Michael L. Ritchey

Surgery-related factors and local recurrence of Wilms tumor in National Wilms Tumor Study 4.

OBJECTIVE To assess the prognostic factors for local recurrence in Wilms tumor. SUMMARY BACKGROUND DATA Current therapy for Wilms tumor has evolved through four studies of the National Wilms Tumor Study Group. As adverse prognostic factors were identified, treatment of children with Wilms tumor has been tailored based on these factors. Two-year relapse-free survival of children in the fourth study (NWTS-4) exceeded 91%. Factors once of prognostic import for local recurrence may lose their significance as more effective therapeutic regimens are devised. METHODS Children evaluated were drawn from the records of NWTS-4. A total of 2482 randomized or followed patients were identified. Local recurrence, defined as recurrence in the original tumor bed, retroperitoneum, or within the abdominal cavity or pelvis, occurred in 100 children. Using a nested case-control study design, 182 matched controls were selected. Factors were analyzed for their association with local failure. Relative risks and 95% confidence intervals were calculated, taking into account the matching. RESULTS The largest relative risks for local recurrence were observed in patients with stage III disease, those with unfavorable histology (especially diffuse anaplasia), and those reported to have tumor spillage during surgery. Multiple regression analysis adjusting for the combined effects of histology, lymph node involvement, and age revealed that tumor spillage remained significant. The relative risk of local recurrence from spill was largest in children with stage II disease. The absence of lymph node biopsy was also associated with an increased relative risk of recurrence, which was largest in children with stage I disease. The survival of children after local recurrence is poor, with an average survival rate at 2 years after relapse of 43%. Survival was dependent on initial stage: those who received more therapy before relapse had a worse prognosis. CONCLUSIONS This study has demonstrated that surgical rupture of the tumor must be prevented by the surgeon, because spills produce an increased risk of local relapse. Both local and diffuse spills produce this risk. Stage II children with local spill appear to require more aggressive therapy than that used in NWTS-4. The continued critical importance of lymph node sampling in conjunction with nephrectomy for Wilms tumor is also established. Absence of lymph node biopsy may result in understaging and inadequate treatment of the child and may produce an increased risk of local recurrence.

Intravascular extension of Wilms tumor

ObjectiveTo define the incidence and manifestations of and optimal therapy for children with intravascular extension of Wilms tumor. MethodsChildren on a collaborative study of Wilms tumor who had intravascular extension into the inferior vena cava (IVC) or atrium were identified. Surgical checklists and surgical and pathology reports were reviewed. ResultsOne hundred sixty-five of 2,731 patients had intravascular extension of Wilms tumor. The level of extension was IVC in 134 and atrium in 31. Sixty-nine had received preoperative therapy (55 with IVC extension and 14 with atrial extension) for a median of 8 weeks. Complications during preoperative chemotherapy were seen in five patients (tumor embolism and tumor progression in one each, and three with adult respiratory distress syndrome, one of which was fatal). The intravascular extension of the tumor regressed in 39 of 49 children with comparable pre- and posttherapy radiographic studies, including 7 of 12 in whom the tumor regressed from an atrial location, thus obviating the need for cardiopulmonary bypass. Surgical complications occurred in 36.7% of the children in the atrial group and 17.2% in the IVC group. The frequency of surgical complications was 26% in the primary resection group versus 13.2% in children with preoperative therapy. When all the complications of therapy were considered, including those that occurred during the interval of preoperative chemotherapy (one of the five also had a surgical complication), the incidence of complications among those receiving preoperative therapy was not statistically different from the incidence among those who underwent primary resection. The difference in 3-year relapse-free survival (76.9% for 165 patients with intravascular extension, 80.3% for 1,622 patients with no extension) was not statistically significant whether or not it was adjusted for stage and histology. ConclusionsPreoperative treatment of these children may facilitate resection by decreasing the extent of the tumor thrombus, but the overall frequency of complications is similar in both groups.

Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D: A report from the National Wilms Tumor Study Group

NWTS‐5 was a multi‐institutional clinical trial for patients less than 16 years of age at diagnosis with specific renal neoplasms who were diagnosed between August 1, 1995 and May 31, 2002. A uniform approach to the treatment of patients with relapse was employed.

Advantages of rectus fascial slings for urinary incontinence in children with neuropathic bladders.

