Lessons learned from a failed multi-institutional randomized controlled study.

BACKGROUND/PURPOSE: In 1996, the Surgical Sections of the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) received National Cancer Institute funding to conduct a prospective, randomized, controlled, surgeon-directed study to evaluate the role of minimally invasive surgery (MIS) in children with cancer. Because of lack of patient accrual, the study was closed in 1998. The purpose of this study is to evaluate and describe those factors that impacted on study failure to ensure future successful clinical trials. METHODS: One hundred forty surgeons representing the surgical membership of CCG and POG as well as 111 institutions within CCG and POG were asked to complete a questionnaire about the failed clinical trial. The questionnaire focused on study objectives, organization, and institutional review board (IRB) submission. It also examined the surgeon's ability to perform the minimal access operation, the influence of the pediatric oncologist, and the existence of preconceived biases by surgeons, oncologists, and families. Statistical analysis was performed as appropriate. RESULTS: Eighty-six of 140 (62%) surgeons responded to the questionnaire. Only 23% of the potential protocols were submitted for IRB approval. Of responding surgeons, 39% were not actively performing MIS when the study opened. A surgeon's support of the study was directly related to when the surgeon received the protocols (P <.001) and whether the participating surgeon was actively participating in MIS (P <.016). The oncologist's knowledge and support of the study affected IRB submission and approval (P <.02) and was influenced by whether MIS was practiced at the institution (P <.05). The majority of responding surgeons believed the experimental question was relevant (P <.05). However, responding surgeons believed that a preconceived bias existed within both their local surgical and oncology communities favoring a particular surgical approach (P <.001), but this bias did not extend to the families (P >.05). CONCLUSION: The study failed because of lack of accrual for a variety of reasons: failure to submit to the institution's IRB, lack of surgical expertise with MIS procedures, and preconceived surgeon bias toward either an endoscopic or traditional open approach.

Childhood cancer: patterns of protocol participation in a national survey.

Cancer is still the chief cause of death by disease in children, ages one to 14. As improved survival rates have been reported for pediatric cancer patients who are treated on controlled clinical trials, it is important to understand the national utilization of such protocols. In 1993, a survey of childhood cancer was conducted by the Commission on Cancer of the American College of Surgeons. Data regarding type of disease, protocol participation, age, sex, race, insurance, and geographical region were voluntarily submitted by more than 200 hospital cancer registries. Included in this study were 2,208 children and adolescents 21 years of age or younger who were diagnosed in 1987, and 2,293 who were diagnosed in 1992. Pediatric centers (i.e., members of the Pediatric Oncology Group or Children's Cancer Group) submitted 55.1% of the cases and other institutions, 44.9%. It was found that more patients treated at pediatric centers were on protocols (53.8%) than were those treated at other institutions (25.1%). In general, the younger the patient (five years of age or younger), the greater the chance of being on protocol (pediatric centers, 63.7%; others, 42.0%), with very poor adolescent protocol participation (pediatric centers, 34.8%; others, 12.1%). Nevertheless, overall protocol participation was still lower than expected, even in children younger than five years of age, and adolescent participation in controlled clinical trials was low and similar to adult figures. The percentage of childhood cancer cases seen at pediatric centers was smaller than in other series. It was concluded that pediatric cancer centers need to continue to encourage patient participation in controlled clinical trials, with special emphasis on adolescents.

