Chromogranin A and neuron-specific enolase in neuroblastoma: Correlation to stage and prognostic factors.

Chromogranin A (CgA) and neuron specific enolase (NSE) are important markers in adult neuroendocrine tumors (NET). Neuroblastoma (NB) has certain neuroendocrine properties. The aim of this study was to correlate blood concentrations of CgA, chromogranin B (CgB), and NSE to prognostic factors and outcome in children with NB. Blood samples from 92 patients with NB, 12 patients with benign ganglioneuroma (GN), 21 patients with non-NB solid tumors, 10 patients with acute leukemias, and 69 healthy children, were analyzed. CgA concentrations were higher in neonates vs. children older than one month in the control group (p < 0.0001), and in neonates with NB vs. the control group (p < 0.01). CgA and NSE concentrations were higher in patients with stages 3 and 4 disease (p < 0.05 and p < 0.05), in patients having tumors with amplification of MYCN (p < 0.05 and p < 0.001), or chromosome 1 p deletion (p < 0.05 and p < 0.05). NSE correlated to the tumor size at diagnosis (p < 0.001) and to tumor related death (p < 0.01) in NB. CgA and NSE concentrations were elevated in patients with NB and especially in those with advanced disease. Both CgA and NSE correlated to genetic markers, while only NSE correlated to primary tumor size and outcome in NB. We found that CgA and NSE are clinically valuable tumor markers in NB and they merit prospective clinical evaluations as such.

Challenges in the local treatment of large abdominal embryonal rhabdomyosarcoma.

BACKGROUND: Embryonal rhabdomyosarcoma is the most common pediatric soft tissue sarcoma. The best local treatment in large, nonmetastatic primary unresected nongenitourinary embryonal rhabdomyosarcoma of the abdomen (LARME) is however unclear. METHODS: We analyzed patients with LARME treated in four consecutive CWS trials. All diagnoses were confirmed by reference reviews. Treatment included multiagent chemotherapy and local treatment of the primary tumor with surgery and/or radiotherapy. The impact of primary debulking surgery (PDS) also was studied. RESULTS: One hundred patients <21 years with a median age of 4 years had LARME. Sixty-one of them had a tumor >10 cm in diameter at diagnosis. PDS was performed in 19 of 100 children. The outcomes of patients with PDS were similar to those of the other patients. In 36 children, the tumor was resected after induction chemotherapy; 60 RME were irradiated. The toxic effects of radiochemotherapy were not significantly increased compared with the nonirradiated patients. With a median follow-up of 10 years, the 5-year EFS and OS were 52 ± 10 and 65 ± 9 %, respectively. Significant risk factors in multivariate analysis were age >10 years; no achievement of complete remission; and inadequate secondary local treatment, defined as incomplete secondary resection or no radiation. CONCLUSIONS: Children with LARME have a fair prognosis, despite an often huge tumor size and unfavorable primary site, if the tumors can either be resected or irradiated following induction chemotherapy. PDS was only performed in a small subgroup. Radiation performed concomitantly with chemotherapy did not increase the acute toxicity significantly.

Proprietary non-animal stabilized hyaluronic acid/dextranomer gel (NASHA/Dx) for endoscopic treatment of grade IV vesicoureteral reflux: Long-term observational study.

BACKGROUND: Since 1993, children aged >1 year with persistent grade III-V vesicoureteral reflux (VUR) and febrile urinary tract infections (UTIs) attending Uppsala University Hospital have undergone endoscopic injection with proprietary non-animal stabilized hyaluronic acid/dextranomer gel (NASHA/Dx; Deflux®). OBJECTIVE: Investigate long-term incidence of UTI, bladder dysfunction, ureteral reimplantation and overall clinical findings following endoscopic injection of NASHA/Dx. STUDY DESIGN: Children with grade IV VUR diagnosed by voiding cystourethrogram (VCUG) and dilating VUR persisting for >1 year were included in this study. 15-25 years after endoscopic treatment, patients' hospital charts were studied. Information on bladder function and UTIs was obtained via questionnaire, 8-18 years after endoscopic treatment. RESULTS: 185 patients (69 boys, 116 girls) were included in the study; 237 grade IV VUR ureters were treated. All study patients were diagnosed with VUR after a febrile UTI (i.e. pyelonephritis). According to the last voiding cystourethrogram, 69% of ureters showed a positive response (VUR grade 0-I), 7% had VUR grade II and 23% had VUR grade ≥ III. 46 patients (25%) required ureteral reimplantation during follow-up. Among patients treated during the second 5-year period compared with the first (1998-2003 versus 1993-1998), there was a significant decrease in the rate of ureteral reimplantation (31% vs 16%; p = 0.0365). This difference may be attributable to developments over time in the injection technique. UTIs occurred in 30 patients (21% of the evaluable population): 28 females and 2 males. Febrile UTIs were reported in 14 patients (10%), all females. Forty-nine patients (34%) had bladder problems (e.g. underactivity, overactivity, incontinence). Five patients underwent ureteral reimplantation 'late', 6-10 years after the last endoscopic injection. In one male patient, calcification around the NASHA/Dx implantation site was observed during routine examination 2 years after endoscopic treatment; no intervention was required. No safety issues were observed in the remaining 97% of the study population. CONCLUSIONS: This study represents the longest published follow-up of Grade IV VUR patients undergoing endoscopic treatment. Three-quarters of patients did not need ureteral reimplantation. Optimal injection technique and higher injection volume were associated with a reduced ureteral reimplantation rate. Treatment with NASHA/Dx was durable and well tolerated: long-term risks of UTI, bladder dysfunction and recurrent VUR were low.

