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The purpose of this study was to determine the relationship of 18F-FDG uptake in the primary tumor at diagnosis, during therapy, and after therapy with a histologic response and event-free survival in pediatric and young adult patients with osteosarcoma (OS). Methods: Serial (baseline and 5 and 10 wk after start of therapy) 18F-FDG PET/CT imaging was performed in patients with newly diagnosed OS treated uniformly in a therapeutic trial at a single institution. Whole-body images were obtained approximately 1 h after injection of 18F-FDG. Logistic regression was used to study the association of tumor uptake and changes in SUVmax between 0, 5, and 10 wk for both clinical endpoints. Results: Thirty-four patients (17 males; median age, 12.2 y; age range, 6.8–19.1 y) underwent PET imaging; 25 (74%) had localized disease. Primary tumor locations included the femur (n = 17; 50%), tibia (n = 9; 26%), and humerus (n = 5; 15%). Logistic regression showed that SUVmax at 5 wk (P = 0.034) and 10 wk (P = 0.022) and percentage change from baseline at 10 wk (P = 0.021) were highly predictive of a histologic response. Using SUVmax of 4.04 at week 5, SUVmax of 3.15 at week 10, and 60% decrease from baseline at week 10 as cutoff values, we determined that the respective sensitivities were 0.93, 0.93, and 0.79 and that the respective specificities were 0.53, 0.71, and 0.76. Conclusion: SUVmax on routine images at 5 or 10 wk and percentage change in SUVmax from baseline to week 10 were metabolic predictors of a histologic response in OS. These findings may be useful in the early identification of patients who are responding poorly to therapy and may benefit from a change in treatment.

BACKGROUND: Tumor biopsies are central to the diagnosis and management of cancer and are critical to efforts in personalized medicine and targeted therapeutics. In the current study, the authors sought to evaluate the safety and accuracy of biopsies in children with cancer. METHODS: All biopsies performed in children at the study institution with a suspected or established diagnosis of cancer from 2003 through 2012 were reviewed retrospectively. Patient characteristics and disease-related and procedure-related factors were correlated with procedure-related complications and diagnostic accuracy using logistic regression analysis. RESULTS: A total of 1073 biopsies were performed in 808 patients. Of 1025 biopsies with adequate follow-up, 79 (7.7%) were associated with an adverse event, 35 (3.4%) of which were minor (grade 1-2) and 32 (3.1%) of which were major (grade 3-4) (grading was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The most common major adverse events were blood transfusion (>10 mL/kg; 24 cases) and infection requiring intravenous antibiotics (6 cases). Eleven deaths (1.4%) occurred within 30 days after the procedure, but the procedure may have contributed to the outcome in only 2 cases. A total of 926 biopsies (90.3%) provided definitive histologic diagnoses. Using multivariable analysis, biopsy site, preprocedure hematocrit level, and body mass index were found to be associated with the risk of postprocedural complications (P

Pediatric desmoid tumors (PDTs) represent a group of rare, distinct lesions. While sparse, available literature suggests that PDT are particularly aggressive and difficult to control when compared with their adult counterpart.A retrospective review identified 39 patients who underwent treatment of PDT at St. Jude Children's Research Hospital over a 12-year period. Clinicopathologic and treatment characteristics were analyzed to identify predictors of outcome.A total of 39 patients were treated during the study period, with a total number of 67 resections. Median age was 12.2 years; 49 % of patients were male, and 51 % were female. Median tumor size was 9.8 cm. PDT most commonly arose in the extremities (40 %), thorax (23 %), head and neck (21 %), and trunk (16 %). Also, 18 % of resections had negative margins (R0), 48 % were microscopic positive (R1), and 30 % were macroscopic positive (R2). The 1- and 5-year recurrence-free survival (RFS) was 97.1 and 73.1 %, respectively. Factors associated with worse RFS were patient age 12 years (HR = 5.08, p = 0.038) and tumor size 5 cm (HR = 1.22, p = 0.0597). Margin status did not affect RFS. Selective use of radiation therapy appeared to improve RFS.Our study suggests that margin status alone at the time of extirpation is not a predictor of ultimate cure or likelihood of recurrence. Many patients received adjuvant therapy, with benefits suggested after analysis. For patients with PDT, surgical extirpation should not come at the expense of functional preservation, as overall survival is excellent.

Background Accurate diagnosis is critical for optimal management of pediatric cancer. Pathologists with experience in pediatric oncology are in short supply in the developing world. Telepathology is increasingly used for consultations but its overall contribution to diagnostic accuracy is unknown. Procedure We developed a strategy to provide a focused training in pediatric cancer and telepathology support to pathologists in the developing world. After the training period, we compared trainee's diagnoses with those of an experienced pathologist. We next compared the effectiveness of static versus dynamic telepathology review in 127 cases. Results were compared by Fisher's exact test. Results The diagnoses of the trainee and the expert pathologist differed in only 6.5% of cases (95% CI, 1.2–20.0%). The overall concordance between the telepathology and original diagnoses was 90.6% (115/127; 95% CI, 84.1–94.6%). Conclusions Brief, focused training in pediatric cancer histopathology can improve diagnostic accuracy. Dynamic and static telepathology analyses are equally effective for diagnostic review. Pediatr Blood Cancer 2012;59:221–225. © 2012 Wiley Periodicals, Inc.

BACKGROUND: The objective of this study was to prospectively evaluate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as an early imaging indicator of tumor histologic response to preoperative chemotherapy and as a possible prognostic factor for event-free survival (EFS) and overall survival in pediatric patients with newly diagnosed, nonmetastatic osteosarcoma who were treated on a single, multi-institutional phase 2 trial. METHODS: Three serial DCE-MRI examinations at week 0 (before treatment), week 9, and week 12 (tumor resection) were performed in 69 patients with nonmetastatic osteosarcoma to monitor the response to preoperative chemotherapy. Four DCE-MRI kinetic parameters (the influx volume transfer constant [Ktrans], the efflux rate constant [kep], the relative extravascular extracellular space [ve], and the relative vascular plasma space [vp]) and the corresponding differences (ΔKtrans, Δkep, Δve, and Δvp) of averaged kinetic parameters between the outer and inner halves of tumors were calculated to assess their associations with tumor histologic response, EFS, and overall survival. RESULTS: The parameters Ktrans, ve, vp, and kep decreased significantly from week 0 to week 9 and week 12. The parameters Ktrans, vp, and Δkep at week 9 were significantly different between responders and nonresponders (P = .046, P = .021, and P = .008, respectively). These 3 parameters were indicative of histologic response. The parameter Δve at week 0 was a significant prognostic factor for both EFS (P = .02) and overall survival (P = .03). CONCLUSIONS: DCE-MRI was identified as a prognostic factor for EFS and overall survival before treatment on this trial and was indicative of a histologic response to neoadjuvant therapy. Further studies are needed to verify these findings with other treatment regimens and establish the potential role of DCE-MRI in the development of risk-adapted therapy for osteosarcoma. Cancer 2012. © 2011 American Cancer Society.

Little is known about brain tumors in early infancy. Investigators reviewed the records of 27 patients (12 boys and 15 girls) diagnosed within 120 days of birth. The median age was 66 days (range, 0-110 days) at diagnosis. All patients underwent surgery; 18 received adjuvant chemotherapy, and 3 received adjuvant chemotherapy and radiation therapy. The median follow-up was 2.1 years (range, 0.2-21.6 years). At last encounter, 15 patients were alive, and 11 had no evidence of disease. Ten patients died of progressive disease, and 2 died of treatment-related complications. All survivors experienced late effects, including endocrine, neurologic, and cognitive deficits. Of the 13 patients who completed neurocognitive assessments, 7 had an IQ score less than 70. Children in whom brain tumors arise during early infancy can be cured with conventional therapy; however, contemporary approaches can adversely affect long-term function, and families need to be aware of these effects when making therapeutic decisions.

