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Background: Tumor invasion of the spinal canal is detected radiographically in approximately 15% of patients with newly diagnosed neuroblastoma (NB). The optimal clinical approach to maintain excellent survival outcomes while minimizing long-term sequelae is yet to be defined., Methods: Patients with intermediate-risk neuroblastoma (IR-NB) and radiographically identified intraspinal tumors who were treated on the Children's Oncology Group study ANBL0531 were studied prospectively to evaluate neurologic outcomes related to cord compression. Patients were defined as being symptomatic versus asymptomatic based on reporting of neurologic motor deficits at diagnosis. Patient characteristics, tumor biology, chemotherapy treatment, surgical interventions, and neurologic and disease outcomes are reported., Results: Of the 92 patients with intraspinal tumors, 42 (46%) were symptomatic and most (73%) had complete resolution of symptoms. Age, degree of motor deficit, and duration of symptoms at diagnosis were not associated with complete resolution. While symptomatic patients were more likely to undergo upfront laminectomy, laminectomy was not associated with improvement of motor symptoms. Administration of additional chemotherapy beyond initial treatment assigned per protocol to achieve the treatment end point was not associated with achieving symptom resolution., Conclusion: Patients presenting with motor deficits due to intraspinal tumor had excellent survival and favorable neurologic outcomes, with the majority reporting complete resolution of motor symptoms regardless of severity and duration of symptoms at diagnosis or neurosurgical intervention. Prompt diagnosis and initiation of first-line chemotherapy treatment remain priority, while neurosurgical intervention should be reserved for patients with rapid neurologic deterioration. Biology-based therapy and tumor response should continue to be used to maintain favorable outcomes., (© 2024 Wiley Periodicals LLC.)

Liver tumors account for approximately 1%-2% of all pediatric malignancies, with the two most common tumors being hepatoblastoma (HB) and hepatocellular carcinoma (HCC). Previous Children's Oncology Group studies have meaningfully contributed to the current understanding of disease pathophysiology and treatment, laying groundwork for the ongoing prospective international study of both HB and HCC. Future work is focused on elucidating the biologic underpinnings of disease to support an evolution in risk categorization, advancements in the multidimensional care required to treat these patients, and the discovery of novel therapies., (© 2023 Wiley Periodicals LLC.)

Background: Survival for children with metastatic hepatoblastoma (HB) remains suboptimal. We report the response rate and outcome of two courses of vincristine/irinotecan/temsirolimus (VIT) in children with high-risk (HR)/metastatic HB., Procedures: Patients with newly diagnosed HB received HR window chemotherapy if they had metastatic disease or a serum alpha-fetoprotein (AFP) level less than 100 ng/mL. Patients received vincristine (days 1 and 8), irinotecan (days 1-5), and temsirolimus (days 1 and 8). Cycles were repeated every 21 days. Responders had either a 30% decrease using RECIST (Response Evaluation Criteria in Solid Tumors) criteria OR a 90% (>1 log 10 decline) AFP decline after two cycles. Responders received two additional cycles of VIT intermixed with six cycles of cisplatin/doxorubicin/5-fluorouracil/vincristine (C5VD). Nonresponders received six cycles of C5VD alone., Results: Thirty-six eligible patients enrolled on study. The median age at enrollment was 27 months (range: 7-170). Seventeen of 36 patients were responders (RECIST and AFP = 3, RECIST only = 4, AFP only = 10). The median AFP at diagnosis was 222,648 ng/mL and the median AFP following two VIT cycles was 19,262 ng/mL. Three-year event-free survival was 47% (95% confidence interval [CI]: 30%-62%), while overall survival was 67% (95% CI: 49%-80%)., Conclusion: VIT did not achieve the study efficacy endpoint. Temsirolimus does not improve the response rate seen in patients treated with vincristine and irinotecan (VI) alone as part of the initial treatment regimen explored in this study. Additionally, AFP response may be a more sensitive predictor of disease response than RECIST in HB., (© 2023 Wiley Periodicals LLC.)

Background: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG)., Methods: Everolimus was administered at 5 mg/m 2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients., Results: Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression., Conclusion: Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population., (© 2020 Wiley Periodicals LLC.)