Treatment with nephrectomy only for small, stage I/favorable histology Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: Children younger than 24 months with small (< 550 g), favorable histology (FH) Wilms tumors (WTs) were shown in a pilot study to have an excellent prognosis when treated with nephrectomy only. PATIENTS AND METHODS: A study of nephrectomy only for the treatment of selected children with FH WT was undertaken. Stringent stopping rules were designed to insure closure of the study if the true 2-year relapse-free survival rate was 90% or lower. RESULTS: Seventy-five previously untreated children younger than 24 months with stage I/FH WTs for which the surgical specimen weighed less than 550 g were treated with nephrectomy only. Three patients developed metachronous, contralateral WT 1.1, 1.4, and 2.3 years after nephrectomy, and eight patients relapsed 0.3 to 1.05 years after diagnosis (median, 0.4 years; mean, 0.51 years). The sites of relapse were lung (n = 5) and operative bed (n = 3). The 2-year disease-free (relapse and metachronous contralateral WT) survival rate was 86.5%. The 2-year survival rate is 100% with a median follow-up of 2.84 years. The 2-year disease-free survival rate (excluding metachronous contralateral WT) was 89.2%, and the 2-year cumulative risk of metachronous contralateral WT was 3.1%. CONCLUSION: Children younger than 24 months treated with nephrectomy only for a stage I/FH WT that weighed less than 550 g had a risk of relapse, including the development of metachronous contralateral WT, of 13.5% 2 years after diagnosis. All patients who experienced relapse on this trial are alive at this time. This approach will be re-evaluated in a clinical trial using a less conservative stopping rule.

Intravascular extension of Wilms tumor.

OBJECTIVE: To define the incidence and manifestations of and optimal therapy for children with intravascular extension of Wilms tumor. METHODS: Children 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. RESULTS: One 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. CONCLUSIONS: Preoperative 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.

Differentiated thyroid cancer: clinical characteristics, treatment, and outcome in patients under 21 years of age who present with distant metastases. A report from the Surgical Discipline Committee of the Children's Cancer Group.

BACKGROUND/PURPOSE: Young patients with differentiated thyroid cancer typically present with regional lymph node involvement (60% to 80%), and 10% to 20% have distant metastases. This study characterizes the clinical presentation, treatment, and outcome in patients with differentiated thyroid cancer who were less than 21 years of age at diagnosis and who presented with distant parenchymal metastases. METHODS: A retrospective, multi-institutional data base that included 327 patients in this age group with differentiated thyroid carcinoma was searched for patients who presented with distant metastases, and 83 cases (25%) were found. The median time to first disease progression was 2.4 years (range, 0.1 to 12.4 years) and the overall median follow-up was 10.9 years (range, 1.0 to 42.1 years). RESULTS: The median age at diagnosis was 14.6 years (range, 6.6 to 20.8 years); 69% were girls and 92% were white. In 12%, there was a history of prior head and neck irradiation, and 10% of these patients had a family history of carcinoma. Preoperative needle biopsies were performed in 25%. Regional lymph nodes were positive in 90%, and extrathyroidal extension occurred in 48%. The site of distant metastases included the lungs in all patients. Total thyroidectomy, subtotal thyroidectomy, lobectomy, and nodule excision was done in 66%, 24%, 3%, and 8% of patients, respectively. There was no residual cervical disease after surgery in 75%, whereas 14% had microscopic and 11% had gross residual. Histopathologic subtypes included papillary-follicular (48%), papillary (42%), and follicular (10%). The median tumor size was 3.0 cm (range, 0.4 to 11.0 cm). In this group, 100% of patients received adjuvant iodine 131I therapy, and the overall survival rate at 10 years was 100%. The progression-free survival rate was 76% at 5 years and 66% at 10 years from diagnosis. CONCLUSIONS: A significant number of young patients with thyroid cancer present with distant metastases and will require radioiodine therapy. This should be considered when planning the surgical approach because total or subtotal thyroidectomy facilitates 131I imaging and treatment. Although about one third of these patients will experience relapse or disease progression, the overall mortality rate is low.

Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective Children's Cancer Group study.