The standard treatment of osteosarcoma includes cisplatin and high-dose methotrexate (HDMTX); both agents exert significant toxicity, and HDMTX requires complex pharmacokinetic monitoring and leucovorin rescue. In the previous OS91 trial, the treatment of localized disease with carboplatin, ifosfamide, doxorubicin, and HDMTX yielded outcomes comparable to those of cisplatin-based regimens and caused less toxicity. To build on this experience, the authors conducted a multi-institutional trial (OS99) that evaluated the efficacy of carboplatin, ifosfamide, and doxorubicin without HDMTX in patients with newly diagnosed, localized, resectable osteosarcoma.Treatment was comprised of 12 cycles of chemotherapy administered over 35 weeks: 3 cycles of carboplatin (dose targeted to area under the concentration-time curve of 8 mg/mL × min on Day 1) and ifosfamide (at a dose of 2.65 g/m(2) daily ×3 days) and 1 cycle of doxorubicin (at a dose of 25 mg/m(2) daily ×3 days) before surgical resection, followed by 2 additional cycles of the combination of carboplatin and ifosfamide and 3 cycles each of doxorubicin (25 mg/m(2) daily ×2 days) combined with ifosfamide or carboplatin.A total of 72 eligible patients (median age, 13.4 years) were enrolled between May 1999 and May 2006. Forty of the 66 (60.6%) evaluable patients had good histologic responses (90% tumor necrosis) to preoperative chemotherapy. The estimated 5-year event-free survival rate was 66.7% ± 7.0% for the OS99 trial compared with 66.0% ± 6.8% for the OS91 trial (P = .98). The estimated 5-year survival rate was 78.9% ± 6.3% for the OS99 trial and 74.5% ± 6.3% for the OS91 trial (P = .40).The regimen used in the OS99 trial was found to produce outcomes comparable to those of cisplatin-containing or HDMTX-containing regimens. This therapy offers a good alternative for patients, particularly those who demonstrate an intolerance of HDMTX, and for institutions that cannot provide pharmacokinetic monitoring for MTX.

Childhood adrenocortical tumor (ACT), a very rare malignancy, has an annual worldwide incidence of about 0.3 per million children younger than 15 years. The association between inherited germline mutations of the TP53 gene and an increased predisposition to ACT was described in the context of the Li-Fraumeni syndrome. In fact, about two-thirds of children with ACT have a TP53 mutation. However, less than 10% of pediatric ACT cases occur in Li-Fraumeni syndrome, suggesting that inherited low-penetrance TP53 mutations play an important role in pediatric adrenal cortex tumorigenesis. We identified a novel inherited germline TP53 mutation affecting the acceptor splice site at intron 10 in a child with an ACT and no family history of cancer. The lack of family history of cancer and previous information about the carcinogenic potential of the mutation led us to further characterize it. Bioinformatics analysis showed that the non-natural and highly hydrophobic C-terminal segment of the frame-shifted mutant p53 protein may disrupt its tumor suppressor function by causing misfolding and aggregation. Our findings highlight the clinical and genetic counseling dilemmas that arise when an inherited TP53 mutation is found in a child with ACT without relatives with Li-Fraumeni-component tumors.

Paediatric choroid plexus carcinomas (CPC) and adrenocortical carcinomas (ACC) are exceedingly rare tumours, each occurring at an annual rate of 0.3 cases per million children or less. Although both tumour types are associated with Li-Fraumeni syndrome (LFS), the penetrance of germline TP53 mutations in CPC remains to be established. We report here a young boy without a family history of cancer who presented with CPC and subsequently ACC. Genetic testing revealed a novel de novo germline TP53 mutation (E285V). Neither tumour underwent loss of heterozygosity. Consistent with this observation, functional analyses demonstrated that E285V acts as a dominant negative mutant that is defective in regulating target gene expression, growth suppression and apoptosis. These results further strengthen the association between germline TP53 mutations and childhood CPC, even when occurring in the absence of familial tumour susceptibility.

BACKGROUND. Approximately 5% of children with Wilms tumor present with bilateral disease. The treatment challenge is to achieve a high cure rate while maintaining adequate long-term renal function. The authors of this report assessed the feasibility and outcome of nephron-sparing surgery in patients with bilateral Wilms tumor who were treated at a single institution. METHODS. A retrospective review was performed of all children who were treated at St. Jude Children's Research Hospital for synchronous, bilateral Wilms tumors from 1999 through 2006. Imaging studies, surgical techniques, and pathology reports were reviewed. The outcomes evaluated included surgical complications, tumor recurrence, renal function, and patient survival. RESULTS. Twelve patients with synchronous, bilateral Wilms tumors were identified, including 10 patients who underwent successful bilateral nephron-sparing procedures. One patient who presented with renal failure and anaplastic histology underwent bilateral nephrectomies, and 1 patient with intra-atrial tumor extension underwent an ipsilateral nephrectomy/thrombectomy and subsequent contralateral partial nephrectomy. Postoperative complications included persistent urine leak in 3 patients, macroscopic residual tumor in 2 patients, and pyelonephritis in 1 patient. Long-term complications included local tumor recurrence in 2 patients, intestinal obstruction in 2 patients, ureteropelvic junction obstruction in 1 patient, and renal failure in 1 patient. The overall survival rate was 83% (mean follow-up, 3.9 years); both patients who died had bilateral, diffuse, anaplastic histology. CONCLUSIONS. All patients who had bilateral Wilms tumors with favorable histology, except for 1 patient who had extensive tumor thrombus, underwent successful bilateral partial nephrectomies. Complications were minimal, and long-term renal function and survival were excellent. From this experience, the authors concluded that bilateral nephron-sparing surgery should be considered for all patients who have bilateral Wilms tumor with favorable histology, even if preoperative imaging studies suggest that the lesions are unresectable.Cancer 2008. © 2008 American Cancer Society.

At presentation or during treatment, patients with malignantdisease can experience severe pulmonary symptoms due to infec-tion, cancer infiltration or metastasis, toxicity of chemotherapy,transfusion-related acute lung injury, or hemorrhage [1,2]. Rarely,they develop pulmonary alveolar proteinosis (PAP), characterizedby intra-alveolar accumulation of surfactant components andcellular debris, with minimal interstitial inflammation or fibrosis[3]. Patients show progressive dyspnea and hypoxemia with in-creased alveolar-arterial oxygen gradient, a restrictive pattern oflung function, and reduced diffusion capacity [3]. High-resolutioncomputed tomography (CT) shows patchy ground-glass opacifica-tion and interlobular septal thickening, a pattern commonlycharacterized as ‘‘crazy paving’’ [4]. Periodic acid-Schiff (PAS)stainingofabronchoalveolarlavage(BAL)orlungbiopsyspecimenis required to establish the diagnosis [3].PAP has three clinically distinct forms: congenital, acquired,and secondary. Congenital and acquired PAP, and some casesof secondary PAP, involve disruption of the granulocyte-macrophagecolony stimulating factor (GM-CSF) signaling pathway, which isessentialfortheterminaldifferentiationofalveolarmacrophages[5–10].Congenital PAP is caused by mutations in genes encoding the commonb chain of the GM-CSF/interleukin-3/interleukin-5 receptor or genesencoding surfactant protein B or C [5–7]. Acquired PAP is the mostcommon form (more than 90% of total PAP cases) and involvesautoantibodiestoGM-CSF,whicharedetectableinBALfluidandserum[8,9]. Secondary PAP is associated with conditions that reduce thefunction or number of alveolar macrophages, such as hematologicmalignancy, exposure to toxic fumes, or pharmacologic immunosup-pression [11–14].MostreportsofPAPinpatientswithmalignantdiseasehavebeenisolated adult cases, and management is not established. Here wedescribe the clinical, imaging, and pathology characteristics of fivepediatric cases of secondary PAP at St. Jude Children’s ResearchHospital.

Paediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here we analyse 37 adrenocortical tumours (ACTs) by whole-genome, whole-exome and/or transcriptome sequencing. Most cases (91%) show loss of heterozygosity (LOH) of chromosome 11p, with uniform selection against the maternal chromosome. IGF2 on chromosome 11p is overexpressed in 100% of the tumours. TP53 mutations and chromosome 17 LOH with selection against wild-type TP53 are observed in 28 ACTs (76%). Chromosomes 11p and 17 undergo copy-neutral LOH early during tumorigenesis, suggesting tumour-driver events. Additional genetic alterations include recurrent somatic mutations in ATRX and CTNNB1 and integration of human herpesvirus-6 in chromosome 11p. A dismal outcome is predicted by concomitant TP53 and ATRX mutations and associated genomic abnormalities, including massive structural variations and frequent background mutations. Collectively, these findings demonstrate the nature, timing and potential prognostic significance of key genetic alterations in paediatric ACT and outline a hypothetical model of paediatric adrenocortical tumorigenesis. Pediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here the authors analyse the genomes, exomes and transcriptomes of 37 such tumours and identify genetic alterations whose nature, timing and potential interactions are key events with prognostic significance in pediatric adrenocortical tumorigenesis.

Limb-salvage surgery for malignant tumors frequently involves reconstruction with an endoprosthesis anchored to bone by using third-generation cementing techniques. A 10-year-old boy with osteosarcoma had a pulmonary embolus caused by polymethylmethacrylate after having limb-salvage surgery that used high-pressure cementing techniques. He experienced transient postoperative chest pain, and a new wedge-shaped radiodense pulmonary lesion appeared on a computed tomography scan of the chest. A thoracotomy for resection of suspected metastatic osteosarcoma revealed a pulmonary infarct caused by cement embolization. Awareness of this potential complication should prompt investigation of possible pulmonary embolism and may prevent unnecessary thoracotomy.

BACKGROUND. The outcome of patients with metastatic osteosarcoma treated in two consecutive trials from 1986 to 1997 was analyzed to evaluate the efficacy of carboplatin-based multiagent chemotherapy and to identify prognostic factors. The initial study (OS-86) used ifosfamide, cisplatin, doxorubicin, and high-dose methotrexate, and the subsequent study (OS-91) used the same agents at similar doses, but carboplatin was substituted for cisplatin. METHODS. Twelve patients (median age, 15.1 yrs) were treated in OS-86 for osteosarcoma metastatic to the lung only (11 patients) or bone only (I patient), and 17 patients (median age, 15.1 yrs) were treated in OS-91 for osteosarcoma metastatic to the lung only (12 patients), bone only (2 patients), lung and bone (2 patients), or other site (1 patient). RESULTS. Patients with metastatic disease enrolled in OS-86 and those with metastatic disease enrolled in OS-91 did not differ in terms of demographic features, histologic subtype, site of primary tumor, or site of metastases. There was a difference in survival according to treatment protocol (P = 0.054). All survivors (four of whom were enrolled in OS-86 and one of whom was enrolled in OS-91) had lung metastases only. Five-year survival estimates for patients with lung metastases only were 45.5 ± 13.7% (OS-86) and 8.3 ± 5.6% (OS-91) (P = 0.084). Unilateral lung metastases (P = 0.006), no more than three lung nodules (P = 0.014), and surgical remission (P = 0.001) were associated with improved survival probability. CONCLUSIONS. The poor outcome of patients with metastatic osteosarcoma treated in OS-91 justifies the use of cisplatin with its associated toxicity in patients with high-risk disease.

Background: An inherited germline P53 mutation has been identified in cases of childhood adrenocortical carcinoma (ACT), a neoplasm with a high incidence in southern Brazil. The penetrance of ACT in carriers of the point mutation, which encodes an arginine-to-histidine substitution at codon 337 of TP53 (R337H), has not been determined. Objective: To investigate the penetrance of childhood ACT in carriers of the R337H TP53 mutation. Methods: The family histories of 30 kindreds of 41 southern Brazilian children with ACT were obtained. A PCR based assay was used to detect this P53 mutation in a large number of relatives of children with ACT. In all, 927 individuals were tested for the mutation, 232 from the non-carrier and 695 (including the 40 probands) from the carrier parental lines. Results: 40 children with ACT carried the TP53 R337H mutation; the remaining child with ACT was not tested. There was no evidence of Li-Fraumeni syndrome in any of the kindreds; however, seven met the criteria for Li-Fraumeni-like syndrome. The carrier parental line was identified in each kindred. Of the 695 individuals tested in the carrier parental line, 240 (34.5%) were positive for the mutation, while none of the 232 individuals in the other parental line carried the mutation. The penetrance of ACT was 9.9% (95% confidence interval, 8.7% to 11.1%). Conclusions: The TP53 R337H mutation dramatically increases predisposition to childhood ACT but not to other cancers, and explains the increased frequency of ACT observed in this geographic region.

As a single agent the ERBB1 inhibitor, gefitinib (Iressa; ZD1839) showed minimal activity against a panel of 10 pediatric tumor xenografts that do not express the ERBB1 receptor. However, combined with irinotecan (CPT-11), significantly greater than additive activity was observed in four of eight models (P < 0.05), and the combination showed enhanced activity against three additional tumor lines. Breast cancer resistance protein (ABCG2), a transporter that confers resistance to SN-38 (the active metabolite of irinotecan), was readily detected in six of nine xenograft models examined by immunohistochemistry. In vitro gefitinib potently reversed resistance to SN-38 only in a cell line that overexpressed functional ABCG2. However, overexpression of ABCG2 did not decrease accumulation nor increase the rate of efflux of [14C]gefitinib. On the basis of these results and the distribution of Abcg2 in mouse tissues, we assessed the ability of gefitinib to modulate irinotecan pharmacokinetics. Oral gefitinib coadministration resulted in no change in clearance of intravenously administered irinotecan. However, gefitinib treatment dramatically increased the oral bioavailability of irinotecan after simultaneous oral administration. It is concluded that gefitinib may modulate SN-38 activity at the cellular level to reverse tumor resistance mediated by ABCG2 through inhibiting drug efflux and may be used potentially in humans to modulate the oral bioavailability of a poorly absorbed camptothecin such as irinotecan.

BACKGROUND With the introduction of molecularly targeted therapy for gastrointestinal stromal tumors (GISTs), it became important to distinguish GISTs from leiomyosarcomas (LMSs). The authors sought to characterize the clinicopathologic features of these tumors in pediatric patients. METHODS The authors reviewed the medical records of 11 patients for whom GIST or LMS was diagnosed between March 1962 and July 2002 at St. Jude Children's Research Hospital and reclassified the tumors according to current histologic and immunophenotypic criteria. The authors also reviewed the literature pertaining to pediatric GISTs and LMSs. RESULTS Seven patients had GISTs, and four had LMS. The median age of the patients at diagnosis was 11.5 years. At diagnosis, metastases were present in one patient with GISTs and in another with LMS. Unlike the focal distribution of CD117 (KIT) in LMS, diffuse and strong immunostaining was observed in GISTs. Only GISTs expressed CD34. Six patients underwent complete resection (four with GISTs and two with LMS), four patients underwent incomplete resection (three with GISTs and one with LMS), and one patient (with LMS) underwent a biopsy only. Radiotherapy or chemotherapy was used to treat one patient with GISTs and three patients with LMS. One patient with a high-risk GIST (largest dimension of 32 cm and high mitotic count) was treated with adjuvant imatinib mesylate outside the preferred setting of a clinical trial, due to concerns regarding the high risk of tumor recurrence. Four patients with GISTs and two with LMS survived median disease-free a median of 10.4 years and 4.3 years after diagnosis, respectively. Tumors in all but one survivor were completely resected. CONCLUSIONS KIT staining helped to distinguish GISTs from LMSs. Surgery was the treatment of choice for both entities, and tumor resectability was a key prognostic factor. Cancer 2004. © 2004 American Cancer Society.

Malignant infantile osteopetrosis (MIOP), a rare genetic disorder of the osteoclast, is fatal without hematopoietic stem cell transplantation. Primary pulmonary hypertension (PPH), a rare progressive disorder of the pulmonary circulation, is predominately fatal in the absence of successful therapy. A clinical association between these two disorders has not been recognized and a pathophysiologic link between osteoclast function and pulmonary vascular pressure as a rationale for such an association is not readily apparent. Here, we report five infants with MIOP, without cardiac abnormalities, who were found to have PPH after undergoing stem cell transplantation. We suggest that PPH may be linked to a specific variant of MIOP and recognizing the potential for pulmonary hypertension in children with MIOP may lead to a more rapid diagnosis and life-saving intervention. © 2003 Wiley-Liss, Inc.

