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The purpose of this study was to determine patient characteristics and outcomes for bladder/prostate (BP) rhabdomyosarcoma (RMS) using an international cohort of prospectively treated patients comparing different treatment algorithms. Data were collected from 379 patients (1979-1998) treated on protocol; Intergroup Rhabdomyosarcoma Study, IRS-IV (n = 239 patients), International Society of Pediatric Oncology Malignant Mesenchymal Tumors (MMT) Committee MMT-84 and -89 (n = 74), Italian Cooperative Group, RMS-79 and RMS-88 Studies (n = 37) or German Cooperative Soft Tissue Sarcoma Study CWS-91 protocols (n = 29). A total of 322 (85%) patients had localized embryonal RMS (ERMS) and 27 had metastatic disease. Thirty patients (21 local disease; 9 metastatic) had nonembryonal BP RMS. Patients with localized ERMS had large tumors (64% >5 cm) that were invasive (54%) with uninvolved regional lymph nodes (N0, 93%). The 5-year failure-free survival (FFS) was 75% and the overall survival (OS) was 84%, with 89% of deaths attributed to disease. Treatment failures were usually local disease recurrence (60%). Predictors of FFS included T-stage (invasiveness), size, and histology. FFS was decreased for patients not receiving initial radiotherapy but this did not translate into a decreased OS. The 21 patients with localized nonembryonal BP RMS had a FFS and OS of 47%. The 36 patients with metastatic disease were more likely to be older and had large tumors that were invasive with alveolar histology and regional lymph node involvement. The 5-year FFS and OS were 41 and 44%, respectively. In conclusion, the majority of BP RMS patients had localized ERMS with a resultant good prognosis using current treatment algorithms. There were differences in FFS between treatment protocols but this did not result in an altered OS.

Purpose The purpose of this study was to compare the outcome of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with standard VAC (vincristine, dactinomycin, and cyclophosphamide) chemotherapy to that of patients treated with VAC alternating with vincristine, topotecan, and cyclophosphamide (VAC/VTC). Patients and Methods Patients were randomly assigned to 39 weeks of VAC versus VAC/VTC; local therapy began after week 12. Patients with parameningeal RMS with intracranial extension (PME) were treated with VAC and immediate x-ray therapy. The primary study end point was failure-free survival (FFS). The study was designed with 80% power (5% two-sided α level) to detect an increase in 5-year FFS from 64% to 75% with VAC/VTC. Results A total of 617 eligible patients were entered onto the study: 264 were randomly assigned to VAC and 252 to VAC/VTC; 101 PME patients were nonrandomly treated with VAC. Treatment strata were embryonal RMS, stage 2/3, group III (33%); embryonal RMS, group IV, less than age 10 years (7%); alveolar RMS or undifferentiated sarcoma (UDS), stage 1 or group I (17%); alveolar RMS/UDS (27%); and PME (16%). At a median follow-up of 4.3 years, 4-year FFS was 73% with VAC and 68% with VAC/VTC (P = .3). There was no difference in effect of VAC versus VAC/VTC across risk groups. The frequency of second malignancies was similar between the two treatment groups. Conclusion For intermediate-risk RMS, VAC/VTC does not significantly improve FFS compared with VAC.

Purpose Some patients with rhabdomyosarcoma (RMS) achieve less than a complete response (CR) despite receiving all planned therapy. We assessed the impact of best response at the completion of all therapy on patient outcome. Patients and Methods We studied 419 clinical group III participants who completed all protocol therapy without developing progressive disease for Intergroup Rhabdomyosarcoma Study (IRS) IV. Response (complete resolution [CR], partial response [PR; ≥ 50% decrease], or no response [NR; < 50% decrease and < 25% increase]) was determined by radiographic measurement and categorized by the best response. Results At the end of therapy, 341 participants (81%) achieved a best response of CR and 78 (19%) had a best response of PR/NR. Five-year failure-free survival was similar for participants achieving CR (80%) and PR/NR (78%). After adjustment for age, nodal status, primary site, and histology, there was no significant indication of lower risk of failure (hazard ratio [HR], 0.77; 95% CI, 0.46 to 1.27; P = .3) nor death (HR, 0.63; 95% CI, 0.36 to 1.09; P = .1) for CR versus PR/NR participants. Seventeen participants with a best response of PR/NR had surgical procedures; eight (50%) of 16 with available pathology reports had residual viable tumor and only three achieved a complete resection. Resection of residual masses was not associated with improved outcome. Conclusion CR status at the end of protocol therapy in clinical group III participants was not associated with a reduction of disease recurrence and death. Aggressive alternative therapy may not be warranted for RMS patients with a residual mass at the end of planned therapy.

Rhabdomyosarcoma (RMS) is the most common soft tissue tumor of childhood. Patient age, size, histologic finding, and site of the tumor are primary determinants of prognosis in RMS. Chest wall RMS is a site in which the limitations of surgical excision are realized. We aim to determine the impact of surgical excision in chest wall RMS.A retrospective chart review was conducted of all 130 pediatric patients enrolled in the Intergroup Rhabdomyosarcoma Study (IRS) with chest wall rhabdomyosarcoma from the first (I) through fourth (IV) IRS with follow-up to June 2005. Median follow-up was 12.1 years (4.6-27.2 years).There was a significant improvement in failure-free survival (FFS) and overall survival (OS) between the first IRS study, I, and IRS-IV. The estimated FFS and OS at 5 years in IRS I was 30% and 40%, respectively, compared to 68% and 78%, respectively, in IRS-IV (P = .03 and P = .05, respectively). There was no association between histologic finding or size and FFS or OS. However, all patients who presented without metastasis had an FFS and OS of 49% and 61%, respectively, compared with metastatic patients, 7% and 7%, respectively (P.001). Five-year FFS of group I, II, and III patients was 52%, 52%, and 45%, respectively, and OS was 65%, 60%, and 59%, respectively. There was no significant difference in 5-year FFS or OS in patients who had a complete resection (group I), complete resection with positive microscopic margins (group II), or biopsy or partial resection only (group III). In groups I to III patients, the local and regional failure rate at 5 years is 25% and 6%, respectively.The most significant impact on outcome in chest wall RMS patients is metastatic disease at diagnosis. The locoregional failure rate is high but does not appear to impact survival. Alternative treatment strategies are needed for chest wall RMS, but aggressive surgical excision may not be necessary.