PURPOSE Many surgical procedures to improve outlet resistance in children with neuropathic bladders are obstructive and increase the detrusor leak point pressure. In contrast, fascial slings are designed to achieve continence by increasing the Valsalva or stress leak point pressure without altering the detrusor leak point pressure. We evaluate the effectiveness of fascial slings in achieving continence in pediatric patients with neuropathic bladder. MATERIALS AND METHODS From October 1994 until February 1999, 10 females and 8 males with neuropathic bladder secondary to myelodysplasia or traumatic spinal cord injury underwent fascial sling procedures. Mean patient age was 14 years (range 8 to 18) and all were incontinent despite aggressive medical management. Urodynamic evaluation was performed preoperatively and postoperatively. Specific urodynamic measurements included detrusor leak point pressure, stress leak point pressure and detrusor compliance. Compliance was only compared in the 12 nonaugmented cases. RESULTS With a mean followup of 21.2 months (range 6 to 57), preoperative and postoperative urodynamics revealed little change in mean detrusor leak point pressure (23.2 versus 23.22 cm. H2O) but a substantial increase in mean stress leak point pressure (41.6 versus 64.5 cm. H2O). Mean compliance was unchanged in the nonaugmented group (22.00 versus 26.78 ml/cm. H2O). Four patients (22.22%) remained wet after surgery, of whom 2 were successfully treated with a repeat sling procedure and 1 with collagen injection for an overall continence rate of 94.44%. CONCLUSIONS Fascial slings can be effectively used in pediatric patients for neuropathic incontinence. Furthermore, stress urinary incontinence is corrected by increasing the Valsalva or stress leak point pressure with preservation of the detrusor leak point pressure. Preservation of detrusor leak point pressure is particularly advantageous because other forms of bladder outlet procedures achieve continence at the expense of increasing detrusor pressures, thus placing the upper tracts at risk for damage.

Decreased Bladder Compliance in Patients With Myelomeningocele Treated With Radiological Observation

PURPOSE Recently others advocated frequent radiological surveillance to detect upper urinary tract deterioration in children with neurogenic bladder secondary to spina bifida. We reviewed the consequences of such expectant management on bladder compliance and urinary continence. MATERIALS AND METHODS We retrospectively reviewed the records of 214 children presenting to our spina bifida clinic in a 13-year period. Follow-up is available for 95 girls and 86 boys. Imaging studies of the kidneys were repeated at 6 to 12-month intervals. Urodynamics were performed when upper urinary tracts deteriorated or in incontinent school age children. RESULTS On radiographic study there was evidence of upper urinary tract deterioration in 79 children, including hydronephrosis in 34, hydronephrosis and vesicoureteral reflux in 19, and reflux only in 26. Follow up studies performed after clean intermittent catheterization and pharmacological therapy were instituted revealed resolution or improvement of upper tract deterioration in 52 patients (69%), while bladder compliance improved in only 42%. Surgical intervention was required in 34 children, despite improvement of upper tract changes in many of these patients on follow up radiographic studies. CONCLUSIONS Although radiological surveillance of patients with myelomeningocele allows recognition of upper tract changes, the effects of elevated outlet resistance on bladder compliance are not as readily reversible as the initial radiographic findings. The incidence of enterocystoplasty exceeds that reported for patients treated prospectively based on urodynamic findings, which should be considered in the treatment of these children.

HIGH FLOW PRIAPISM ASSOCIATED WITH SICKLE CELL DISEASE

Priapism associated with sickle cell disease is classically described as a low flow state. We report 2 cases of high flow priapism associated with sickle cell disease. High flow priapism has previously been reported almost exclusively in patients with traumatic rupture of the cavernous artery. Neither of our patients had historical or radiographic findings consistent with injury to the penile vasculature. One patient was treated unsuccessfully with intracorporeal injection of methylene blue and 1 underwent successfully bilateral pudendal artery embolization. The pathophysiological mechanism(s) responsible for the production of high flow priapism in patients with sickle cell disease is not known.

Management and outcome of inoperable Wilms tumor. A report of National Wilms Tumor Study-3.

MethodsThe authors reviewed 131 children enrolled in National Wilms Tumor Study-3 (NWTS-3) who received preoperative treatment for tumors unable to be resected at surgery or judged inoperable by imaging evaluation. Preoperative biopsies were performed on 103 patients. Patients were assigned a pretreatment stage: stage II (11 patients), stage III (39 patients), stage IV (66 patients), and unknown (15 patients). The chemotherapy regimen included dactinomycin and vincristine (81 patients), dactinomycin, vincristine, and doxorubicin (30 patients), dactinomycin, vincristine, doxorubicin, and cyclophosphamide (10 patients), and other (8 patients). Preoperative radiation therapy was started concurrently with chemotherapy (27 patients) or because of lack of response (14 patients). Two patients were given preoperative irradiation without chemotherapy. ResultsResponse to therapy was assessed after the first trial of chemotherapy. Partial responses were noted in 110 patients (85%), 3 had complete responses, 13 had no response or progression of disease, and 5 patients were not able to be evaluated. There were no significant differences in preoperative response to the different chemotherapy regimens. Median time interval from diagnosis to nephrectomy was 58.5 days. When compared with NWTS-3 patients not receiving preoperative treatment, survival was reduced for patients treated preoperatively (88% vs. 74%, respectively, 4-year survival), which was only partially explained by differences in stage distribution. Median duration of follow-up was 5.9 years. Lack of response to the preoperative treatment was associated with a poor prognosis. Eight children died before removal of the primary tumor. All eight had either progressive disease or no response to the preoperative treatment. ConclusionsThe use of preoperative treatment can facilitate subsequent surgical resection in selected patients with inoperable Wilms tumors. Although these very large tumors—judged unable to be resected—have a somewhat worse prognosis, nephrectomy was completed in 93% of patients after preoperative treatment. However, preoperative treatment wil lead to less accurate surgical and pathologic staging, and undertreatment should be avoided in these high-risk patients.