Background: Pediatric paraganglioma is rare and extraadrenal paraganglioma has not been characterized in children. Methods: The authors reviewed the medical records and pathology samples of children with extraadrenal paraganglioma treated at our institution between December 1978 and September 2000. Clinical presentation, treatment, and outcome were evaluated. Results: Eight patients (median age, 11.4 years) were identified, 4 were boys and none had a family history of paraganglioma or associated syndromes. Primary tumors arose in the retroperitoneum (n = 3), carotid body (n = 2), jugulotympanic ganglion (n = 1), cervical-paraspinal region (n = 1), and lung (n = 1). Extraadrenal paraganglioma had not been suspected at presentation in any patient. Of 5 patients who underwent gross total resection at the time of diagnosis, 4 remain disease free, 1 had microscopic residual tumor and died of disease. Three patients had initially unresectable disease, 2 are disease free after neoadjuvant therapy and delayed surgery, and 1 has persistent disease after tumor embolization and radiotherapy. Conclusions: Pediatric extraadrenal paraganglioma occurs most commonly in the retroperitoneum and head and neck, and the diagnosis usually is not suspected at the time of presentation. Surgery is the mainstay of treatment, and outcome is good after gross total resection. Neoadjuvant therapy can facilitate complete resection of initially unresectable tumors.

BACKGROUND Malignant fibrous histiocytoma (MFH) is a controversial entity. In the current study, the authors reviewed their institutional experience with these tumors to characterize their clinical features in pediatric patients and assess the impact of surgical resection on outcome. METHODS The records of the 28 patients who were diagnosed with MFH or MFH variants of soft tissue between January 1971 and December 2000 were reviewed and the tumors were reclassified according to the World Health Organization guidelines. RESULTS Seventeen patients had MFH; 10 patients had angiomatoid fibrous histiocytoma (FH), and 1 patient had a plexiform fibrohistiocytic tumor. The median age of patients at the time of diagnosis was 7.3 years. The most common primary tumor site was the extremity (n = 14). Metastatic disease (to the lung) was present in only three patients, each of whom had MFH. Of the 17 MFH tumors, 13 were high grade, 8 were invasive, and 6 measured > 5 cm. All angiomatoid FH tumors and the plexiform fibrohistiocytic tumor were noninvasive, and 10 measured ≤ 5 cm. Surgical treatment was comprised of wide local excision with clear margins (n = 18), amputation (n = 3), excision with positive or indeterminate surgical margins (n = 4), partial resection (n = 2), or biopsy only (n = 1). Primary reexcision was performed for 21 patients. The 5-year survival and event-free survival (EFS) estimates for patients with MFH were 76.5% ± 11.2% and 70.6% ± 12.1%, respectively; the 5-year survival and EFS estimates were 100% ± 0% for patients with angiomatoid FH or plexiform fibrohistiocytic tumor. Compared with partial resection or excision, wide local excision or amputation was found to have a positive impact on the probability of EFS in patients with localized disease (P = 0.008). All four patients with metastatic or unresectable MFH had died by the time of last follow-up. CONCLUSIONS MFH should be distinguished from angiomatoid FH and plexiform fibrohistiocytic tumors, both of which are less aggressive. Wide local excision is the treatment of choice, regardless of the histology or grade of the tumor. Patients with metastatic or unresectable MFH appear to have a poor outcome and would benefit from more effective therapies. Cancer 2003;97:2839–47. © 2003 American Cancer Society. DOI 10.1002/cncr.11384

Background and objectives Second pathology review has been reported to improve accuracy in oncologic diagnoses, including pediatric malignancies. We assessed the impact of second review on the diagnosis of pediatric malignancies at a tertiary care referral center in Beirut, Lebanon. Methods Pathology reports of patients treated at the Children's Cancer Institute in Lebanon were retrospectively reviewed for the period 2008–2016 and compared with same samples’ diagnoses at St. Jude Children's Research Hospital. Diagnostic disagreements were divided into major, minor, and none based on their effect on diagnosis and/or patient management. Results Second review was requested for 171 cases, accounting for 19% of all cases during that period. Second opinion was mostly requested for brain tumors (62% of all brain tumor cases) and neuroblastoma for NMYC testing (65% of all neuroblastoma), while hematologic malignancies had the fewest referrals (3% of all hematologic cases). Major disagreements in second review occurred in 20 cases (12% of total), and minor disagreements in 21 cases (12% of total). The largest proportion of major disagreements (71%) occurred in pediatric brain tumors, and novel molecular tests contributed to the diagnosis in 55% of these cases. Conclusions The availability of a specialized pediatric neuropathologist and a basic panel of relevant molecular testing are essential for appropriate diagnosis of pediatric brain tumors. Centers that do not have the available infrastructure in place can benefit greatly from second review referrals for this challenging subset of tumors.

Most prior studies evaluating subsequent malignant neoplasms (SMNs) in patients with neuroblastoma are restricted to long-term survivors and/or their treatment exposures. This study investigates SMNs in patients diagnosed with neuroblastoma at our institution.Records of 646 patients treated for neuroblastoma at St Jude Children's Research Hospital between 1961 and 2005 were reviewed. Data from patients with SMNs were analyzed and the 20- and 30-year cumulative incidence of SMNs and standardized incidence ratio were calculated.Twenty-one patients had a SMN. The 20- and 30-year cumulative incidences of a SMN were 2.6%±0.7% and 4.6%±1.1%, respectively. The standardized incidence ratio was 8.3 (95% confidence interval, 5.0-13.0). Five patients developed a SMN within 5 years from diagnosis. The median latency for the development of acute myeloid leukemia/myelodysplastic syndrome (n=4), sarcomas (n=7), and carcinomas (n=5) were 3.6, 9, and 24.2 years, respectively. Nine patients died from their SMN, including all with acute myeloid leukemia/myelodysplastic syndrome.Patients with neuroblastoma have an increased risk of secondary neoplasia. Modification of risk-adapted therapies will likely alter the affected patient population and the incidence of SMNs. Future studies are necessary to link SMNs to treatment exposures and to evaluate the risk of SMNs beyond 30 years from diagnosis.

Background: The spectrum of cutaneous metastasis of non-hematopoietic neoplasms in the pediatric population is not well documented. We report the histologic diversity of this unusual process over a 30-year period at a tertiary care center for pediatric malignancy (St. Jude Children's Research Hospital, Memphis, TN, USA). Methods: Of 1,971 pathology accessions which included histologic material on skin (1,604 surgical cases and 367 autopsy cases) we found 40 cases (2% of total skin accessions) coded for metastatic non-hematopoietic malignancy. Results: The patients (n=34) ranged in age from 1 month to 20 years (mean=9.8 years) and had a male:female ratio of 1:1. The histologic dtagnoses were as follows: rhabdomyosarcoma NOS (6 cases), embryonal rhabdomyosarcoma (4 cases), alveolar rhabdomyosarcoma (4 cases), neuroblastoma (8 cases), osteosarcoma (2 cases), choriocarcinoma (2 cases), peripheral neuroepithelioma or Ewing's sarcoma (2 cases), malignant rhabdoid tumor (1 case), paraganglioma (1 case), nasopharyngeal carcinoma (1 case), sarcoma NOS (1 case), colon adenocarcinoma (1 case), and malignant melanoma (I case). Conclusions: Cutaneous or subcutaneous metastasis of non-hematopoietic malignancies in children and adolescents is a rare occurrence but in a high percentage of cases may be the first manifestation of disease. The tumors most likely to metastasize to the skin in children are rhabdomyosarcoma and neuroblastoma and they are more likely than adult malignancies to disseminate to multiple distant sites.