Purpose Currently, novel therapies to improve survival of patients with rhabdomyosarcoma (RMS) are being investigated. One of the new approaches involves immunotherapy using tumor-specific T-lymphocytes. An effective prolonged immune-mediated response against tumor cells is dependent upon the response of helper T-lymphocytes (HTLs) to tumor-associated antigens in the presence of histocompatibility lymphocyte antigen surface proteins. Methods Rhabdomyosarcoma tumor lysate-pulsed human dendritic cells were used to stimulate HTL precursors (naive CD4+ T-cells) in vitro. After 3 rounds of antigen stimulation with antigen-presenting cells, the T-cells were tested for reactivity (T-cell proliferation assays) against a large panel of tumor lysate-pulsed autologous antigen-presenting cells. Results Using peripheral blood mononuclear cells from normal naive donors, we have been able to generate HTL clones that recognize and proliferate to multiple tumor cell lines. The HTLs were induced using lysate from a single alveolar RMS tumor cell line (RMS13). The clones generated recognized all of the alveolar RMS cell lines (RMS13, Rh18, Rh28, Rh30, and Rh41), prostate cancer cell lines (LNCAP and LAPC4), melanoma cell lines (Mel 624 and G361), and breast cancer cell line (SKBR3). Helper T-lymphocytes recognition was also confirmed by interferon- γ production. The clones did not recognize colon, lymphoma, ovarian carcinoma, ERMS or Epstein-Barr virus (EBV) transformed B-cells. This recognition was histocompatibility lymphocyte antigen class II restricted and was not an allogeneic response. Conclusion The results of this work demonstrate that HTLs, exposed to RMS lysate, are able to recognize and respond to a broad range of tumor types suggesting that a common antigen exist among these different tumors. These findings suggest novel treatment strategies for patients with RMS using tumor lysate to induce antitumor immune responses.

Purpose Patients with metastatic rhabdomyosarcoma (RMS), except those younger than 10 years with embryonal RMS, have an estimated long-term event-free survival (EFS) of less than 20%. The main goal of this study was to improve outcome of patients with metastatic RMS by dose intensification with interval compression, use of the most active agents determined in phase II window studies, and use of irinotecan as a radiation sensitizer. Patients and Methods Patients with metastatic RMS received 54 weeks of therapy: blocks of therapy with vincristine/irinotecan (weeks 1 to 6, 20 to 25, and 47 to 52), interval compression with vincristine/doxorubicin/cyclophosphamide alternating with etoposide/ifosfamide (weeks 7 to 19 and 26 to 34), and vincristine/dactinomycin/cyclophosphamide (weeks 38 to 46). Radiation therapy occurred at weeks 20 to 25 (primary) but was also permitted at weeks 1 to 6 (for intracranial or paraspinal extension) and weeks 47 to 52 (for extensive metastatic sites). Results One hundred nine eligible patients were enrolled, with a median follow-up of surviving patients of 3.8 years (3-year EFS for all patients, 38% [95% CI, 29% to 48%]; survival, 56% [95% CI, 46% to 66%]). Patients with one or no Oberlin risk factor (age > 10 years or < 1 year, unfavorable primary site of disease, ≥ three metastatic sites, and bone or bone marrow involvement) had a 3-year EFS of 69% (95% CI, 52% to 82%); high-risk patients with two or more risk factors had a 3-year EFS of 20% (95% CI, 11% to 30%). Toxicity was similar to that on prior RMS studies. Conclusion Patients with metastatic RMS with one or no Oberlin risk factor had an improved 3-year EFS of 69% on ARST0431 compared with an historical cohort from pooled European and US studies; those with two or more risk factors have a dismal prognosis, and new approaches are needed for this very-high-risk group.

Terminally differentiated rhabdomyoblasts are common after or during therapy for rhabdomyosarcoma (RMS). Case reports have suggested that their presence after therapy does not indicate a poor prognosis, but significance and relationship to outcome has not been systematically studied. Management of patients with this finding can cause confusion. Slides and pathology reports from 44 patients with bladder/prostate RMS treated on Fourth Intergroup Rhabdomyosarcoma Study were examined by a pathologist experienced in RMS, and findings compared with institutional reports. Details regarding patient characteristics, outcome, and management were reviewed. Outcome of patients with various pathologic findings was assessed. One of 10 patients with only mature rhabdomyoblasts at their last procedure recurred, versus 4 of 17 patients with viable tumor and 2 of 17 patients with no viable tumor and no rhabdomyoblasts. Sixteen of 42 cases reviewed had results differing from our review. Mature rhabdomyoblasts are a discrete entity which may not be predictive of recurrence, but should be evaluated by a pathologist experienced with this entity. The presence of mature rhabdomyoblasts at the end of therapy for bladder/prostate RMS does not justify radical surgery. Sequential biopsies are subject to sampling error and should only be performed in the context of protocol-directed therapy to avoid unnecessary radical surgeries.

The transcription factor PAX3 is expressed during early embryogenesis and in multiple cancer types, including embryonal rhabdomyosarcoma (ERMS), Ewing sarcoma (ES) and malignant melanoma (MEL), suggesting that it could function as a general tumor associated antigen. Major histocompatibility complex (MHC) peptide binding algorithms were used to predict potential epitopes in PAX3 capable of stimulating in vitro naïve HLA-A0201 restricted cytotoxic T-lymphocytes (CTLs). Two peptides, PAX3-282 (QLMAFNHLI) and a modified version of this peptide PAX3-282.9V (QLMAFNHLV), were capable of inducing antigen-specific CTLs. Of these peptides, PAX3-282.9V was the most efficient inducer of primary CTL response. These CTLs were able to lyse HLA-A0201 expressing target cells that were pulsed with peptide, and more importantly, were effective in killing tumor cells that express PAX3, including ERMS, ES and MEL cell lines. These findings provide compelling evidence that peptide PAX3-282 is naturally processed by tumors and is presented in the context of HLA-A0201 in adequate amounts to allow CTL recognition. Also, PAX3-282.9V is an effective immunogenic peptide able to induce CTL recognition of PAX3-containing tumors and may be used as an antitumor peptide vaccine.

Objective. Primary hyperparathyroidism (HPT) is unusual in children. We reviewed our experience with HPT to better characterize these children. Methods. The retrospective review of patients Results. Fifty-two patients were identified. Median age was 16.8 years (range: 4–18.9) with a female-to-male ratio of 3:2. Eighty-five percent had an elevated parathyroid hormone (PTH) level, and 15% had an inappropriately normal PTH level during hypercalcemia. Serum calcium was elevated in all patients except for 2 with multiple endocrine neoplasma (MEN)-IIA and 1 with familial non-MEN HPT, but both had elevated PTH levels. Alkaline phosphatase levels were significantly higher in children with documented bone involvement. At presentation 41 patients (79%) were symptomatic and end-organ damage (nephrocalcinosis, nephrolithiasis, acute pancreatitis, or bone involvement) occurred in 23 patients (44%). Thirty-four patients (65%) had a single adenoma; hyperplasia was identified in 16 patients (27%), and of these cases, 57% occurred in patients diagnosed with MEN-I. Short-term complications included transient hypocalcemia in 29 patients (56%) and transient vocal cord paralysis in 2 patients (4%). Long-term complications were significant for permanent hypocalcemia in 2 patients (4%) and no recurrent laryngeal nerve injuries. No parathyroid abnormalities were identified during exploration in 4 (8%) children. Long-term follow-up was achieved in 98% of patients for a mean and median of 13 years. Resolution of hypercalcemia was achieved in 94% of cases. Conclusion. The diagnosis of primary HPT in pediatric patients is frequently delayed, is commonly symptomatic, and has significant morbidity. For children in whom HPT is suspected, evaluation of serum calcium and PTH levels is diagnostic in 100% of children. Parathyroid resection is effective at restoring normal serum calcium, has few complications, and is the treatment of choice for children with primary hyperparathyroidism.