PURPOSE: A prospective Children's Cancer Group study, CCG-3881, has been completed to determine if a more accurate prediction of prognosis by biologic features can identify subgroups of infants with stage IV neuroblastoma (NBL) who require differing intensities of treatment. PATIENTS AND METHODS: One hundred thirty-four infants were registered from June 1989 to August 1995, with a median follow-up of 47.1 months (range, 0 to 88 months). The biologic factors examined were tumor MYCN copy number, Shimada histopathologic classification, serum ferritin, and bone marrow immunocytology (sensitivity, one tumor cell per 10(5) bone marrow cells). Patients treated on CCG-3881 (n = 116) received four-drug chemotherapy for 9 months (cisplatin, cyclophosphamide, doxorubicin, and etoposide), with surgery and local radiation to residual disease. After January 1991, all subsequent infants with tumor MYCN amplification (n = 18) were transferred after one cycle of therapy to the high-risk CCG-3891 protocol (open January 1991 to April 1996) for more intensive treatment. RESULTS: The 3-year event-free survival (EFS) and overall survival (mean +/- SD) for the 134 infants were 63% +/- 5% and 71% +/- 5%, respectively. Patients whose tumors were without MYCN amplification had a 93% +/- 4% 3-year EFS, whereas those with amplified MYCN had a 10% +/- 7% 3-year EFS (P <. 0001). Each of the other biologic features studied had prognostic significance in univariate analysis but not after stratifying by MYCN copy number. CONCLUSION: Infants less than 1 year of age at diagnosis with stage IV NBL have a much improved outcome compared with children >/= 1 year of age. Nonamplified MYCN tumors identify a group of infants with a 93% +/- 4% EFS, whereas amplified MYCN copy number clearly identifies patients who are unlikely to survive despite intensive chemotherapy.

Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a children's cancer group study.

PURPOSE: To determine prospectively whether surgery alone is sufficient therapy for Evans stages I and II neuroblastoma and to define biologic and clinical features having prognostic potential for this group. PATIENTS AND METHODS: Between June 1989 and August 1995, 374 eligible children (age range, 0 to 18 years) with newly diagnosed stage I (n = 141) and stage II (n = 233) neuroblastoma were registered onto Children's Cancer Group trial 3881. Surgical resection was the only primary therapy except in cases with spinal cord compression, where radiation therapy was allowed. Event-free survival (EFS) and overall survival (OS) were analyzed by life-table methods according to clinical and biologic features. RESULTS: EFS and OS (mean +/- SE) for all stage I patients were 93% +/- 3.0% and 99% +/- 1.0%, respectively, compared with 81% +/- 4.0% and 98% +/- 2. 0%, respectively, for stage II patients. The significantly higher recurrence rate among stage II patients was managed successfully in 38 of 43 children with either surgery or multimodality treatment. There was one death among stage I patients and six among stage II. For stage II patients tumor MYCN gene amplication, unfavorable histopathology, an age greater than 2 years, and positive lymph nodes predicted a lower OS (P <.05). CONCLUSION: Children with stages I and II neuroblastoma have 98% survival with surgery alone as primary therapy. Supplemental treatment was necessary in only 10% of stage I patients and 20% of stage II patients. In children with localized neuroblastoma, a subset of patients that are at higher risk for death can be defined as those with stage II disease who have tumor MYCN amplification or who are >/= 2 years of age with either unfavorable histopathology or positive lymph nodes.

Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival.

PURPOSE: The goal of this study was to determine the incidence of metastatic sites in neuroblastoma and the extent to which metastatic sites correlate with age, tumor biology, and survival. PATIENTS AND METHODS: All 648 patients with stage IV and IVS neuroblastoma registered on Children's Cancer Group protocols 3881 and 3891 were analyzed. Metastatic site data were provided by treating institutions and reviewed in patients with central nervous system (CNS), intracranial, lung, or "other" metastases. RESULTS: The incidence of metastatic sites at diagnosis was 70.5% in bone marrow, 55.7% in bone, 30.9% in lymph nodes, 29.6% in liver, 18.2% in intracranial and orbital sites, 3.3% in lung, and 0.6% in CNS. Event-free survival (EFS) was decreased in patients with bone, bone marrow, CNS, intracranial/ orbital, lung, and pleural metastases, and improved in those with liver and skin metastases. In infants, MYCN amplification and unfavorable Shimada histopathology correlated with increased frequencies of bone and intracranial or orbital metastases. In older patients, MYCN amplification correlated with increased frequencies of intracranial or orbital, liver, and lung metastases. Multivariate analysis revealed that metastatic site is not an independent prognostic factor. CONCLUSIONS: Metastatic pattern in neuroblastoma differs with age and correlates with tumor biological features and EFS. These correlations could reflect changes in host or tumor biological features with age resulting in differences in metastatic capacity or tumor affinity for specific sites.