Background: Subcutaneous fat necrosis associated with pancreatic disease is a rare event. The clinical cutaneous findings are non-specific erythematous nodules with central softening located predominantly on the lower extremities. The histopathologic features of these lesions are very characteristic and diagnostic. Methods: We present an unusual case of pancreatic panniculitis associated with lupus pancreatitis in a 21-year-old African American female. The patient presented with lower extremity skin nodules, arthralgia, and serositis prior to the diagnosis of systemic lupus and pancreatitis. The skin lesions progressed despite normalization of serum pancreatic enzymes. Following femoral vein catheterization for renal dialysis, she developed a large indurated area over the left lower quadrant, flank, groin, and upper thigh measuring 25 cm. She was treated with repeated debridement, tissue grafts, and hyperbaric oxygen because of a clinical suspicion of necrotizing fasciitis. Results: Examination of skin biopsies and debrided tissue revealed the pathognomonic features of pancreatic panniculitis without any evidence of necrotizing fasciitis. Organisms were not detected by tissue examination or microbiologic cultures. Conclusions: This case illustrates the potential role of vascular trauma in the pathogenesis of pancreatic panniculitis.

Ocular manifestations have been attributed to the Epstein-Barr virus (EBV), largely on the basis of seroepidemiologic data. Two patients who developed conjunctival disease as the presenting feature of EBV infection are reported, each confirmed by in situ hybridization of EBV genome in affected tissue biopsy specimens. Recognition of EBV-induced ocular disease as an initial presentation of clinical EBV infection is important to the practitioner because of the ubiquitous nature of this herpesvirus.

BACKGROUND Bone sarcomas of the head and neck are difficult to resect. The authors reviewed their institutional experience with these tumors to characterize patients' clinical findings and to assess the impact of surgical resection on outcome. METHODS The records of the 28 patients with bone sarcomas originating in the head and neck treated at St. Jude Children's Research Hospital between March 1962 and January 1998 were reviewed. RESULTS There were 10 males and 18 females (median age, 12.6 years) each with a single sarcoma: osteosarcoma (18), Ewing sarcoma (7), malignant fibrous histiocytoma (MFH) (2), and fibrosarcoma (1). Primary tumor sites included the maxilla (13), skull (10), mandible (2), and other sites (3). All but one patient with Ewing sarcoma had localized disease at the time of diagnosis. All patients underwent surgery: complete resection, 8; gross total resection, 4; incomplete resection, 14; and biopsy only, 2; 22 also received chemotherapy. Radiotherapy was given to all patients with Ewing sarcoma and to four patients with primary osteosarcoma. Twelve patients survived a median of 8.4 years after diagnosis, 14 died of disease, and 2 died of unrelated causes. Local disease progression was evident in 12 patients (9 with osteosarcoma, 2 with MFH, and 1 with Ewing sarcoma) who died of disease, 9 of whom had the initial treatment of biopsy alone or incomplete resection. Patients with osteosarcoma who had the initial treatment of incomplete resection or biopsy alone were more likely to experience local failure (P = 0.001) and had poorer survival (P = 0.014) than those who underwent complete or gross total resection. CONCLUSIONS Bone sarcomas of the head and neck are rare among children and most often are localized at the time of diagnosis. Incomplete resection of osteosarcoma is associated with local failure and poor outcome. Although aggressive surgery is essential for the cure of osteosarcoma, its necessity in the treatment of Ewing sarcomas remains controversial. Cancer 2000;88:2172–80. © 2000 American Cancer Society.

In pediatric oncology patients, hemorrhagic cystitis may be a life-threatening complication of bone-marrow transplantation, chemotherapy, and/or radiation therapy. The inciting agent in urine can affect the entire urothelium from the renal collecting system to the bladder, and the severity of disease can vary. The radiologist often plays a key role in the diagnosis, follow-up, and occasionally the treatment of hemorrhagic cystitis and its complications. This review discusses the imaging findings in the kidneys and bladder in patients with hemorrhagic cystitis both before and after treatment for this disease. Findings on two-dimensional sonography, color Doppler and power Doppler sonography, computed tomography, magnetic resonance imaging, antegrade pyleography, and cystography are presented.

BACKGROUND Hemangiopericytoma (HPC) is a soft-tissue neoplasm most commonly seen in adults; only 5–10% of cases occur in children. Childhood HPC comprises two distinct clinical entities. In children older than 1 year, it behaves in a manner similar to adult HPC. Infantile HPC, however, although histologically identical to adult HPC, has a more benign clinical course. The reasons for these differences in the natural history of HPC are not well understood. METHODS The authors reviewed the clinicopathologic features of HPC as well as the treatment and outcomes of the 12 children (9 males and 3 females) treated for this disease at St. Jude Children's Research Hospital over a 35-year period. RESULTS At diagnosis, 9 patients were older than 1 year and 3 were younger than 1 year. Among the 9 older patients, tumors were most commonly found in the lower extremities (n = 5). One patient had been treated for acute lymphoblastic leukemia 15 years earlier. One patient had metastatic disease at diagnosis, and three had unresectable tumors. Two patients experienced objective responses to chemotherapy. Three patients died of disease progression. Among the three infants, two had unresectable disease at diagnosis, and both experienced excellent responses to neoadjuvant chemotherapy. In one case, the response of the tumor to chemotherapy correlated with maturation to hemangioma. All three infants are alive without evidence of disease. CONCLUSIONS HPC in children older than 1 year does not differ from adult HPC, and aggressive multimodality therapy is required. Infantile HPC, on the other hand, is characterized by better clinical behavior, with documented chemoresponsiveness and spontaneous regression, and requires a more conservative surgical approach. In some cases of infantile HPC, this benign behavior correlates with maturation to hemangioma. Cancer 2000;88:198–204. © 2000 American Cancer Society.

Purpose: The occurrence of extraosseous Ewing’s sarcoma (ES) in deep soft tissues has been well described, but cases in which this tumor occurs in a primary cutaneous or subcutaneous site have rarely been reported. The superficial variant may be less aggressive than are the more common bony and deep soft tissue counterparts with an apparently favorable outcome. A retrospective review of patients with cutaneous or subcutaneous ES was conducted to analyze outcome and patterns of failure. Methods and Materials: Between July 1985 and March 1997, 14 patients with cutaneous or subcutaneous ES were treated at St. Jude Children’s Research Hospital. The median age at presentation was 16 years (range 7–21 years). Anatomic locations included trunk and pelvis (7), upper or lower extremity (4), and head and neck (3). The median size of the lesion was 3 cm (range, 1–12 cm). Thirteen had definitive surgical resections, and one had biopsy of the mass at the time of referral. They were enrolled on institutional (12) or cooperative group (2) protocols. All patients received chemotherapy, composed of vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide, and dactinomycin. Patients on institutional protocols received radiation (36 Gy) to the operative bed (150–180 cGy/fraction/day). Postoperative radiotherapy was omitted for 2 patients who had complete resection on the cooperative group study. Results: No patients had metastatic disease at presentation. Thirteen patients had wide local excision of the primary tumors prior to enrollment on chemotherapy; surgical margins were negative (10), microscopically positive (2), and indeterminate (1). Eleven patients received radiotherapy to the tumor bed; 2 with clear surgical margins were treated without irradiation. The patient who had biopsy only received induction chemotherapy followed by definitive surgical resection and postoperative radiotherapy. The median follow-up was 77 months (range 17–111 months). None of the patients has developed local recurrence or distant metastasis. Several of the patients developed treatment-related sequelae, including veno-occlusive disease of the lung and hemorrhagic cystitis (1), myelodysplastic syndrome (1), chemotherapy-induced ovarian failure (1), moist desquamation (1), and dermatofibroma within the radiotherapy volumes (1). Conclusions: Cutaneous and subcutaneous ES are associated with an indolent course and a favorable prognosis when treated with combined modality therapy. Elimination of radiation therapy following complete resection has been tested in the POG 9354 trial. The high rate of local control, low rate of metastatic disease, and excellent overall outcome may suggest a role for less intensive chemotherapy, as well as tailoring to diminish or avoid radiation therapy in completely resected cases, with a goal to minimize toxicity while maintaining a high cure rate.