Purpose: More than half of pediatric rhabdomyosarcoma cases have intermediate-risk features and suboptimal outcome (3-year failure-free survival estimates, 55 to 76%). Dose intensification of known active agents may improve outcome. Experimental Design: This pilot study evaluated the feasibility of dose intensification of cyclophosphamide in previously untreated patients ages < 21 years with intermediate-risk rhabdomyosarcoma. Induction therapy comprised four 3-week cycles of VAC: vincristine (V) 1.5 mg/m2 on days 0, 7, and 14; actinomycin D (A) 1.35 mg/m2 on day 0; and dose-intensified cyclophosphamide (C) on days 0, 1, and 2. The three cyclophosphamide dose levels tested were as follows: (a) 1.2 g/m2/dose; (b) 1.5 g/m2/dose; and (c) 1.8 g/m2/dose. Continuation therapy comprised nine additional cycles of VAC with 2.2 g/m2/cycle of C. Radiotherapy was administered at week 0 (parameningeal tumors with intracranial extension) or week 12 or 15 (all others). Results: Between October 1996 and August 1999, 115 eligible patients were enrolled. Three of 15 patients treated at dose level 2 experienced life-threatening dose-limiting toxicity (typhlitis ± other severe toxicity). Dose level 1 was the maximum-tolerated dose, and 91 evaluable patients were treated at this level. The 3-year failure-free and overall survival estimates for patients treated at the maximum-tolerated dose were 52% (95% confidence interval, 41–64%) and 67% (95% confidence interval, 56–77%), respectively, at a median follow-up of 3 years. Conclusions: A 64% increase in the standard cyclophosphamide dosage during induction (to 3.6 g/m2/cycle) was tolerated. However, outcomes were similar to those observed at lower dosages, suggesting that alkylator dose intensification does not benefit patients with intermediate-risk rhabdomyosarcoma.

Tracheal agenesis (TA) was diagnosed by endoscopy after esophageal intubation in a 34-week newborn. Diagnosis, work-up, and management approach are discussed. Similar to previous reports, this case of tracheal agenesis presented with multiple associated defects found at autopsy. Tracheal agenesis had previously been reported as a part of the VATER (vertebral defects, anal atresia, tracheoesophageal fistula and/or esophageal atresia, radial dysplasia, renal defects) and VACTERL (VATER plus cardiovascular and limb defects) associations/syndromes. More recently, cases of TA have been reported with associated anomalies described as TACRD (tracheal agenesis/atresia, complex congenital cardiac abnormalities, radial ray defects, and duodenal atresia) association/syndrome. We present a case of TA with anomalies found in both VACTERL and TACRD associations, which support the speculation that both are different manifestations of a spectrum of mesodermal dysplasia.

Background/purpose The aim of this study was to assess and correlate functional outcomes and surgical results with health-related quality of life after ileal pouch-anal anastomosis (IPAA) in pediatric patients. Methods Functional outcome was determined by questionnaire and telephone interview. Surgical results were determined by retrospective chart review. Results Data were gathered from 26 patients (mean age at IPAA, 12 years; mean follow-up, 3.7 years). Diagnoses were ulcerative colitis in 18, indeterminate colitis in 4, and familial polyposis in 4. Indications for IPAA included intractability, medication toxicity, growth delay, and cancer prophylaxis. Short-term complications (5 patients; 19%) included partial small bowel obstruction, stomal revision, pouch abscess, and negative exploration. Long-term complications (8 patients; 31%) were chronic pouchitis and anal stricture. The average number of stools per 24 hours was 3.9. No incontinence was reported; dietary restrictions were negligible. Although there were minimal differences from population norms, parental anxiety remained high. Chronic pouchitis correlated negatively with physical summary score. Nocturnal stooling negatively affected psychosocial quality of life. Conclusions Pediatric IPAA resulted in excellent bowel health. Quality of life, physical function, mental health, and self-esteem were equivalent to those of healthy children. These data may help families and physicians make informed surgical decisions.

On the Fourth Intergroup Rhabdomyosarcoma study, older children experienced excessive neurotoxicity, whereas younger children had increased myelosuppression. The purpose of this study was to determine whether the same pattern of toxicity was seen on the successor study when use of growth factor was required and dosing of chemotherapy was different by performing a retrospective cohort analysis on patients treated on Children's Oncology Group protocol D9803. Toxicity data were analyzed by stratifying children into 4 age groups. The frequency of grade 3/4 neurotoxicity, myelosuppression, infection, and mucositis was predicted for each age group. The cumulative doses of vincristine and cyclophosphamide administered were measured as percent of protocol-prescribed dose. Adolescents (aged 15+) were more likely to experience neurotoxicity compared with younger patients (odds ratio, 3.6; P

The majority of intermediate risk Rhabdomyosarcoma (RMS) patients have gross residual disease (Group III) after their first operative procedure. It is currently not known if local control rates can be maintained when, following induction chemotherapy, the radiation therapy (RT) dose is decreased after a delayed primary excision (DPE). To answer this question we evaluated patients enrolled on COG D9803 (1999-2005) who had Group III tumors of the bladder dome, extremity, or trunk (thorax, abdomen, pelvis) were candidates for DPE at week 12 if the primary tumor appeared resectable. RT dose was then adjusted by the completeness of DPE: no evidence of disease (NED) 36 Gy, microscopic residual (MR) 41.4 Gy, and gross residual disease (GRD) 50.4 Gy. A total of 161 Group III patients were evaluated (24 bladder dome, 63 extremity, and 74 trunk). Seventy-three patients (45%) underwent DPE which achieved removal of all gross disease in 61 (84%) who were then eligible for reduced RT dose [43/73 received 36 Gy, 19/73 received 41.4 Gy]. The local 5-year failure rate (0% for bladder dome, 7% for extremity and 20% for trunk) was similar to IRS-IV, which did not encourage DPE and did not allow for DPE adapted RT dose reduction. In conclusion, DPE was performed in 45% of Group III RMS patients with tumors at select anatomic sites (bladder dome, extremity and trunk), and 84% of those who had DPE were eligible for RT dose reduction. Local control outcomes were similar to historic results with RT alone.