Current aspects of biology, risk assessment, and treatment of neuroblastoma.

Neuroblastoma is one of the most intensely studied solid malignancies that affect the pediatric age groups; its clinical presentation, treatment strategies and ultimate prognosis vary greatly. The biologic and genetic character of each tumor has an important impact on disease behavior, and clinical staging now incorporates these factors to generate an overall therapy plan. The clinical presentation of neuroblastoma is related to primary tumor location, production of metabolically active substances, and the presence of metastatic disease. There are also prognostically important associated syndromes including opsoclonus-myoclonus, Horner's syndrome, neurofibromatosis, and a variety of other neurocristopathies. The histologic features of the tumor are of prognostic significance and are utilized in treatment stratification. The International Neuroblastoma Staging System (INSS) has unified classic clinical staging. Features at diagnosis and those determined by initial operation are combined with biologic prognostic factors to achieve risk group assignment for virtually all patients. There are groups of children in which limited therapy is curative and intermediate-risk situations where standard multimodality treatment provides favorable outcomes. Unfortunately, there are many patients with high-risk disease that require intensive strategies, but success is still limited. It is in these most resistant patients that innovative approaches are being undertaken and novel strategies are being investigated.

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.

Gastric necrosis after fundoplication: a novel approach for esophageal preservation.

An 11-year-old boy presented moribund, with massive abdominal distension. A Nissen fundoplication and gastrostomy tube had been established at age 2 years. After attempts to pass a nasogastric tube were unsuccessful, the old gastrostomy site was used to gain percutaneous access to the stomach resulting in release of gastric contents and stabilization of blood pressure and perfusion. During operation, massive gastric distention with gastric necrosis was found. Subtotal gastrectomy was performed with stapled closure of the distal intraabdominal esophagus and prepyloric region. Sump suction was placed in the proximal esophagus and the abdomen was drained widely. A distal esophageal perforation was apparent on postoperative day 19 confirmed by imaging and endoscopy. A nasoesophageal tube was passed into the abdomen, tied to a Jackson-Pratt drain, and the composite tube repositioned in the midesophagus allowing controlled proximal and distal drainage. Six months later, a Hunt-Laurence esophagojejunal pouch was created. At age 13, the child is clinically well, and enjoys 50% of his nutritional needs orally, with the remainder delivered overnight via tube feedings. This case describes gastric necrosis after gas bloat syndrome as a late complication of Nissen fundoplication. A novel approach to the management of distal esophageal perforation allowed preservation of a functional, intact native esophagus.

Pharmacokinetics of once-daily gentamicin dosing in pediatric patients.