Primary malignant liver tumors are rare but all require surgical resection as part of therapy with curative intent. A minority of patients have resectable tumors at diagnosis. Chemotherapy has a therapeutic role in hepatoblastoma but only one-third of patients have resectable disease at diagnosis. Two children with hepatoblastoma and suboptimal responses to initial chemotherapy received therapy with transarterial radioembolization utilizing yttrium-90 (TARE-Y90) and had significant response leading to resection and remission. The role of TARE-Y90 needs to be studied further to define its use in primary pediatric liver neoplasms., (© 2020 Wiley Periodicals, Inc.)

Background/purpose: To determine the maximum tolerated dose, toxicities, and response of sirolimus combined with oral metronomic therapy in pediatric patients with recurrent and refractory solid and brain tumors., Procedure: Patients younger than 30 years of age with recurrent, refractory, or high-risk solid and brain tumors were eligible. Patients received six-week cycles of sirolimus with twice daily celecoxib, and alternating etoposide and cyclophosphamide every three weeks, with Bayesian dose escalation over four dose levels (NCT01331135)., Results: Eighteen patients were enrolled: four on dose level (DL) 1, four on DL2, eight on DL3, and two on DL4. Diagnoses included solid tumors (Ewing sarcoma, osteosarcoma, malignant peripheral nerve sheath tumor, rhabdoid tumor, retinoblastoma) and brain tumors (glioblastoma multiforme [GBM], diffuse intrinsic pontine glioma, high-grade glioma [HGG], medulloblastoma, ependymoma, anaplastic astrocytoma, low-grade infiltrative astrocytoma, primitive neuroectodermal tumor, nongerminomatous germ cell tumor]. One dose-limiting toxicity (DLT; grade 4 neutropenia) was observed on DL2, two DLTs (grade 3 abdominal pain and grade 3 mucositis) on DL3, and two DLTs (grade 3 dehydration and grade 3 mucositis) on DL4. The recommended phase II dose of sirolimus was 2 mg/m 2 (DL3). Best response was stable disease (SD) in eight patients, and partial response (PR) in one patient with GBM. A patient with HGG was removed from the study with SD and developed PR without further therapy. Western blot analysis showed inhibition of phospho-S6 kinase in all patients during the first cycle of therapy., Conclusion: The combination of sirolimus with metronomic chemotherapy is well tolerated in children. A phase II trial of this combination is ongoing., (© 2019 Wiley Periodicals, Inc.)

Purpose: In children treated for nasopharyngeal carcinoma, proton therapy and postchemotherapy target volumes can reduce the radiation dose to developing tissue in the brain and the skull base region. We analyzed outcomes in children with nasopharyngeal carcinoma treated with induction chemotherapy followed by moderate-dose proton therapy., Methods/materials: Seventeen patients with nonmetastatic nonkeratinizing undifferentiated/poorly differentiated nasopharyngeal carcinoma underwent double-scattered proton therapy between 2011 and 2017. Median age was 15.3 years (range, 7-21). The American Joint Committee on Cancer T and N stage distribution included the following: T1, one patient; T2, five patients; T3, two patients; and T4, nine patients; and N1, six patients; N2, nine patients; and N3, two patients. Median radiation dose to the primary target volume and enlarged lymph nodes was 61.2 Gy (range, 59.4-61.2). Uninvolved cervical nodes received 45 Gy (range, 45-46.8). All radiation was delivered at 1.8 Gy/fraction daily using sequential plans. In 11 patients, photon-based intensity-modulated radiotherapy was used for elective neck irradiation to optimize dose homogeneity and improve target conformity. All patients received induction chemotherapy; all but one received concurrent chemotherapy. Five received adjuvant beta-interferon therapy., Results: Median follow-up was 3.0 years (range, 1.6-7.9). No patients were lost to follow-up. Overall survival, progression-free survival, and local control rates were 100%. Fifteen patients developed mucositis requiring enteral feeding (n = 14) or total parenteral nutrition (n = 1) during radiotherapy. Serious late side effects included cataract (n = 1), esophageal stenosis requiring dilation (n = 1), sensorineural hearing loss requiring aids (n = 1), and hormone deficiency (n = 5, including three with isolated hypothyroidism)., Conclusion: Following induction chemotherapy, moderate-dose proton therapy can potentially reduce toxicity in the brain and skull base region without compromising disease control. However, further follow-up is needed to fully characterize and evaluate any reduction in long-term complications., (© 2019 Wiley Periodicals, Inc.)