We reviewed clinicopathologic features and treatment outcomes in 7 patients diagnosed withStage 4/Group IV orbital sarcoma and treated on IRSG protocols I-III. Three patients hadembryonal rhabdomyosarcoma (RMS), and 2 patients each had alveolar RMS or unclassifiedsarcoma. Median age at diagnosis was 1.8 years (range 0.2 – 6.9 years). All patients had bonemarrow involvement, including 6 with normal CBC at diagnosis. Cerebrospinal fluid (CSF) wasnormal in 6 patients. Three patients survived > 5 years, including one with local recurrence. Conclusion— Further study is needed to determine necessity of bone marrow and CSFexamination in orbital sarcoma patients. Keywords orbit; rhabdomyosarcoma; sarcoma; metastasis; pediatric Introduction Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood, and RMSof the orbit constitutes approximately 10% of all RMS cases. 1 - 2 Fortunately, most patientswith orbital RMS (ORMS) present with localized disease, and the overall prognosis forlocalized ORMS is excellent.

Heat shock proteins (HSPs) are present in neutrophils (PMNs) from critically ill patients. We investigated whether HSPs were present in PMNs from burn patients and whether heat shock contributed to the functional defects observed in burn PMNs. Using both flow cytometry and Western blot techniques it was observed that inducible HSP72 (iHSP72) was present in PMNs and leukocytes from burn patients, especially in patients with inhalation injury. Similar to burn PMNs, and in contrast to normal cells, heat shocked PMNs (43° incubation) expressed iHSP72 and were unable to increase the expression of CD11b/CD18 in response to pro-inflammatory stimuli. Degranulation after pro-inflammatory stimuli was decreased for both burn- and heat-shocked PMNs when compared to normal controls. In burn PMNs these functional abnormalities were mainly due to decreased quantities of proteins (CD11b, albumin, B12 binding protein, β-glucuronidase) present within cytoplasmic granules. However, in heat-shocked PMNs the abnormalities were primarily related to abnormal exocytosis. In conclusion, our data show that decreased quantities of cytoplasmic granule proteins and, to a smaller degree, defective exocytosis are involved in the functional abnormalities observed in burn PMNs. J. Leukoc. Biol. 66: 773–780; 1999.

CD14, the leukocyte receptor for lipopolysaccharide (LPS), is important in the response of human polymorphonuclear leukocytes (PMNs) to infection with gram-negative bacteria. The level of CD14 on the PMN surface increases after exposure to some inflammatory stimuli such as N-formyl-methionyl-leucyl-phenylalanine (fMLP). These newly expressed CD14 molecules probably come from an intracellular pool of preformed receptors. We sought to further characterize PMN CD14 expression, upregulation, and shedding and to define the intracellular location of CD14 molecules. Our results demonstrate that both LPS and fMLP significantly increased CD14 cell surface expression; however, neither phorbol myristate acetate (PMA) or A23187 increased receptor levels on the PMN surface. Neither fMLP, PMA, or A23187 stimulated the release of soluble CD14 from PMNs. Intracellular CD14 was observed in >90% of PMNs examined by flow cytometry and confocal microscopy. Additional analyses using CD14 enzyme-linked immunosorbent assays and electron microscopy studies, examining PMN granules separated by discontinuous sucrose or Percoll gradients, showed that CD14 was present in both the plasma membrane-secretory vesicle fractions and azurophilic granules.

Background The prognostic significance of response to induction therapy for rhabdomyosarcoma (RMS) by anatomic imaging [computerised tomographic (CT) or magnetic resonance imaging (MRI) scan] is controversial. We previously reported no relationship between early response and failure-free survival (FFS) on Intergroup Rhabdomyosarcoma Study (IRS)-IV. We repeated the same analysis using a more recent clinical trial as an independent cohort of patients with non-metastatic, initially unresected RMS. Methods A total of 338 patients enrolled in Children’s Oncology Group (COG) study D9803 met the inclusion criteria for this analysis: (1) non-metastatic, initially unresected (Group III); (2) embryonal (ERMS) or alveolar (ARMS) histology; (3) documented protocol week 12 response to induction chemotherapy (excluding progressive disease) based on anatomic imaging (CT/MRI) and (4) documented protocol therapy beyond week 12. Response at week 12 was determined by the treating institution as complete response (CR), partial response (PR) or no response (NR). FFS was estimated using the Kaplan–Meier method and comparisons between patient subsets were made using the log-rank test. Results Overall objective response rate (CR + PR) at week 12 of therapy was 85% and was similar between ERMS and ARMS. FFS was similar among all patients with CR, PR or NR (p = 0.49). Restricting the analysis to either ERMS or ARMS, there was no difference in FFS by response within either histology subset (p = 0.89 and p = 0.08, respectively). Conclusions These findings provide additional evidence that anatomic imaging to assess early response to therapy among patients with RMS does not predict outcome and has questionable use in tailoring subsequent therapy.

This study investigated the role of intracellular calcium concentration ([Ca]i) as a possible intermediate in the lipopolysaccharide (LPS) second messenger pathway for the activation of neutrophils (polymorphonuclear leukocytes [PMNs]). Isolated PMNs were loaded with the calcium-sensitive fluorescent dye fura-2. The PMNs were stimulated with either LPS or the positive control formyl-Met-Leu-Phe (fMLP). As expected, PMN exposure to fMLP increased [Ca]i. However, LPS stimulation did not induce any detectable changes. Depletion of intracellular Ca stores with thapsigargin, or extracellular Ca with EGTA, significantly inhibited the upregulation of the CD11b/CD18 integrin in response to fMLP but not LPS. We conclude that [Ca]i is not an early intermediate in the second-messenger pathway for the activation of PMNs by LPS.

Accidental burial in sand is a tragically unrecognized risk associated with a popular childhood recreational activity. We describe 4 boys, aged 10 to 13 years, who were accidentally buried by sand. One boy died after his self-made tunnel in a sandbox collapsed. In a separate incident at a construction site, 1 boy died, and 2 were injured after a 30-foot sandpile collapsed as they ran down the embankment; all 3 were buried by the sand. In both incidents, play was unsupervised, and burial was sudden and complete. The calculated weight of the sand exceeded the expected maximal muscle effort of the chest, leading to traumatic asphyxiation secondary to restrictive compression of the chest. Only 15 accidental burials have been reported in the literature. To our knowledge, this is the first report describing children who died of respiratory asphyxia due to overwhelming thoracic compression after sand burial. Greater awareness by public health and safety officials at beaches, sandboxes, sandpiles, and natural play areas may nprevent potentially lethal accidents.