BACKGROUND/PURPOSE: To achieve cost-effective health care in adults, once-daily aminoglycosides administration has been used and judged to be safe and efficacious. A similar strategy in children requires the characterization of pharmacokinetic parameters and the development of a therapeutic monitoring protocol for this antibiotic regimen. METHODS: A prospective, controlled, randomized (2:1) study was undertaken in 50 pediatric patients between June 1995 and September 1997. Children between 6 months and 18 years who required gentamicin therapy based on independent clinical assessment were eligible if they had normal renal function, no aminoglycoside allergies, were not neutropenic, or did not have cystic fibrosis. Measurements included a peak, 4-hour, 8-hour, and trough gentamicin levels to determine volume of distribution (Vd) and elimination constant (Ke). Ototoxicity and nephrotoxicity were monitored by pre- and postaudiology examinations and serial calculated creatinine clearance determinations, respectively. RESULTS: Thirty-three patients received 7.5 mg/kg every 24 hours, and 17 patients received 2.5 mg/kg every 8 hours. Most frequent indications for treatment were ruptured appendicitis (n = 19) followed by wound infections caused by trauma (n = 4), but the spectrum of treatment was broad including enteric, genitourinary, central nervous system, biliary, ophthalmologic, and orthopedic infections. Pharmacokinetic data indicated that 24-hour dosing resulted in higher peak levels compared with 8-hour dosing (20.4 +/- 45.4 v 7.2 +/- 6.2 mg/L, P < .0001) and lower trough levels (0.29 +/- .02 v 0.69 +/- 0.13, P < .0001), whereas rate of elimination constant and volume of distribution were not significantly different. No nephrotoxicity or ototoxicity has been noted in either group. CONCLUSIONS: These data confirm that once-daily dosing of gentamicin is a safe method of treatment that provides equivalent pharmacokinetics compared with traditional dosing and enhances bactericidal effect based on higher peak levels, avoids toxicity, and allows cost savings.

Differentiated thyroid cancer: determinants of disease progression in patients <21 years of age at diagnosis: a report from the Surgical Discipline Committee of the Children's Cancer Group.

OBJECTIVE: This study was done to define the extent of disease and evaluate the effect of staging and treatment variables on progression-free survival in patients with differentiated thyroid carcinoma who were less than 21 years of age at diagnosis. SUMMARY BACKGROUND DATA: Differentiated thyroid cancer in young patients is associated with early regional lymph node involvement and distant parenchymal metastases. Despite this, the overall long-term survival rate is greater than 90%, which suggests that biologic rather than treatment factors have a greater effect on outcome. METHODS: Variables analyzed for their impact on progression-free survival in a multi-institutional cohort of 329 patients included age, antecedent thyroid irradiation, extrathyroidal tumor extension, size, nodal involvement, distant metastases, technique of thyroid surgery and lymphatic dissection, initial treatment with 131Iodine, residual cervical disease, and histopathologic subtype. Surgical complications were correlated with the specific procedures completed on the thyroid gland or cervical lymphatics. RESULTS: The overall progression-free survival rate was 67% (95%, CI: 61%-73%) at 10 years with 2 disease-related deaths. Regional lymph node and distant metastases were present in 74% and 25% of patients, respectively. Progression-free survival was less in younger patients (p = 0.009) and those with residual cervical disease after thyroid surgery (p = 0.001). Permanent hypocalcemia was more frequent after total or subtotal thyroidectomy (p = 0.001) while wound complications increased after radical neck dissections (p < 0.00001). CONCLUSIONS: The progression-free survival rate was better after a complete resection and in older patients. Progression-free survival rate was the same after lobectomy or more extensive thyroid procedures, but comparison was confounded by the increased use of total or subtotal thyroidectomy in patients with advanced disease. The risk of permanent hypocalcemia increased when total or subtotal thyroidectomy was done. Thyroid lobectomy alone may be appropriate for patients with small localized lesions while total or subtotal thyroidectomy should be considered for more extensive tumors.

Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study.