Diagnostic ultrasound-guided cutting needle biopsies in neuroblastoma: A safe and efficient procedure.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor of childhood and accounts for 15% of deaths in pediatric oncology. Apart from the clinical stage at diagnosis, molecular factors are important for the characterization of the tumor and for decision on adequate treatment. Pretreatment diagnosis and molecular profiling are based on analysis of a tumor sample, obtained either by fine needle aspiration cytology (FNAC), cutting needle biopsy or open surgical biopsy. The method used depends on local tradition and routines. Ultrasound-guided cutting needle biopsy (UCNB) has been used at the Uppsala University Hospital since 1988 for diagnosis of pediatric solid tumors. PROCEDURES: Medical records of 29 patients with NB who underwent pretreatment, diagnostic, ultrasound-guided needle biopsy were reviewed. Information extracted from the patients' records included: age at diagnosis, gender, tumor site, clinical stage, molecular profiling made on biopsies (e.g. MYCN status, ploidy and chromosomal aberrations), and UCNB complications (i.e. bleeding, pain, or anesthesiologic complications). RESULTS: A total of 34 UCNBs were performed in the 29 patients. Repeated biopsies were done in three patients. UCNB was diagnostic in 90% (26/29). A complete molecular profiling was obtained in all UCNBs after 2008. Two patients (7%) developed a significant bleeding and two (7%) needed analgesics following UCNB. Neither infection nor tumor growth in the needle tract was observed. There were no anesthesiologic complications. CONCLUSIONS: UCNB is reasonably safe in patients with NB and usually gives a sufficient amount of tumor tissue for a histological diagnosis, molecular profiling, and biobank storage.

The angiogenic growth factors HGF and VEGF in serum and plasma from neuroblastoma patients.

AIM: To determine whether concentrations of the angiogenic growth factors hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGF-A) correlate with clinical and genetic markers in samples taken at diagnosis in children with neuroblastoma (NB). PATIENTS AND METHODS: Heparin plasma (P-) and serum (S-) samples of healthy controls (n=73, mean age +/- SD 3.5+/-2.1; females/males: 23/50) and patients with NB (n=62; 2.2+/-1.8; 26/36) were collected between 1988 and 1999. Clinical data included age at diagnosis, gender, stage, outcome, amplification of the oncogene MYCN, loss of heterozygosity at the short arm of chromosome 1 (1p LOH) and ploidy. RESULTS: HGF and S-VEGF-A were elevated in NB as compared to controls (38/62 patients, p<0.0001 and p<0.05, Mann-Whitney U test). HGF concentrations were higher in high-stage (stage 3-4) as compared to low-stage (stage 1-2) disease (p<0.01). P-HGF was elevated in patients with 1p LOH (p<0.01), MYCN amplification (p<0.001) and di- or tetraploidy (p<0.001). S-HGF concentration was elevated in patients MYCN-amplified tumors only. Plasma and S-HGF concentrations were higher in the deceased group (p<0.05), but not P or S-VEGF-A. CONCLUSION: This study showed that concentrations of HGF and S-VEGF-A are elevated in patients with NB. Furthermore, HGF and S-VEGF-A concentrations correlate to higher stage disease and HGF correlates to genetic markers known to indicate a poor outcome. These observations imply that HGF and VEGF-A have biological roles in NB and suggest the possibility of interference with HGF or VEGF-A signaling as a therapeutic strategy.