Background: Congenital hepatoblastoma, diagnosed in the first month of life, has been reported to have a poor prognosis; however, a comprehensive evaluation of this entity is lacking., Procedure: We retrospectively reviewed two patients from the senior authors' personal series and 25 cases identified in the databases of several multicenter group studies (INT-0098, P9645, 881, P9346, HB 89, HB94, and HB 99). We compared this series with cases of congenital hepatoblastoma previously published in the literature., Results: The 3-year survival in our case series was 86% (18/21) with a follow-up of 44-230 months (median 85.5 months). Presentation and treatment were not substantially different from hepatoblastoma cohorts unselected for age. Survival was comparable to the reported disease free survival for a similar cohort of hepatoblastoma patients unselected for age between 1986 and 2002 (82.5%) [von Schweinitz et al., Eur J Cancer 1997; 33:1243-1249]. The 2-year survival of cases reported in the literature was 0% (0/9) and 42% (10/24) for patients reported before and after 1990, respectively., Conclusions: Congenital hepatoblastoma does not appear to confer a worse prognosis. The improved survival of our current series of patients, collected from the past 20 years of German and American multicenter trials and personal series, suggests that the outcome of hepatoblastoma at this young age is much better than has been historically reported. More rigorous analysis should be conducted in future multicenter trials. It is possible that congenital hepatoblastoma should be treated like all other patients with hepatoblastoma provided that the child is stable enough to proceed with surgery and chemotherapy., (Copyright © 2013 Wiley Periodicals, Inc.)

Surgical resection is the foundation of therapy in hepatoblastoma (HB), yet most patients have unresectable tumors at diagnosis. Patients with resectable tumors have event-free survival (EFS) of 80-90% and can be cured with cisplatin, 5-fluorouracil, and vincristine. Patients whose tumors are unresectable but without overt metastases at diagnosis have EFS of 60-70%, and many can be rendered resectable without doxorubicin. Children with metastatic disease have fared poorly with 20-50% EFS, and new approaches for these patients remain desperately needed. Dose intensification of cisplatin and doxorubicin appears beneficial in high-risk patients. Future treatment strategies, which may be useful, include increasing intensity and/or duration of therapy, developing a maintenance regimen (oral irinotecan), using liver transplantation more often for patients to undergo complete resection, and identifying and incorporating novel agents. A better understanding of the biologic and pathologic factors is critical for predicting tumor behavior and developing more logical risk-based treatments., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Patients with relapsed pediatric sarcomas have a poor outcome and are in need of novel effective therapies., Methods: We retrospectively reviewed the records of patients at Children's Healthcare of Atlanta who were treated with gemcitabine (675 mg/m(2)) intravenously (IV) on Day 1 and Day 8, and docetaxel (75 mg/m(2)) IV on Day 8, repeated every 3 weeks., Results: Nineteen patients with a median age of 11 years were treated from 2006-2010 and received 123 total courses. Two patients (11%), both with rhabdomyosarcoma, demonstrated objectives responses [one complete response (CR) and one partial response (PR)]. Seven other patients (39%) had stable disease (SD). The 1-year progression-free survival (PFS) of the entire cohort was 24% ± 10% with a median time to progression of 2 months (range: 0.5-14 months). The 1-year overall survival (OS) was 43% ± 11%. Grade 3 or 4 toxicities occurred in 14 patients (74%) and 52 courses (42%), and were most commonly hematologic (neutropenia = 37, anemia = 17, and thrombocytopenia = 23 courses)., Conclusions: The dismal outcomes for patients with relapsed and refractory sarcomas and the lack of effective sarcoma salvage regimens highlight the need for new approaches. This report of the therapeutic activity of gemcitabine and docetaxel (GEMDOX) in rhabdomyosarcoma and other pediatric reports describing activity in osteosarcoma and Ewing sarcoma suggest that this combination should be considered for formal evaluation in a pediatric specific clinical trial. At a minimum, it appears to offer a reasonable, tolerable, palliative option., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Despite aggressive treatment for high-risk neuroblastoma (NB), event-free survival (EFS) remains <40%. In single arm studies, intensifying therapy with high-dose chemotherapy and tandem autologous stem cell rescue (HDC/SCR) improved outcome. We retrospectively describe our institutional experience in using HDC/SCR for patients with high-risk NB, focusing on outcome and acute toxicities., Methods: Eighty-four patients with high-risk NB at Children's Healthcare of Atlanta treated over a 12-year time period underwent HDC/SCR as part of upfront therapy; 28 patients received a single HDC/SCR and 56 patients received tandem HDC/SCR. The two groups were compared in terms of EFS, overall survival (OS), and acute transplant related toxicities., Results: Patients who received tandem HDC/SCR had a significantly improved EFS compared with patients who received a single HDC/SCR (4-year EFS 59.3 ± 6.7% vs. 26.8 ± 9.2%, P=0.01). Similarly, the 4-year OS was improved in patients receiving tandem HDC/SCR, though this did not reach statistical significance (70.6 ± 9.2% vs. 44.7±11.2%, P=0.06). Multivariate regression confirmed the prognostic role of the treatment group. None of the patients who underwent a single HDC/SCR developed veno-occlusive disease (VOD), while 17% of patients who underwent tandem HDC/SCR developed mild-to-severe VOD. Rates of other transplant-related acute toxicities were similar., Conclusion: Tandem HDC/SCR for patients with high-risk NB seems to improve survival without significant increases in acute toxicities. This needs to be validated in randomized prospective trials., (Copyright © 2011 Wiley Periodicals, Inc.)