A mixture of helium and oxygen is less dense than room air. This property allows the gas to flow with less turbulence past airway narrowings, thereby decreasing airway resistance and increasing the volume of gas exchange. Previous studies demonstrated that airway obstruction that is manifested by stridor was present in 92% of patients requiring reintubation. Eight pediatric patients with burns in whom postextubation stridor or retractions unresponsive to racemic epinephrine developed, were treated with "heliox" (helium and oxygen) for 28 +/- 5 hours with an initial helium concentration between 50% and 70%. Of the eight patients treated with heliox, only two experienced respiratory distress and required reintubation. Both patients had stridor for a longer time before the initiation of heliox therapy compared with those patients who did not require reintubation. After initiation of heliox therapy, patients experienced a significant decrease in respiratory distress scores (6.8 +/- 0.7 vs 2.0 +/- 0.7). Heliox was able to relieve persistent stridor and thereby aid in the prevention of respiratory distress and reintubation.

10549Background: Change in tumor size by anatomic imaging is not a reliable predictor of outcome in RMS. We reviewed metabolic response by FDG-PET for patients with IR and HR RMS enrolled on two CO...

BACKGROUND: The objectives of this study were to compare tumor volume and patient weight versus traditional factors of tumor size (greatest dimension) and patient age and to determine which parameters best discriminated outcome among pediatric patients with intermediate-risk rhabdomyosarcoma (RMS). METHODS: Complete information was available for 370 patients with nonmetastatic RMS who were enrolled in the Children's Oncology Group (COG) intermediate-risk study D9803 (1999-2005). The Kaplan-Meier method was used to estimate survival distributions. A recursive partitioning model was used to identify prognostic factors that were associated with event-free survival (EFS). Cox proportional hazards regression models were used to estimate the association between patient characteristics and the risk of failure or death. RESULTS: For all patients with intermediate-risk RMS, a recursive partitioning algorithm for EFS suggested that prognostic groups should be defined optimally by tumor volume (with a transition point at 20 cm3), patient weight (with a transition point at 50 kg), and embryonal histology. Tumor volume and patient weight added significant outcome information to the standard prognostic factors, including greatest tumor dimension and patient age (P = .02). The ability to resect the tumor completely was not associated significantly with the size of the patient, and patient weight did not significantly modify the association between tumor volume and EFS after adjustment for standard risk factors (P = .2). CONCLUSIONS: The factors that had the strongest association with EFS were tumor volume, patient weight, and histology. On the basis of regression modeling, tumor volume and patient weight were superior predictors of outcome compared with greatest tumor dimension and patient age in children with intermediate-risk RMS. The current results indicated that the prognostic performance of tumor volume and patient weight should be assessed in an independent prospective study. Cancer 2011. © 2010 American Cancer Society.

To assess local control, event-free survival (EFS), and overall survival (OS) rates in 71 patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma (ALV RMS) and their relation to radiation therapy (RT) on IRSG Protocols III and IV, 1984-1997.Chart review and standard statistical procedures. PATIENTS AND TUMORS: Patients were 1-18 years at diagnosis (median, 6 years). Primary tumor sites were extremity/trunk (N = 54), head/neck (N = 9), genitourinary tract (N = 7), and perineum (N = 1). Thirty patients received VA +/- C with RT; 41 received VA +/- C alone. RT was assigned, not randomized.Fifty-four patients had Stage 1 (favorable site, any size) or Stage 2 (unfavorable site,or = 5 cm) tumors. Eight-year EFS was 90%, with 100% local control for 17 patients given RT. Eight-year EFS was 88%, with 92% local control for 37 patients without RT; P = 0.52 for EFS comparisons, 0.3 for local control comparisons. In 17 Stage 3 patients (unfavorable site, tumors5 cm, N0), 8-year EFS was 84% with 100% local control in 13 patients given RT; 8-year EFS was only 25% and local control 50% in 4 patients without RT. Local recurrence was the most common site of first failure in non-irradiated patients.Patients with Stage 1-2 ALV RMS had slightly but statistically insignificantly improved local control, EFS, and OS rates when local RT was given. The need for local RT in Stage 1-2 patients deserves evaluation in a randomized study. Local control, EFS, and OS rates were significantly improved in Stage 3 patients receiving local RT.

Purpose To evaluate the incidence and prognostic factors for regional failure, with attention to the in-transit pathways of spread, in children with nonmetastatic rhabdomyosarcoma of the extremity. Methods and Materials The Intergroup rhabdomyosarcoma studies III, IV-Pilot, and IV enrolled 226 children with rhabdomyosarcoma of the extremity. Failure at the in-transit (epitrochlear/brachial and popliteal) and proximal (axillary/infraclavicular and inguinal/femoral) lymph nodes was evaluated. The median follow-up for the surviving patients was 10.4 years. Results Of the 226 children, 55 (24%) had clinical or pathologic evidence of either in-transit and/or proximal lymph node involvement at diagnosis. The actuarial 5-year risk of regional failure was 12%. The prognostic factors for poor regional control were female gender and lymph node involvement at diagnosis. In the 116 patients with a distal extremity primary tumor, 5% had in-transit lymph node involvement at diagnosis. The estimated 5-year incidences of in-transit and proximal nodal failure was 12% and 8%, respectively. The in-transit failure rate was 0% for patients who underwent radiotherapy and/or underwent lymph node sampling of the in-transit nodal site but was 15% for those who did not ( p = .07). However, the 5-year event-free survival rate did not differ between these two groups (64% vs. 55%, respectively, p = .47). Conclusion The high incidence of regional involvement necessitates aggressive identification and treatment of regional lymph nodes in patients with rhabdomyosarcoma of the extremity. In patients with distal extremity tumors, in-transit failures were as common as failures in more proximal regional sites. Patients who underwent complete lymph node staging with appropriate radiotherapy to the in-transit nodal site, if indicated, were at a slightly lower risk of in-transit failure.

Pulmonary barotrauma is a frequent, life-threatening complication in the pediatric patient who is treated with mechanical ventilation. The volumetric diffusive respiration (VDR) ventilator, which employs a high-frequency progressive accumulation of subtidal volume breaths in a pressure-limited format with a percussive waveform, is capable of providing adequate gas exchange at lower airway pressures; this theoretically decreases the incidence of pulmonary barotrauma compared with conventional mechanical ventilation (CV). The incidence of pulmonary barotrauma since 1988 was evaluated in pediatric patients with burns who were younger than 2 years of age. Twenty-four patients who were treated with only CV were compared with 15 patients who were treated with only VDR. Pulmonary barotrauma was defined as the development of pneumothorax, pneumomediastinum, pneumopericardium, or pneumoperitoneum. There were no significant differences between CV-treated and VDR-treated groups (mean +/- SEM) in the patient characteristics of age (15.9 +/- 1.3 months vs 16.6 +/- 1.8 months), weight (11.2 +/- 0.5 kg vs 12.5 +/- 0.7 kg), percent total body surface burn (46.2% +/- 4.9% vs 55.6% +/- 6.2%), percent full-thickness burn (38.1% +/- 5.3% vs 50.0% +/- 6.6%), inhalation injury (40% vs 60%), or total number of days that mechanical ventilation was required (18.2 +/- 4.2 days vs 22.4 +/- 5.9 days); although these parameters show a slightly more severe degree of injury in the VDR-treated group. There was a reduction in the incidence of pulmonary barotrauma when VDR was used.(ABSTRACT TRUNCATED AT 250 WORDS)

The roles of pediatric surgeons in the treatment of RMS have changed signi”cantly through the years,as other adjuvant therapies have become more ef”cacious.The purpose of this manuscript is todescribe the current surgical therapy recommen-dations of the Soft Tissue Sarcoma Committee of theChildren’s Oncology Group (COG),formerly knownas the Intergroup Rhabdomyosarcoma Group(IRSG).