The large cell (LC) subtype is a recently described histologic variant of medulloblastoma (Mb) associated with a rapid and aggressive clinical course. We describe the genomic profile of a LC-Mb tumor obtained from a patient who developed recurrent and fulminant disease despite ‘good-risk’ features at diagnosis and state- of-the-art multidisciplinary therapy. The tumor sample was analyzed using comparative genomic hybridization (CGH) and complementary molecular approaches. CGH revealed amplicons at chromosome bands 2p24–25, 2q12–22, and 17p11; losses of chromosomes 11q and 18; and low-level gains of 3q, 11p, 13q and 14q. Southern blot analysis confirmed N-myc amplification. No evidence of p53 mutation was detected. The genomic profile of this LC-Mb tumor sample revealed a distinctive pattern of genetic alterations including amplification of N-myc and anonymous oncogenes at chromosome bands 2q12–22 and 17p11. These genomic abnormalities are uncommon in other subtypes of Mb.

Second malignancies occur in 2-3% of survivors of pediatric osteosarcoma; treatment-related hematologic and solid malignancies have both been described. We present two cases of patients with pulmonary nodules that developed more than 2 years after treatment of osteosarcoma. Both lesions were completely resected and pathology revealed bronchioloalveolar carcinoma (BAC). Primary BAC is extremely rare in children; however, cases of this malignancy have been described in survivors of pediatric cancer. BAC may present as a solitary pulmonary nodule indistinguishable from a metastatic lesion and should be included in the differential diagnosis of pulmonary nodules in survivors of pediatric cancer.

PURPOSE: The rarity and heterogeneity of pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) has precluded meaningful analysis of prognostic factors associated with surgically resected disease. To define a population of patients at high risk of treatment failure who might benefit from adjuvant therapies, we evaluated the relationship between various clinicopathologic factors and clinical outcome of children and adolescents with resected NRSTS over a 27-year period at our institution. PATIENTS AND METHODS: We analyzed the records of 121 consecutive patients with NRSTS who underwent surgical resection between August 1969 and December 1996. Demographic data, tumor characteristics, treatment, and outcomes were recorded. Univariate and multivariate analyses of prognostic factors for survival, event-free survival (EFS), and local and distant recurrence were performed. RESULTS: At a median follow-up of 9.2 years, 5-year survival and EFS rates for the entire cohort were 89% ± 3% and 77% ± 4%, respectively. In univariate models, positive surgical margins (P = .004), tumor size ≥ 5 cm (P < .001), invasiveness (P = .002), high grade (P = .028), and intra-abdominal primary tumor site (P = .055) adversely affected EFS. All of these factors except invasiveness remained prognostic of EFS and survival in multivariate models. Positive surgical margins (P = .003), intra-abdominal primary tumor site (P = .028), and the omission of radiation therapy (P = .043) predicted local recurrence, whereas tumor size ≥ 5 cm (P < .001), invasiveness (P < .001), and high grade (P = .004) predicted distant recurrence. CONCLUSION: In this largest single-institution analysis of pediatric patients with surgically resected NRSTS, we identified clinicopathologic features predictive of poor outcome. These variables should be prospectively evaluated as risk-adapted therapies are developed.

In normal somatic cells, the methylation pattern of DNA is stably maintained by DNA (cytosine-5-)-methyltransferase (DNA methyltransferase). Increased expression of DNA methyltransferase has been detected in many types of human cancer and has been thought to play an important role in tumorigenesis. In our study, we developed a standardized reverse transcription-polymerase chain reaction (RT-PCR) assay to determine the mRNA levels of DNA methyltransferase in rhabdomyosarcoma, the most common soft tissue cancer in children. Using this assay, expression of DNA methyltransferase was analyzed for 32 rhabdomyosarcomas and 12 normal skeletal muscle samples. All tumor samples, of which 18 were embryonal and 14 were alveolar subtype, showed increased expression of DNA methyltransferase after normalization to beta-actin. Compared to normal skeletal muscle, the average increase of DNA methyltransferase expression was 6.7-fold (6.7 +/-()0.96) in the embryonal tumors and 3.7-fold (3.7 +/- 0.46) in the alveolar rhabdomyosarcomas. The difference in the average increase of the DNA methyltransferase expression was statistically significant in the 2 rhabdomyosarcoma subtypes, which have distinct etiologies and clinical behaviors. Our results are consistent with previous reports that an increase in DNA methyltransferase activity is associated with neoplastic transformation; however, the role of increased DNA methyltransferase expression in the development and progression of rhabdomyosarcoma needs to be investigated in future studies.

Background Because the natural history of pediatric patients with metastatic nonrhabdomyosarcomatous soft-tissue sarcomas (NRSTS) had not been well described, we retrospectively reviewed our single-institution experience with these tumors. Procedure We identified 26 patients with metastatic NRSTS who were treated at St. Jude Children's Research Hospital from December 1971 through July 1995. We evaluated the characteristics of each patient, including age, sex, primary site, stage, type of therapy received, and outcome. Sites of metastatic disease at diagnosis and relapse were noted. Results The median age of the 26 study patients at diagnosis was 14.8 years; 54% of patients were male and 69% were white. The most common histologies were synovial sarcoma, alveolar soft-part sarcoma, and malignant fibrous histiocytoma. Most primary tumors (73% of cases) occurred in the trunk or extremities. Most patients presented with large (>5 cm), high-grade lesions. All 26 patients received chemotherapy, and 8 responded to an ifosfamide- or cyclophosphamide-doxorubicin–based regimen. Radiotherapy was administered to 15 patients, and 13 had a partial or complete resection of the primary tumor. Six patients underwent thoracotomy. The estimated 2-year survival for the cohort was 34.6% ± 8.9%; the 2-year progression-free survival was 15.4% ± 6.3%. The lung was the most common site of failure. Conclusions Children with metastatic NRSTS have a poor outcome, which is similar to that in adults. More effective systemic chemotherapy is needed to facilitate complete surgical resection of primary and metastatic sites. Aggressive pulmonary metastatectomy can increase disease control. Med. Pediatr. Oncol. 33:76–82, 1999. © 1999 Wiley-Liss, Inc.

Purpose To evaluate the long-term sequelae of treatment for malignant germ cell tumors (GCT) during childhood and adolescence. Patients and methods Of 128 patients treated for GCT at St. Jude Children's Research Hospital between 1962 and 1988, 73 are long-term survivors (continuously disease-free for > or =5 years after diagnosis), with a median follow-up of 11.3 years). Survivors' ages at diagnosis ranged from birth to 18.3 years (median, 9.2 years); 64% (47 patients) were female. Initial surgical resection was followed by observation for stage I germinomas (n = 2), testicular tumors (n = 13), and selected cases of ovarian or sacrococcygeal tumors (n = 2), and by radiation therapy (RT) for patients with stage II to III germinoma (n = 8). The remaining 48 patients received postoperative chemotherapy (vincristine, dactinomycin, and cyclophosphamide [VAC] +/- doxorubicin, 1962 to 1978; VAC and/or cisplatin, vinblastine, and bleomycin [PVB], 1979 to 1988). RT was added to the chemotherapy for 21 patients. Late complications involving various organ systems and their relationship to treatment were evaluated. Results More than two-thirds of long-term survivors (n = 50) had at least 1 complication, and half (n = 38) had > 1 organ system affected. The systems most often involved included the musculoskeletal (41% of survivors), endocrine (42%), cardiovascular (16% excluding those who had only abnormal chest radiograph), gastrointestinal (25%), genitourinary tract (23%), pulmonary (19%), and neurologic (16%) systems. High-frequency hearing loss occurred in 58% (11 of 19) of patients treated with cisplatin. Musculoskeletal, gastrointestinal, and urinary tract abnormalities were most frequent in patients whose treatment included RT. Conclusions A high frequency of late effects after treatment for pediatric GCT, particularly in patients who received RT, was demonstrated. Treatment sequelae could be anticipated from the intensity and type of therapeutic modalities. Treatment-directed screening evaluations may improve quality of life in long-term survivors of pediatric GCT through timely identification of sequelae that can be prevented or ameliorated.