Granulocyte transfusions may be useful for neutropenic pediatric patients with refractory bacterial or fungal infections. Many potential adverse sequelae associated with granulocyte transfusions are well recognized, including febrile reactions, fluid overload, alloimmunization, and lung injury. Other potential adverse sequelae, however, are less well known. This case report describes an infant with familial hemophagocytic lymphohistiocytosis who developed polycythemia (hemoglobin 10-17.6 g/dl) following four daily transfusions of 20 ml/kg of apheresis collected, steroid stimulated donor granulocytes. Expanded knowledge of potential risks of transfused granulocytes will allow for rapid recognition of transfusion-related complications, should they occur., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: The third generation bisphosphonate zoledronic acid has demonstrated efficacy in reducing skeletal-related events in adult patients with multiple cancer types that have skeletal disease. The use of zoledronic acid in pediatric oncology patients with bone metastases for the purpose of reducing pain, improving bone strength and altering the progression of metastatic disease has not been thoroughly evaluated., Procedure: From October 2005 to December 2008, 19 patients at the Aflac Cancer Center received one or more doses of zoledronic acid as part of their therapy. A retrospective review of these patients was performed and information was collected including indication for treatment, toxicities, and outcomes., Results: Most patients (n = 15) received zoledronic acid following relapse of their malignancy with metastatic disease present in one or more bony sites. Hypocalcemia and hypophosphatemia were frequent, but did not result in clinical symptoms. More significant toxicities associated with zoledronic acid, including clinically apparent renal insufficiency and osteonecrosis of the jaw, were not seen. Overall, zoledronic acid was well tolerated in this population., Conclusions: The benefits of zoledronic acid seen in randomized trials of adults with bone metastases have sparked interest in its use for children with metastatic cancer. The administration of zoledronic acid in pediatric oncology appears safe, and may result in improved bone strength and pain control. Further evaluation is warranted to prospectively evaluate its efficacy and long-term safety in pediatric patients with cancer and skeletal metastases., (Copyright © 2010 Wiley-Liss, Inc.)