Purpose Initial response to induction chemotherapy predicts failure-free survival (FFS) in osteosarcoma and Ewing's sarcoma. For Intergroup Rhabdomyosarcoma Study (IRS) IV patients with group III rhabdomyosarcoma, we assessed whether reported response assessed by anatomic imaging at week 8 predicted FFS. Patients and Methods We studied 444 group III patients who received induction therapy, had response assessed at week 8 by anatomic imaging, and continued with protocol therapy. Induction chemotherapy was generally followed by radiation therapy (RT) starting after week 9. Response to induction therapy was determined at weeks 0 and 8. Local institutions coded response. Results Response rate for the entire cohort at week 8 was 77% (95% CI, 73% to 81%; complete response [CR], 21%; partial response [PR], 56%) but response had no influence on FFS (P = .57). Two hundred seventy-two patients received standard-timing RT at week 9 and thus only chemotherapy during induction. Response rate was 81% (95% CI, 76% to 86%; CR, 22%; PR, 59%). In these patients, response did not influence FFS except for those with alveolar histology. One hundred thirty-two other patients received chemotherapy and RT during induction (up-front RT). Response rate was 65% (95% CI, 57% to 73%; CR, 12%; PR, 53%), but response had no influence on FFS (P = .69). Forty patients received no RT at all (protocol violation) and response to induction therapy had no effect on FFS. Conclusion In IRS-IV, response rate to induction therapy was 77% in group III patients, was independent of histology, and had no influence on FFS overall.

A malignant tumor of striated muscle origin, Rhabdomyosarcoma (RMS) is a childhood tumor that has benefited from 30 years of multimodality therapeutic trials culminating in a greater than 70% overall current 5-year survival. Prognosis for RMS is dependent on anatomic primary tumor site, age, completeness of resection, presence and number of metastatic sites, histology and biology of the tumor cells. Multimodality treatment is based on risk stratification according to pretreatment stage, postoperative group, histology and site. Therefore, pretreatment staging is vital for assessment and is dependent on primary tumor site, size, regional lymph node status, and presence of metastases. Unique to RMS is the concept of postoperative clinical grouping that assesses the completeness of disease resection and takes into account lymph node evaluation both at the regional and metastatic basins. At all sites, if operative resection of all disease is accomplished, including microscopic disease, survival is improved. Therefore, the surgeon plays a vital role in determining risk stratification for treatment and local control of the primary tumor for RMS.

Direct T cell allorecognition underlies the development of a vigorous immune response in the clinical setting of acute graft rejection. The Notch pathway is an important regulator of Th immune responses, yet the molecular underpinnings of directional Notch signaling, otherwise critical for binary cell fate decisions, are unknown during autologous or allogeneic Th:DC interactions. Using the development of immune synapses (IS) in the allogeneic, human physiological Th:DC interaction, we demonstrate that Th-Notch1 receptor and DC-Notch ligands (Delta-like1, Jagged1) cluster in their apposed central-supramolecular-activation-clusters (cSMAC), whereas DC-Notch1 receptor and Th-Notch ligands cluster in their apposed peripheral-SMAC (pSMAC). Numb, a negative regulator of Notch, is excluded from the IS-microdomains where Notch1 receptor accumulates. This antiparallel arrangement across the partnering halves of the IS supports reciprocal Notch signal propagation in the DC-to-Th direction via the cSMAC and Th-to-DC direction via the pSMAC. As a result, processed Notch1 receptor (Notch-intracellular-domain, NICD1) and its ligands, as well as their downstream targets, HES-1 and phosphorylated-STAT3, accumulate in the nuclei of both cell-types. There is also enhancement of GLUT1 expression in both cell-types, as well as increased production of Th-IFN-γ. Significantly, neutralizing Notch1R Ab inhibits NICD1 and HES-1 nuclear translocation, and production of IFN-γ. In contrast, the IS formed during Ag-nonspecific, autologous Th:DC interaction is immature, resulting in failure of Notch1 receptor segregation and subsequent nuclear translocation of NICD1. Our results provide the first evidence for the asymmetric recruitment of Notch components in the Th:DC immunological synapse, which regulates the bidirectional Notch signal propagation.

10063 Background: VU RMS is rare and recognized as one of the most favorable site of RMS. In an attempt to determine optimal therapy in relation both to cure and to late effects, the experience of ...

10044 Background: Treatment recommendations for localized PT RMS differ based on clinical trials conducted by cooperative groups in North America and Europe. We conducted a meta-analysis to identify effects of demographic features and treatment choices on outcome for patients with localized PT RMS. Methods: We analyzed demographic and treatment variables from 12 studies conducted by the Children’s Oncology Group (COG; n = 416), Cooperative Weichteilsarkom Studiengruppe (CWS; n = 106), European paediatric Soft Tissue Sarcoma Group (EpSSG; n = 99), Italian Cooperative Group (ICG; n = 64), and SIOP Malignant Mesenchymal Tumor Group (MMT; n = 159) that enrolled 844 eligible patients with localized PT RMS from 1988-2013. Categorical and continuous variables were checked for association. Event-free survival (EFS) and survival (S) were compared among groups using univariate and multivariate analyses. Results: Mean patient age at enrollment differed among the cooperative groups (7 yrs [MMT] – 11 yrs [EpSSG]; p < ...

The aim of the study was to evaluate the safety and outcomes of simultaneous bilateral thoracotomy in pediatric patients compared with traditional bilateral staged thoracotomy.This is a retrospective review of 30 consecutive patients 18 years or younger undergoing either bilateral staged or bilateral simultaneous thoracotomy between March 1994 and July 2004. Follow-up (mean, 47 months) was available for all patients.Thirty patients (17 boys, 13 girls; average age, 12 years) underwent bilateral staged or bilateral simultaneous thoracotomy. Eighteen patients underwent staged thoracotomy, 9 patients underwent simultaneous thoracotomy, and 3 patients underwent both procedures. Diagnosis included sarcoma (n = 21), Wilms tumor (n = 4), indeterminate pulmonary nodules (n = 3), and germ cell tumor (n = 2). When we compared outcomes for patients undergoing simultaneous versus staged bilateral thoracotomy, mean hospital stay (5.2 vs 10.6 days; P.002), intensive care unit stay (1 vs 2 nights; P.0001), days with tube thoracostomy (4 vs 8 days; P.0005), and time to initiation of adjuvant chemotherapy (13 vs 30 days; P.05) were all significantly less for patients undergoing bilateral simultaneous thoracotomy. In addition, postoperative complications were less frequent in patients undergoing simultaneous versus staged thoracotomy (0 vs 3 events; P = .25).In selected patients, bilateral simultaneous thoracotomy is safe and may lessen morbidity and hospital stay while avoiding delay in initiation of adjuvant chemotherapy.