PURPOSE: To identify a biologically favorable and unfavorable subset of patients with Evans stage III neuroblastoma and to determine whether treatment stratification would improve the event-free survival (EFS) for high-risk patients and maintain excellent EFS for the lower-risk patients. PATIENTS AND METHODS: Risk stratification was performed by age, MYCN gene copy number, Shimada histopathologic classification, and serum ferritin level. Lower-risk patients were treated on the less intensive Children's Cancer Group (CCG)-3881, whereas high-risk patients were treated on CCG-3891, which included more intensive multimodality therapy and, in some cases, autologous bone marrow transplantation (ABMT). RESULTS: Of 228 Evans stage III patients entered onto the study, 92% also met the definition of International Neuroblastoma Staging System (INSS) stage 3. One hundred forty-three patients met the lower-risk criteria, which included 89 patients less than 1 year of age and 54 patients 1 year of age or greater, and favorable biology, whereas 85 patients were 1 year of age or greater and biologically unfavorable. Biologically unfavorable patients 1 year of age or greater who underwent gross surgical resection had improved survival, whereas the outcome of infants or biologically favorable older patients did not change according to resection. The EFS rate at 4 years was 100% for the patients with favorable biology of any age, 90% for those less than 1 year of age but with at least one unfavorable characteristic, and 54% for Evans stage III patients 1 year of age or greater with unfavorable biology. Age, ferritin level, MYCN copy number, Shimada histopathology, primary site, and intraspinal extension were significant univariate prognostic factors for all patients, but only MYCN copy number and age were independent factors in multivariate analyses. CONCLUSION: The excellent survival of the biologically favorable group and the historically improved EFS of the biologically unfavorable group suggest that biologic staging should be used to define the prognosis and treatment of stage III neuroblastoma.

Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: The National Wilms' Tumor Study (NWTS)-4 was designed to evaluate the efficacy, toxicity, and cost of administration of different regimens for the treatment of Wilms' tumor (WT). PATIENTS AND METHODS: Between August 6, 1986 and September 1, 1994, 1,687 previously untreated children less than 16 years of age with stages I to II/favorable histology (FH) or stage I/anaplastic histology WT (low-risk [LR] group) or stages III to IV/FH WT or stages I to IV/clear cell sarcoma of the kidney (high-risk [HR] group) were randomized to treatment that included vincristine and either divided-dose (standard [STD]) courses (5 days) or single-dose (pulse-intensive [PI]) treatment with dactinomycin. HR patients also received either STD courses (3 days) or PI treatment with doxorubicin. RESULTS: The 2-year relapse-free survival (RFS) rates for LR patients were 91.3% for 544 randomized to treatment with PI and 91.4% for 556 randomized to treatment with STD chemotherapy (P = .988). The 2-year RFS rates for HR patients were 87.3% for 299 randomized to treatment with PI and 90.0% for 288 randomized to treatment with STD chemotherapy (P = .865). CONCLUSION: We conclude that patients treated with PI combination chemotherapy for LR or HR WT or clear cell sarcoma of the kidney have equivalent 2-year RFS to those treated with STD regimens. PI drug administration is recommended as the new standard based on demonstrated efficacy, greater administered dose-intensity, less severe hematologic toxicity, and the requirement for fewer physician and hospital encounters.

Prospective, randomized evaluation of the efficacy of fibrin sealant as a topical hemostatic agent at the cannulation site in neonates undergoing extracorporeal membrane oxygenation.

BACKGROUND: The topical hemostatic effect of fibrin sealant that has been solvent/detergent treated and plasminogen depleted was evaluated in a multicenter prospective, randomized controlled study at the cannulation site wound of infants undergoing extracorporeal membrane oxygenation (ECMO). METHODS: The test group received standard cauterization and Fibrin sealant, while the control group was given cauterization alone to control hemostasis at this site. Efficacy data were available on 173 randomized study subjects of whom 149 met study entry criteria. All were managed according to standard ECMO practice. RESULTS: Fibrin sealant reduced the risk of bleeding, was associated with less shed blood, and was associated with shorter duration of hemorrhage. Further, control infants showed an increased bleeding risk with less depressed fibrinogen levels and prothrombin time elevations >18 seconds prior to ECMO. CONCLUSION: Fibrin sealant is useful as a topical hemostatic agent in patients with coagulopathy not responding to standard surgical techniques.