Background: Local control is essential for the successful treatment of pediatric solid tumors. Complete excision is often not possible and local control therapies are limited. Intracavitary cisplatin (IC-CDDP) may be utilized to supplement local control. The aim of the study was to determine the toxicity and efficacy of locally instilled intracavitary cisplatin in patients with recurrent tumors in closed body cavities., Procedure: From 2001 to 2009, 12 patients (1-20 years) with recurrent or unresectable malignant tumors were treated with IC-CDDP. Nine had pulmonary lesions. Three patients had abdominal tumors. CDDP (200 mg/m(2)) was instilled by chest tube or Tenckhoff catheter. Patients were shifted every 15-30 min to allow distribution. After 4 hr, residual was drained by gravity. In 10/13 courses, sodium thiosulfate (STS) was administered to prevent nephrotoxicity. Three other patients received amifostine., Results: Malignant pleural effusions resolved in 5/7 patients. This response was temporary in three patients. No patients had ascites prior to treatment. Three patients are alive and disease-free, 18 months, 4 years, and 6 years from treatment. They also had surgery and chemotherapy. Transient renal toxicity was noted in most patients. One patient, treated with amifostine, had persistent renal dysfunction., Conclusions: IC-CDDP was effective in treating malignant pleural effusions and may be a palliative option for refractory disease. Long-term survival was achieved in two patients, treated at first diagnosis. The benefit of IC-CDDP in these patients is difficult to assess. Renal dysfunction is usually mild, and typically resolves, but warrants preventive measures with IC-CDDP therapy., (2010 Wiley-Liss, Inc.)

Children with high-risk hepatoblastoma (metastatic disease or a low alpha-fetoprotein at presentation) and those with recurrent disease have an extremely poor prognosis and are in need of novel therapeutic agents and strategies. We describe three patients who were treated with irinotecan (two in combination with vincristine). In two patients, this contributed to a clinical remission. All three patients received a 1- to 2-year course of irinotecan as maintenance therapy and all remain disease free. Treatment was well tolerated with minimal toxicity. Further evaluation of the use of irinotecan as maintenance therapy in high-risk and recurrent HB patients is warranted.

Background: PRETEXT is used to stratify risk in children with hepatoblastoma by the Liver Tumor Strategy Group (SIOPEL) of the International Society of Pediatric Oncology (SIOP). A recent analysis excluding patients that did not survive neoadjuvant chemotherapy, concluded that PRETEXT was superior to Children's Oncology Group (COG) stage for predicting survival. Puzzled by this result, we made a similar comparison of PRETEXT and COG stage. This time, however, we include all patients, and we compare predictive value at diagnosis, instead of after neoadjuvant chemotherapy., Methods: Hepatoblastoma patients in INT-0098 were retrospectively reviewed for PRETEXT and other potential prognostic factors including pathologic subtype, and alpha-fetoprotein (AFP)., Results: Five-year overall survival by PRETEXT was 88.9%, 84.5%, 71.6%, and 30.9%, for PRETEXT I, II, III, and IV, respectively. The 5-year overall survival rates by COG stage were 100%, 97.5%, 100%, 70.2%, and 39.3% for Stage I pure fetal histology (PFH), Stage I unfavorable histology (UH = not PFH), Stage II, Stage III, and Stage IV, respectively. PRETEXT added significant additional prognostic information within the COG Stage III, but not COG Stage IV. Additional prognostic factors statistically significant for an increased risk of death were small-cell-undifferentiated (SCU) histologic subtype and AFP < 100 at diagnosis., Conclusions: PRETEXT, COG stage, SCU histology, and AFP < 100, as assessed at diagnosis, are important determinants of survival that will allow us to better develop common international criteria for risk stratification. Common risk stratification is an essential prerequisite to establish effective cooperation across the ocean in this field of rare tumors.

Atypical hemolytic uremic syndrome remains a challenge to diagnose and treat, with significant acute morbidity and risk for progression to end stage renal disease. Treatment strategies center on plasma exchange but do not necessarily affect the progression of disease. We report the case of a patient with atypical HUS resulting from a mutation in the complement pathway who responded to treatment with steroids and IVIG, therefore avoiding transfusion or plasma exchange., (Copyright 2009 Wiley-Liss, Inc.)