In many different murine models, the immunogenicity of tumor cells can be increased by transduction with a range of immunostimulatory genes, inducing an immune response that causes regression of pre-existing unmodified tumor cells. To investigate the relevance of these animal models to pediatric malignancy, we used autologous unirradiated tumor cells transduced with an adenovirus-IL-2 to immunize 10 children with advanced neuroblastoma. In a dose-escalation study, we found that this tumor immunogen induced a moderate local inflammatory response consisting predominantly of CD4+ T lymphocytes, and a systemic response, with a rise in circulating CD25+and DR+ CD3+ T cells. Patients also made a specific antitumor response, manifest by an IgG antitumor antibody and increased cytotoxic T-cell killing of autologous tumor cells. Clinically, five patients had tumor responses after the tumor immunogen alone (one complete tumor response, one partial response, and three with stable disease). Four of these five patients were shown to have coexisting antitumor cytotoxic activity, as opposed to only one of the patients with nonresponsive disease. These results show a promising correlation between preclinical observations and clinical outcome in this disease, and support further exploration of the approach for malignant diseases of children. © 1998 by The American Society of Hematology.

BACKGROUND This study attempted to evaluate the childhood malignancies associated with computed tomography (CT) detected peritoneal metastases as well as the diagnostic imaging characteristics of these metastases as shown on CT. METHODS The authors reviewed all available pathology specimens and abdominopelvic CT scans of patients identified as having peritoneal metastases at three childhood cancer centers. Patient demographics, primary diagnosis, and CT characteristics of such metastases were evaluated. RESULTS Peritoneal metastases were identified by CT in 32 children with cancer either at diagnosis (n = 20) or up to 6.2 years from diagnosis (n = 12). On CT, peritoneal disease appeared as a mass in 26 cases, as studding in 11 cases, as peritoneal enhancement in 15 cases, and as diffuse caking in 4 cases (15 patients had > 1 category of peritoneal metastasis). Thirteen patients had concurrent metastases in other sites. Fourteen patients died of progressive disease at a median of 10 months from the time peritoneal metastases were identified on CT. At last follow-up, the remaining 18 patients were alive, with follow-up ranging from 1 month to 9.7 years. As expected, peritoneal metastases were identified in patients with germ cell tumors and colon carcinoma. However, they also were observed in patients with epithelioid carcinoma, leiomyosarcoma, pineoblastoma, neuroblastoma, melanoma, and peripheral neuroectodermal tumor. CONCLUSIONS Peritoneal metastases have variable appearance on CT, but most commonly appear mass-like. They are associated with a wider range of primary diagnoses than reported previously. The outcome varies with the type of the primary tumor and its responsiveness to existing therapies. Cancer 1998;83:385-390. © 1998 American Cancer Society.

Tumor cells that have been genetically modified to express immunostimulatory genes will induce effective antitumor responses in a range of syngeneic animal models. For human applications, transduced autologous tumor cell lines are often difficult or impossible to prepare, so that there are strong incentives for substituting a standardized allogeneic tumor cell line. However, such lines may be inferior immunogens if they differ from host tumors in the antigens they express. We have evaluated the safety, immunostimulatory, and antitumor activity of an interleukin-2-secreting allogeneic neuroblastoma cell line in 12 children with relapsed stage IV neuroblastoma. They received two to four subcutaneous injections of cells in a dose-escalating schedule, up to a maximum of 10(8) cells per injection. There was induration and pruritus at the injection site, and skin biopsies revealed mild panniculitis with CD3+ cells surrounding scanty residual tumor cells. There was a limited but significant peripheral monocytosis. No patient showed any increase in direct cytotoxic effector function against the immunizing cell line, but 3 patients had a rise in the frequency of neuroblastoma-reactive cytotoxic T lymphocyte precursor cells. One child had > 90% tumor response (PR), 7 had stable disease, and 4 had progressive disease in response to vaccine alone. Although these results offer some encouragement for the continued pursuit of allogeneic vaccine strategies in human cancer, the antitumor immune responses we observed are inferior to those obtained in an earlier immunization study using autologous neuroblastoma cells. Hence, we suggest that this earlier approach remains preferable, its difficulties notwithstanding.

Background. Standard therapy for pediatric nonrhabdomyosarcoma soft tissue sarcomas (PNRSTS) consists of surgical resection with or without radiotherapy. The role of chemotherapy in the treatment of these tumors has not yet been defined. We investigated the efficacy and toxicity of an ifosfamide-based regimen in controlling disease in children with high-risk PNRSTS. Patients and Methods. Between January 1992 and June 1994 at St. Jude Children's Research Hospital, we treated 11 children and young adults with PNRSTS who were at high risk for treatment failure by using a combined modality regimen that comprised aggressive surgery, radiotherapy, and chemotherapy including vincristine, ifosfamide, and doxorubicin (VID). Nine of these patients had grade 3 disease and one had grade 2 tumor; due to insufficient tissue, the disease grade of the remaining patient could not be established. Metastases were present at diagnosis in 2 children. Results. Therapy was generally well tolerated, with minimal morbidity and no mortality. The most common toxicity was grade 4 neutropenia, which occurred in 51% of evaluable courses. Among 4 patients evaluable for response to chemotherapy alone, 1 child attained a partial response and 3 had stable disease. One child had a response to chemotherapy and concurrent irradiation. At a median follow-up of 30 months, 10 of 11 patients are alive; 8 of 11 patients are alive without evidence of disease. Conclusion. Aggressive multimodality therapy for PNRSTS is well tolerated, despite frequent and profound neutropenia. Although adjuvant chemotherapy for this group of cancers remains unproved, the rate of tumor control achieved in this pilot study encourages further investigation in a multi-institutional setting.

Background The objectives of this study were to compare vincristine/actinomycin D/cyclophosphamide/adriamycin (VACA) with VACA plus imidazole carboxamide (DTIC) (VACAD) therapy in regards to complete/partial response and event free survival rates in children and adolescents with metastatic non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) or previously chemotherapy-naive recurrent NRSTS or locally persistent gross residual tumor after surgery and radiation therapy. Procedures Between 1986 and March 1994, 75 patients entered this randomized study comparing VACA and VACAD, given at 3 week intervals. Sixty-one patients were considered eligible and received chemotherapy and radiation therapy to the primary tumor and areas of metastases. Thirty-six patients had regional unresected (Group III) disease, and 25 had metastatic disease (Group IV) at time of accession. Thirty-six patients received VACA(11 were not randomized), and 25 received VACAD. Results With a median follow-up of greater than 4 years, overall and event-free survival for all eligible patients are 30.6% and 18.4%, respectively (S.E: 9.5% and 6.8%). There was insufficient evidence that DTIC offered any advantage to event free survival, but there was evidence for better outcome for patients in Group III disease in comparison to patients with Group IV disease, and for patients with a Grade 1 and 2 histology in comparison to Grade 3 lesions. Conclusions Combination chemotherapy with VACA and VACAD were insufficient to prevent recurrent or progressive disease in children and adolescents with high stage NRSTS. The use of vincristine/ifosfamide/doxorubicin with cytokine support is under study. Med. Pediatr. Oncol. 30:201–209, 1998. © 1998 Wiley-Liss,Inc.

The predisposition to malignancy that is dominantly inherited in Li-Fraumeni syndrome is associated with germline mutations of the tumour suppressor gene p53. Although second malignant neoplasms have been described in children with p53 mutations, the synchronous occurrence of two embryologically different tumours in these children has not been reported. A 20 month old girl with failure to thrive and congenital heart defects was found to have unilateral adrenal masses which, at surgical removal, proved to be an adrenocortical carcinoma and a ganglioneuroblastoma. Further investigation showed a germline p53 mutation and Turner syndrome. It remains to be determined what effect the 45,X chromosomal complement may have on the expression of neoplasms seen in patients with p53 germline mutations.