To characterize the risk factors and patterns of injury for children involved in snowmobile incidents.We reviewed the medical records of patients younger than 18 years who required hospital admission for snowmobile-related incidents from 1992 to 2001. Information obtained from these records and from the trauma database included patient demographics, mechanism of injury, injury patterns, medical care, and outcomes.Forty-three patients were admitted to our hospital for snowmobile-related incidents. Snowmobile incidents occurred most commonly in male adolescents. The 2 most common mechanisms of injury were ejection and striking a stationary object. Twenty-seven (63%) of the patients drove the snowmobile. Only 23 patients (53%) wore a helmet. At presentation, the mean +/- SEM Injury Severity Score (ISS) was 12.1 +/- 1.4. Orthopedic injuries predominated (n = 42); however, abdominal (n = 12) and head (n = 8) injuries were also common. Four patients were intubated, and 15 required intensive care unit admission. Twenty-nine patients (67%) required surgical intervention. The mean +/- SEM length of hospitalization was 6.7 +/- 1.4 days. No deaths occurred; however, 7 patients (16%) had long-term disabilities. A significant improvement occurred in both Glasgow Coma Scale (GCS) score and ISS for patients using a helmet. In addition, helmet use increased with age (P = .01). Days in the intensive care unit were proportional to both GCS score (r(s) = -0.47; P = .002) and ISS (r(s) = 0.6; P.001). Length of hospitalization also correlated with both GCS score (r(s) = -0.03; P = .008) and ISS (r(s) = 0.54; P = .02).Snowmobiles are a significant source of multitrauma for children. Orthopedic injuries predominate, especially in older children, and can lead to long-term disabilities. Helmet use significantly reduces injuries; however, vulnerable younger patients do not frequently wear helmets.

The identification of novel markers and therapeutic targets in advanced cancer is critical for improving diagnosis and therapy. Six-transmembrane epithelial antigen of the prostate (STEAP) is expressed predominantly in human prostate tissue and in other common malignancies including prostate, bladder, colon, and ovarian carcinomas, and in Ewing's sarcoma, suggesting that it could function as an almost universal tumor antigen. We have used MHC peptide binding algorithms to predict potential STEAP sequences capable of stimulating in vitro naïve HLA-A2–restricted CTLs. Four of six peptides predicted by these algorithms were able to induce antigen-specific CTLs that killed peptide-pulsed HLA-A2 target cells. Two of these peptides, STEAP-292 (MIAVFLPIV) and a modification of this peptide STEAP-292.2L (MLAVFLPIV), were the most efficient in the induction of primary CTL responses. More importantly, these CTLs were able to respond to tumor cells that express HLA-A2 and STEAP (colon, bladder, prostate, Ewing's sarcoma, and melanoma). Our results provide strong evidence that STEAP-292 is naturally processed by many tumor types and is presented in the context of HLA-A2 in sufficient amounts to allow recognition by CTLs. Also because STEAP-292.2L is a more immunogenic peptide able to induce CTL recognition of these STEAP-containing tumors and may have potential as an antitumor peptide vaccine.

Purpose To better understand outcomes in children with rhabdomyosarcoma (RMS) and lung-only metastatic disease, the authors reviewed the experience from Intergroup Rhabdomyosarcoma Studies IV Pilot and IV. Methods Patients with lung-only (n = 46) vs other sites of metastatic disease (n = 234) were reviewed using patient charts and the database of Children's Oncology Group (COG). Results Sixteen percent of patients with RMS and metastatic disease had isolated lung metastases. Thirty-one (67%) had more than 5 metastatic lung lesions. These were bilateral in 34 (74%). Only 6 patients were biopsied at diagnosis. Sixteen children (35%) did not receive any lung radiotherapy. Patients that received lung radiotherapy had fewer lung recurrences ( P = .04), although this has no significant impact on overall survival (OAS, 47% radiotherapy vs 31% no radiotherapy). Compared with patients with other sites of metastatic disease, patients with lung-only metastases have a greater proportion of favorable histology (67% vs 39%, P = .0017), negative nodal involvement (67% vs 32%, P = .0013), and parameningeal primaries (39% vs 12%) and a smaller proportion of extremity primaries (20% vs 33%, P = .0005 for site of primary tumor). Overall survival at 4 years for lung-only metastases was not significantly different from other single-site metastasis (42% vs 34%). Survival was not improved for unilateral disease or fewer than 5 metastatic lesions. Factors associated with diminished OAS include unfavorable histology ( P = .0001) and age >10 years ( P = .015). Conclusions Children with RMS and lung-only metastases usually present with extensive bilateral disease that is frequently not biopsied nor given protocol-recommended radiotherapy (XRT). However, outcome is comparable, although slightly better, than patients with other single-site metastasis.

Background This study was conducted to evaluate the incidence of adverse medical conditions and to assess the risk of developing these conditions in a cohort of long-term survivors of rhabdomyosarcoma (RMS) diagnosed before age 21. Procedure Using data from the Childhood Cancer Survivor Study (CCSS), we evaluated the incidence of self-reported adverse medical conditions for 606 RMS survivors and 3,701 siblings of cancer survivors. Cancer and treatment data abstracted from medical records were used to evaluate the effects of primary tumor site and combined modality therapy on the risk of developing sequelae in survivors. Results The relative risk (RR) for developing sequelae among survivors compared with siblings was greatest within 5 years after diagnosis. RR was elevated more than 5 years after diagnosis for several conditions (RR, 95% CI) as follows: eye impairment (cataract: 7.4, 2.9–18.9; visual disturbances: 3.2, 2.0–5.1; very dry eyes: 2.0, 1.2–3.3), endocrine impairment (growth hormone deficiency: 83.9, 33.0–213.6; hypothyroidism: 6.9, 4.1–11.3; need for medications to induce puberty: 90.4, 30.2–270.5), cardiopulmonary impairment (congestive heart failure: 43.0, 12.7–145.5; angina-like symptoms: 2.0, 1.3–2.9), neurosensory impairment (legal blindness: 9.8, 4.8–20.0; abnormal sensations: 1.5, 1.0–2.2), and neuromotor impairment (repeated seizures: 2.3, 1.2–4.4; motor problems: 3.7, 2.2–6.4; problems chewing or swallowing: 3.8, 1.9–7.5). Conclusions Survivors are at risk for developing sequelae many years after their initial diagnosis and treatment. Continued medical surveillance is necessary to ensure the long-term health and well-being of RMS survivors. Pediatr Blood Cancer 2005;44:643–653. © 2005 Wiley-Liss, Inc.