Endoscopic treatment with stabilized nonanimal hyaluronic acid/dextranomer gel is effective in vesicoureteral reflux associated with bladder dysfunction.

PURPOSE: Endoscopic injection of stabilized nonanimal hyaluronic acid/dextranomer gel is an established treatment for vesicoureteral reflux in children. We performed a subgroup analysis to assess this treatment in reflux associated with bladder dysfunction. MATERIALS AND METHODS: Of 308 consecutive children treated endoscopically with stabilized nonanimal hyaluronic acid/dextranomer gel for dilating vesicoureteral reflux 54 were observed retrospectively to have bladder dysfunction. Initial followup consisted of voiding cystourethrogram at 3 and 12 months after injection, with positive response defined as reflux grade 0 or I. At 7 to 12 years following treatment patient charts were checked for urinary tract infections and bladder dysfunction, and a followup survey (postal questionnaire) was administered. RESULTS: A positive response to therapy (cure) was observed in 45 children (83%) after 1 to 3 endoscopic treatments. Concurrently, bladder dysfunction had resolved in 32 patients (59%). After the last stabilized nonanimal hyaluronic acid/dextranomer gel implantation 45 patients (83%) were free of urinary tract infections. Questionnaire results were similar to chart based findings. Stabilized nonanimal hyaluronic acid/dextranomer gel implantation was well tolerated, with no associated complications. CONCLUSIONS: Endoscopic treatment with stabilized nonanimal hyaluronic acid/dextranomer gel appears to be similarly effective in patients with vesicoureteral reflux with and without bladder dysfunction. These data indicate that bladder dysfunction should not be considered a contraindication to endoscopic treatment for reflux.

Endoscopic treatment of vesicoureteral reflux with dextranomer/hyaluronic acid copolymer is effective in either double ureters or a small kidney.

PURPOSE: Endoscopic injection of dextranomer/hyaluronic acid (Dx/HA) copolymer is an increasingly established treatment for primary vesicoureteral reflux (VUR) in children. We performed a retrospective analysis to assess this treatment for VUR associated with either double ureters or a small kidney. MATERIALS AND METHODS: The study included 68 children with duplex ureters and 40 with a small kidney (1 kidney contributing 10% to 35% of total renal function) who underwent endoscopic treatment with Dx/HA copolymer for VUR. Followup consisted of voiding cystourethrography 3 and 12 months after injection. Positive response was defined as reflux grade 0 or I. As many as 2 repeat injections were offered to nonresponders, and those with persistent reflux were referred for open surgery. Long-term clinical followup with renal function testing was continued for 4 to 9 years. RESULTS: A positive response was observed in 63% of children with duplex ureters, with only 17 (25%) patients requiring open surgery. Among children with a small kidney the response rate was 70%, and open surgery was performed in 9 (23%). In both treatment groups a positive response to treatment was sustained throughout the followup period in all cases. The treatment was well tolerated, with no complications associated with the procedure. CONCLUSIONS: Endoscopic treatment with Dx/HA copolymer appears to be an effective and well tolerated alternative to open surgery for first line treatment of VUR associated with double ureters or a small kidney.

Diagnosing childhood tumors: A review of 147 cutting needle biopsies in 110 children.

BACKGROUND/PURPOSE: The aims of this study were to evaluate the diagnostic accuracy and safety of cutting needle biopsy for diagnosis in children with tumors suspected for malignancy. METHODS: Medical records and biopsy slides recorded from 1988 to 1999 were reviewed. One hundred ten patients had undergone a total of 147 cutting needle biopsies. The biopsy was performed under ultrasound guidance, using a 1.2-mm (18 gauge) Biopsy-cut biopsy needle. The diagnoses were benign tumors (n = 8), malignant tumors (n = 84), and nonneoplastic diseases (n = 18), with repeat biopsy performed in 24 patients. RESULTS: The diagnostic accuracy of cutting needle biopsies was 89% (131 of 147). The accuracy for pretreatment diagnosis was 88% (102 of 116), and for confirming or excluding a recurrence or metastasis 93% (26 of 28). The sensitivity of this method was 82% (86 of 105), and the positive predictive value 99% (86 of 87). Nondiagnostic cutting needle biopsy (n = 16) was not related to the age of the patient, experience of the radiologist, number of needle insertions, or site of puncture. No patient exhibited tumor growth along the needle tract. Complications occurred in 10 cases (7%) and pain in 20 (14%). CONCLUSION: Cutting needle biopsy is an accurate and safe procedure with a low learning threshold that is recommended for diagnosing malignancies in childhood.