, respectively. Minimal FEV1 for the same period identified a threshold of 48% under which the sensitivity and the specificity were 80% and 67%, respectively. CONCLUSION: QPLS early after transplantation in our patients predicted the development of chronic rejection in patients with single-lung transplantation for emphysema and pulmonary fibrosis, whereas surgical complications, acute rejection, infection episodes, and lung function tests did not predict the outcome. This early prediction could not be obtained from lung function tests performed at the same time.

Tc-99m MIBI to evaluate children with Ewing's sarcoma.

PURPOSE: Tc-99m MIBI has been used increasingly to evaluate benign and malignant tumors because of its tumor-seeking properties and ability to provide an imaging assessment of multiple-drug resistance. This study investigated the clinical utility of Tc-99m MIBI in the management of Ewing's sarcoma in children. METHODS: Thirteen Tc-99m MIBI studies in nine (six male, three female) patients ages 6.5 to 20 years (mean, 13.4 years) with Ewing's sarcoma were reviewed. All patients had imaging studies at diagnosis, and four had follow-up studies during or after therapy. Scintigraphy was evaluated for Tc-99m MIBI uptake within the tumor and in metastases, which other imaging modalities had shown to be present in four patients. Scintigraphic results were correlated with the clinical course in all patients and with tumor P-glycoprotein status in six patients. RESULTS: Tc-99m MIBI accumulated in 6 of 9 primary tumors and did not accumulate in one recurrent tumor. No metastases showed Tc-99m MIBI uptake. The presence or absence of Tc-99m MIBI uptake at diagnosis or after therapy carried no prognostic significance. Tc-99m MIBI was present in the two tumors that were P-glycoprotein positive and in only one of four tumors that were P-glycoprotein negative. CONCLUSION: Tc-99m MIBI imaging does not appear to be useful in Ewing's sarcoma.

Retinoic acid-receptor activation of SP-B gene transcription in respiratory epithelial cells.

Retinoids are known to play important roles in organ development of the lung. Retinoids exert their activity by modulating the expression of numerous genes, generally influencing gene transcription, in target cells. In the present work, the mechanism by which retinoic acid (RA) regulates surfactant protein (SP) B expression was assessed in vitro. RA (9-cis-RA) enhanced SP-B mRNA in pulmonary adenocarcinoma cells (H441 cells) and increased transcriptional activity of the SP-B promoter in both H441 and mouse lung epithelial cells (MLE-15). Cotransfection of H441 cells with retinoid nuclear receptor (RAR)-alpha, -beta, and -gamma and retinoid X receptor (RXR)-gamma further increased the response of the SP-B promoter to RA. Treatment of H441 cells with RA increased immunostaining for the SP-B proprotein and increased the number of cells in which the SP-B proprotein was detected. An RA responsive element mediating RA stimulation of the human SP-B promoter was identified. RAR-alpha and -gamma and RXR-alpha but not RAR-beta or RXR-beta and -gamma were detected by immunohistochemical analysis of H441 cells. RA, by activating RAR activity, stimulated the transcription and synthesis of SP-B in pulmonary adenocarcinoma cells.

Pediatric skeletal scintigraphy: applications of pinhole magnification.

Pinhole magnification scintigraphy is an effective means of evaluating the pediatric skeleton because it provides optimal high-resolution images. This technique is indicated when diagnostic uncertainty persists after high-resolution imaging with parallel hole collimation. Pinhole magnification scintigraphy requires approximately 20 minutes of acquisition time per image and meticulous attention to details such as choice of pinhole insert, collimator positioning, and patient immobilization. However, the technique is superior to planar imaging in demonstrating acute osteomyelitis in bone adjacent to growth centers and epiphyseal involvement that is either primary or the result of local spread of infection. In addition, pinhole imaging has proved highly reliable in the early diagnosis of Legg-Calvé-Perthes disease and is useful in depicting osteonecrosis related to specific causes such as corticosteroid treatment or trauma. Scintigraphic manifestations of femoral head ischemia or infarction and findings indicative of osteomyelitis associated with a hip effusion are well demonstrated with pinhole imaging. This technique also helps characterize osteoid osteomas and may be used intraoperatively to confirm the complete excision of this benign tumor. Finally, pinhole magnification scintigraphy clearly depicts fractures of the femoral neck and allows a high degree of confidence in diagnosing injuries to the small bones of the hands and feet.

Scintigraphy of lower extremity cadaveric bone allografts in osteosarcoma patients.

PURPOSE: To describe scintigraphic characteristics of bone allografts used in limb salvage reconstruction after resection of lower extremity osteosarcoma. MATERIALS AND METHODS: The authors reviewed 85 skeletal scintigrams of 20 pediatric patients followed up for 0.5-5.7 years after resection of lower extremity osteosarcoma and allograft reconstruction. Uptake in the allograft and adjacent host tissues was assessed visually. RESULTS: Lack of tracer uptake in the allografts was seen in 99% of the studies and a faint rim of tracer localization outlining the allograft's periphery was seen in 95% of the studies. Increased uptake was noted at the allograft-host bone junction in 78% of the studies. Uptake was increased in the joint surfaces of native bones articulating with allografts (97% of studies), including the patella (93% of studies) when the knee was involved. These findings were stabilized as time passed. CONCLUSION: Cadaveric bone allografts have a characteristic scintigraphic appearance in this selected patient group that reflects the physiology of their incorporation process.

Vesicoureteral reflux in children: incidence and severity in siblings.

PURPOSE: We attempted to determine the incidence of vesicoureteral reflux in asymptomatic siblings of children with reflux at different ages and assess the incidence of renal damage in asymptomatic siblings with reflux. MATERIALS AND METHODS: We reviewed radionuclide cystograms of 482 consecutively referred siblings of children with vesicoureteral reflux, including 295 girls and 187 boys 2 weeks to 12.8 years old (mean age 2.8 years). Ultrasonograms and renal cortical scintigrams of children with reflux were evaluated. All siblings were considered asymptomatic by the referring physicians. RESULTS: The overall incidence of vesicoureteral reflux was 36.5%, and the incidence in girls and boys was 39.3 and 32.1%, respectively. Children 24 months old or younger had the highest incidence (45.7%) and the highest risk of bilateral reflux. From ages 25 to 72 months the incidence of reflux was 33.1% and in siblings older than 72 months it was 7%. Reflux of urine to the level of the renal pelvis was detected in 28.6% of all referred siblings. Renal damage was observed on sonography or scintigraphy in 4.7% of the siblings with reflux. CONCLUSIONS: The high incidence of vesicoureteral reflux through age 72 months indicates that it is important to screen siblings of children with reflux at an early age to prevent renal damage, which can occur in the absence of symptomatic urinary tract infection.