Clinical features and treatment of 36 consecutive pediatric patients with thalamic glial tumors confirmed by histology and characterized by neuroimaging were reviewed to identify prognostic factors. The median age at diagnosis was 10 years (range 1–18 years). Twenty-four patients had low-grade tumors (juvenile pilocytic astrocytoma n = 9, fibrillary astrocytoma n = 6, astrocytomas not otherwise specified n = 6, ganglioglioma n = 2 and oligodendroglioma n = 1) and 12 patients had high-grade tumors (glioblastoma multiforme n = 7, anaplastic astrocytoma n = 4 and unclassified malignant tumor n = 1). With a median follow-up of 4.3 years among survivors, estimates of 4-year progression-free survival (PFS) and overall survival (OS) for the entire group are 28 ± 10 and 37 ± 10%, respectively. Low-grade tumors were associated with a significantly better 4-year PFS (36 ± 12 vs. 0% for the high-grade group; p = 0.03) and OS (52 ± 12 vs. 0%; p < 0.001). This review identified that bithalamic involvement, characterized by neuroimaging, exerted an independent and significant negative impact on PFS and OS for patients with low-grade tumors. Estimates of 4-year PFS and OS among patients with low-grade bithalamic versus monothalamic tumors were 58 ± 15 vs. 0% and 85 ± 11 vs. 0% (p < 0.00001), respectively. The presence of bithalamic involvement did not affect outcome among patients with high-grade tumors. Additionally, age at diagnosis, enhancement with neuroimaging contrast, extension beyond the thalamus and extent of surgical resection did not correlate with overall outcome. Because treatment approaches varied during the study period, the impact of radiation therapy or chemotherapy could not be assessed. This contemporary, single-institution series of pediatric thalamic glial tumors demonstrates, for the first time, the statistical significance of bithalamic involvement as a marker of poor prognosis among patients with low-grade glial lesions.

Epithelioid sarcoma is a rare soft tissue sarcoma with a propensity for local aggressiveness, regional nodal spread, and pulmonary metastases. We report a case of epithelioid sarcoma in a neonate with bilateral optic nerve hypoplasia who developed liver, kidney, and bone metastases. The unusual presenting features and pattern of disease progression in this patient suggest that a different disease evaluation strategy should be considered for infants with epithelioid sarcoma.

BACKGROUND Neuroblastoma is the most common extracranial solid tumor among pediatric patients, and orbital metastatic disease is not uncommon in these children. Physical signs as a consequence of orbital metastases, such as proptosis and periorbital ecchymosis, frequently are encountered. However, subsequent blindness is rare. METHODS A retrospective study was conducted to determine the incidence, related physical findings, treatment, and outcome of children who developed visual loss during treatment for neuroblastoma. Medical records for a 24-year period (1971-1994) were reviewed to identify these patients. The charts, diagnostic imaging studies, and autopsy material of these patients were reviewed. RESULTS Of the 450 patients treated for neuroblastoma at the study institution during this period, 47 presented with abnormalities in physical examination of the eye. Eight of these 47 patients and 7 others developed visual loss in at least 1 eye during the first week after diagnosis (n = 5), during primary therapy (n = 6), at recurrence (n = 2), or after completion of therapy (n = 2). In ten patients the visual loss was a direct consequence of the primary disease process, whereas a direct relationship between loss of vision and neuroblastoma could not be identified in the remaining five patients. Proptosis and periorbital ecchymosis were the most common associated physical findings. Although ten patients received steroids and eight received radiation, visual loss could not be prevented or reversed in these patients. CONCLUSIONS Early initiation of effective, multiagent chemotherapy remains the primary approach for the treatment of neuroblastoma and its ophthalmologic complications. Radiation therapy and steroids may have benefit but failed to show good effect in this series. The prevention and treatment of blindness is probably most relevant in infants and children age < 2 years because they have the best chance for cure. Cancer 1997; 80:1997-2004. © 1997 American Cancer Society.

BACKGROUND The authors hypothesized that the outcomes for young patients who present with primary osteosarcoma of flat bones or secondary osteosarcoma after other primary malignancies are similar because the sites of these tumors rarely makes them amenable to complete surgical resection. METHODS The authors reviewed their experience with 27 patients with primary osteosarcomas involving flat bones and 18 patients with secondary osteosarcomas of any site, evaluating treatment, metastatic patterns, and outcome. RESULTS Eleven of the 27 primary osteosarcomas and 10 of the 18 secondary osteosarcomas were at least partially resectable at the time of initial diagnosis. At last follow-up, 10 of the 27 patients with primary flat bone osteosarcoma were alive, eight of whom were disease free. Three of 18 with the secondary osteosarcoma patients were alive, including one with locally recurrent disease after recent disease resections. Chemotherapy with single or combinations of agents rarely yielded responses for primary flat bone or secondary osteosarcomas. CONCLUSIONS Outcome for both groups of patients was poor due to metastases and failure of local control. Sixteen of the 27 patients with primary osteosarcoma of flat bones died of their tumor; an additional patient died of doxorubicin-related cardiomyopathy and had microscopic disease in the primary site at autopsy. Thirteen of the 18 patients with secondary osteosarcoma died of their second metastatic cancer, 2 additional patients died of doxorubicin-related cardiomyopathy/coccidioidomycosis, and another of acute renal toxicity. Cancer 1997; 80:1171-7. © 1997 American Cancer Society.

BACKGROUND Second malignant neoplasms have been noted infrequently in survivors of osteosarcoma treated before 1970. METHODS For the above reason, the authors surveyed their patients to determine the actuarial incidence and relative risk of second malignancies among patients treated with adjuvant chemotherapy for osteosarcoma. RESULTS Between March 1962 and March 1996, 334 patients received chemotherapy for newly diagnosed primary or metastatic osteosarcoma. Of these patients, 47 presented with metastases, 14 had multifocal osteosarcoma, and 273 had localized disease. Nine patients developed second malignant neoplasms 0.45-17.8 years (median, 6.3 years) after receiving definitive surgery and adjuvant chemotherapy for primary osteosarcoma; 2 of these patients had pulmonary metastasectomies before receiving adjuvant chemotherapy. The second neoplasms comprised two cases of malignant fibrous histiocytoma and one case each of melanoma, glioblastoma multiforme, chondrosarcoma, and carcinoma of the breast: stomach, colon, rectum. The overall 10-year cumulative incidence of second malignancies was 2% ± 1%; by comparison, this rate was 2% ± 1% for patients with localized osteosarcoma but was 8% ± 5% (P = 0.15) for those who presented with metastatic disease. CONCLUSIONS Since the advent of successful adjuvant chemotherapy, more patients are surviving primary osteosarcoma; therefore, the number of osteosarcoma patients who develop second malignancies can be expected to increase. Recognition of osteosarcoma patients who are members of families with Li-Fraumeni syndrome may lead to earlier intervention for these individuals. Cancer 1997; 80:960-5. © 1997 American Cancer Society.

Purpose The outcome for children with advanced-stage rhabdomyosarcoma remains poor with contemporary treatment regimens. Evaluation of new drugs is important to improve clinical outcome. Because methotrexate has shown promising activity in the treatment of patients with recurrent rhabdomyosarcoma, we conducted a phase II trial in untreated children with advanced-stage disease to evaluate the efficacy and safety of this agent. Purpose Patients and Methods: Fifteen patients received 1 to 4 courses of high-dose methotrexate (HDMTX, 12 g/m2). Patients then received standard multiagent chemotherapy (vincristine, dactinomycin, cyclophosphamide, ifosfamide, mesna) with cytokine support and local radiotherapy. Patients who responded to HDMTX received four additional courses of this drug during continuation therapy. Purpose Results: Twelve patients were evaluable for response after 2 or more courses of HDMTX; 4 achieved a partial response (33.3%). After administration of standard chemotherapy and radiation, the estimated 2-year progression-free survival for all patients was 56% (SD 15%). The drug was well-tolerated and the most common side effects included mucositis, transient elevation of transaminases, and neutropenia. The four patients who received additional courses of HDMTX during continuation therapy had limited toxicity which included mucositis, anemia, and thrombocytopenia. Purpose Conclusions: About one-third of children with previously untreated advanced-stage rhabdomyosarcoma responded to HDMTX. Its different mechanism of action and non-overlapping toxicity with other agents make HDMTX an attractive candidate for incorporation into front-line treatment regimens for rhabdomyosarcoma.