CURRENT CONCEPTS IN THE BIOLOGY AND MANAGEMENT OF WILMS TUMOR

PURPOSE There have been a number of advances that have increased our understanding of the biology of Wilms tumor during the last decade. This information is now being incorporated into current pediatric oncology protocols. We present a summary of these advances and outline the current treatment of Wilms tumor. MATERIALS AND METHODS The medical literature was reviewed with an emphasis on the molecular biology of Wilms tumor. RESULTS The development of Wilms tumor involves several genes, including WT1, the Wilms tumor suppressor gene at 11p13. In addition, certain chromosomal regions (16q and 1p) might be used as prognostic factors for determining the intensity of therapy. CONCLUSIONS Future protocols conducted by pediatric oncology groups will incorporate biological studies. The goal is to identify patients at low risk for relapse which will allow a reduction in treatment intensity and subsequent toxicity. Children at an increased risk for relapse can be selected for more intensive treatment.

Clinicopathologic Findings Predictive of Relapse in Children With Stage III Favorable-Histology Wilms Tumor

PURPOSE Stage III designation in NWTS-5 (National Wilms Tumor Study-5) was determined by four pathologic criteria: positive lymph nodes (LNs), peritoneal implants, residual disease, and tumor rupture. The objective of this study was to determine the prognostic significance of each of the stage III criteria. PATIENTS AND METHODS Children with stage III Wilms tumor (WT) treated in NWTS-5 were assessed for event-free (EFS) and overall survival (OS). Sites of relapse and molecular status of tumors are reported. EFS and OS are reported 8 years after diagnosis. RESULTS There were 569 patients with local stage III favorable-histology (FH) WT in this analysis, of whom 109 had overall stage IV disease. LN involvement alone was the most frequent criterion for stage III designation (38%), followed by microscopic residual disease alone (20%), microscopic residual disease and LN involvement (14%), and spill or soilage alone (9%). The 8-year EFS and OS estimates for all patients with local stage III FHWT were 82% and 91%, respectively. Multivariate analysis demonstrated that both LN involvement (relative risk, 1.89; P = .005) and microscopic residual disease (relative risk, 1.87; P = .007) were predictive of EFS, and OS results were similar. There was no apparent difference in pattern of relapse according to stage III subtype. The rate of loss of heterozygosity was higher (6%) for those with positive LNs than for those without (2%; P = .05). CONCLUSION LN involvement and microscopic residual are the stage III criteria highly predictive of EFS and OS for patients with stage III FHWT. It is possible that in future studies, patients with different stage III criteria may receive different therapies.

Ring block for neonatal circumcision.

Objective To determine whether a difference in the behavioral and physiologic response to circumcision can be demonstrated between neonates undergoing the procedure with ring block and those receiving no anesthesia. Methods Forty healthy male newborns were assigned randomly to receive either ring block or no anesthesia. Indices of perceived pain including crying time, behavioral state, oxygen saturation, and heart and respiratory rates were recorded at baseline and at intervals during the circumcision. Infants were reassessed 2 minutes and 2 hours postoperatively. Results Infants receiving ring block cried less than did controls (P < .001). Anesthetized infants had smaller increases in heart rate (P < .005) and demonstrated less arousal (P < .005) during each operative interval. For all operative intervals combined, anesthetized infants had a smaller decrease in oxygen saturation (P < .001) and a smaller increase in respiratory rate (P = .005) than did controls. Two minutes postoperatively, anesthetized infants had returned to their baseline behavioral state, whereas controls remained significantly more aroused (P < .005). Two hours postoperatively, there were no significant differences in any variables between the groups, nor between each group and its baseline. There were no complications related to anesthesia administration. Conclusion Neonatal circumcision causes behavioral and physiologic changes consistent with the perception of pain. Ring block is an effective method of anesthesia for this procedure.