Background Pediatric inflammatory myofibroblastic tumor (IMT) is rare, with unpredictable clinical behavior. Recently, it has been associated with anaplastic lymphoma kinase (ALK) expression. Methods Patients under age 16, treated for IMT between 1976 and 2000 were reviewed. Mean follow-up was 8 years (range 1 month–22 years). Results Eight children had IMT, with a mean age of 6 years (range, 11 months–14 years) and female to male ratio of 3:1. Tumor location was lung (four patients), abdomen (two patients), lung and abdomen (one patient), and abdomen, head, and neck (one patient). Presenting symptoms included anemia (seven patients), fever (six patients), and dyspnea (four patients). Laboratory results included thrombocytosis (six patients), hypergammaglobulinemia (four patients), elevated sedimentation rate (four patients), and leukocytosis (three patients). Immunohistochemistry revealed ALK expression in four of eight tumors. Four children had complete resection and are alive. Two of these children had ALK-positive tumors. Four patients had incomplete resection, and two had recurrences treated successfully with resection and radiotherapy; the other two died of disease. For the incomplete resection patients, those that were ALK-positive lived, and those that were ALK-negative did not. Conclusions Eight children were treated for IMT over a 15-year period. ALK expression was found in half the tumors. Prognosis was improved with ALK expression and complete surgical resection. © 2004 Wiley-Liss, Inc.

T-cell immunotherapy is a promising treatment option for cancer. The identification of tumor antigens that are recognized by the immune system has allowed for the generation of vaccines for various malignancies. Due to the ease of manufacturing and characterizating peptide-based vaccines they have been used to stimulate antitumor T-cells. This article will review the use of peptide-based vaccines for the treatment of cancer by inducing antitumor T-lymphocyte responses.

CpG oligodeoxynucleotides (ODNs) are synthetic DNA sequences that mimic bacterial DNA and have potent immunostimulatory effects on dendritic cells (DCs), B cells, and natural killer cells. To evaluate CpG ODN antitumor effects against solid tumors, we used an orthotopic murine model of embryonal rhabdomyosarcoma.The systemic administration of CpG 2006 was tested beginning on day 9 or 19 when tumors were not yet palpable or palpable, respectively, and after surgical resection of the tumor. CpG was also administered in combination with the chemotherapeutic agents, cyclophosphamide (CY) and topotecan, or surgical resection.Systemic CpG prolonged survival when begun at day 9 but had no effect with a large tumor burden. CpG administered after surgical resection of tumor significantly improved survival of mice (P0.03). On day 9, CY plus CpG 2006 resulted in improved survival compared with CY alone (70% versus 41%, respectively). Survival was significantly improved when CpG 2006 was administered systemically with CY beginning on day 19 (15% versus 0% survival). The administration of CpG 2006 with topotecan significantly improved survival in mice with large tumors. Cell-depletion studies demonstrated that the antitumor effects of systemically administered CpG 2006 combined with CY were predominantly T cell dependent.These data are the first to show that immune stimulatory agents such as CpGs may enhance the antitumor effects of chemotherapeutic agents and improve survival after surgical resection of a solid tumor.

A 12-year-old girl underwent laparoscopy-assisted splenectomy and cholecystectomy with removal of her spleen through a small Pfannenstiel incision. She had an unremarkable postoperative course but returned 16 days later because of increasing right-sided abdominal pain. The pain was constant, sharp, and stabbing without radiation. Abdominal examination showed diffuse right upper quadrant and epigastric tenderness without peritoneal irritation. Laboratory test results included white blood cell count, 14.4 x 10(9)/mm3; hemoglobin, 8.5 g/dL; platelets, 1,483,000; and normal values for lipase, amylase, aspartate transaminase, and alanine transaminase. Evaluation with ultrasonography and vessel Doppler studies showed an occlusive thrombus throughout the portal and splenic veins. The patient underwent intravenous heparin anticoagulation therapy. Her symptoms resolved completely over the next 2 days. The patient is currently receiving warfarin and anagrelide as an outpatient (international normalized ratio, 2). There were no long-term complications caused by portal vein thrombosis. This is the first reported case of portal vein thrombosis after laparoscopic splenectomy in the pediatric population.

Background/Purpose: Rhabdomyosarcoma (RMS) of the perineum or anus is a rare sarcoma of childhood with a poor prognosis. This study reviews the Intergroup Rhabdomyosarcoma Study Group (IRSG) studies I through IV to identify determinants of patient outcome and to refine surgical treatment guidelines. Methods: From 1972 through 1997, 71 eligible patients were treated and studied. The median patient age was 6 years. The majority (64%) were at an advanced stage (clinical group III and IV) at initial presentation and 50% had positive regional lymph node (LN) involvement. Results: The 5-year failure-free survival rate (FFS) for all patients was 45% and the overall survival rate (OS) was 49%. Characteristics that were associated with significantly improved survival rate were primary tumor size less than 5 cm, lower (less advanced) clinical group and stage, negative regional lymph node status, and age less than 10 years. When the extent of disease was controlled for in multivariate analysis, only age less than 10 predicted an improved outcome. The 5-year overall survival rate for patients less than 10 years of age was 71% versus 20% in older patients ( P Conclusions: Because of the high incidence of regional LN involvement in these patients, a strategy of routine surgical evaluation of ilioinguinal lymph nodes in all patients with perineal or anal RMS is recommended. J Pediatr Surg 38:347-353. Copyright 2003, Elsevier Science (USA). All rights reserved.

10004 Background: The long-term event free survival (EFS) for IRRMS is 65%. Since VI had significant activity in metastatic and recurrent RMS, we tested whether adding VI to VAC would improve EFS for IRRMS. Methods: Patients (pts) with alveolar (A)RMS or incompletely resected (Group III) embryonal (E)RMS arising in an unfavorable primary site (Stage 2/3), both without distant metastases, < 50 years, and adequate organ function were eligible to be randomized to 42 weeks of VAC (V=1.5 mg/m2, A=0.045 mg/kg, C=1.2 g/m2 every 3 weeks) vs VAC/VI (I=50 mg/m2/day x 5 days) intravenously; doses were adjusted for children < 3 years; radiation therapy (36-50.4 Gy) was started at week 4, with individualized local control for children < 2 years allowed. The primary study endpoint was EFS. The study was designed with 80% power (5% 1-sided alpha level) to detect an increase in 5 yr EFS from 65% to 76%, a relative risk of 0.64. Results: 481 pts were entered between 12/2006-12/2012, with 461 confirmed eligible. Clinical f...