Articles

Impact of pulmonary tumor burden in favorable histology Wilms tumor outcomes: A report from the Children’s Oncology Group Study AREN0533. [1] Dix DB et al., J Clin Oncol. 2025 Dec 20;43(36):3822-3832. PMID: 41223336.

Favorable histology Wilms tumor (FHWT) prognostication is influenced by disease stage, with children with pulmonary metastases having poorer outcomes than those with localized disease. Additional factors that influence prognosis of FHWT include biologic markers such as loss of heterozygosity at 1p and 16q and 1q chromosome gain. Patients with 1q gain have been found to have higher rates of pulmonary metastases at presentation (18.3%) than those without a 1q gain (9.4%); with 1q gain negatively impact pulmonary nodule response to chemotherapy.

This study included 288 patients enrolled on AREN0533 from 2007 to 2013 with FHWT who presented with Stage IV disease with pulmonary-only metastases. The impact of pulmonary nodule burden (size and number) on event free survival and overall survival as well as the association with 1q gain were assessed. The study identified no association between the size or number of pulmonary nodules and the presence of a 1q chromosomal gain. Similarly, they identified no association between the size/number of pulmonary nodules and EFS/OS in FHWT patients. However, on multivariable modeling, the study identified that in children with FHWT with pulmonary metastases at presentation, 1q gain was significantly associated with poorer EFS and OS.

Key Findings:

• Children with FHWT who present with increased numbers of pulmonary metastases and larger pulmonary metastases were more likely to be slow incomplete pulmonary nodule responders to therapy (both p< 0.001), receive pulmonary radiation therapy (both p< 0.001), and be treated on regimen M (both p< 0.001). There was no association between increased number of pulmonary metastases nor larger pulmonary nodules and the presence of 1q gain (p=0.746 and p=0.558, respectively).
• In children treated on regimen DD-4A without pulmonary radiation therapy, children with a largest pulmonary nodule >1 cm had poorer EFS than those with a largest nodule from 6 mm – 1 cm (4-year EFS 63.0% vs 4-year EFS 94.1%, p=0.022).
• On multivariable modeling, including pulmonary nodule size and pulmonary nodule number, 1q gain was independently associated with poorer EFS (HR 3.15 [p=0.0015]) and OS (HR 3.41 [p=0.039]).

Preoperative Radiotherapy in Patients with Localized Ewing Sarcoma Enrolled on AEWS1031: A Report from the Children’s Oncology Group. Indelicato DJ et al., [2] Pediatr Blood Cancer. 2025 Aug;72(8):e31820. PMID: 40415235.

Patients with centrally localized Ewing sarcoma including the chest wall and pelvis have higher rates of microscopically positive margins after resection than Ewing sarcoma in other locations. Historically, post operative XRT has been offered to these patients, but preoperative XRT has the advantage of reducing the volume of normal irradiated tissue and improving tumor resectability due to peripheral tumor fibrosis and necrosis. These advantages have been demonstrated with the use of pre-operative XRT in other sarcoma subtypes.

AEWS1031 was the first North American/Australasia ES cooperative group trial allowing standardized preoperative radiotherapy, intended to minimize the morbidity of combined modality local tumor control as well as improve the likelihood of clear surgical margins. While only a small number of patients received preoperative radiation in this trial, its use facilitated a reduced dose and smaller target volume while maintaining a high rate of R0 resection. The robust pathologic response rate strengthens existing evidence illustrating the radiosensitivity of Ewing sarcoma.

Key Findings:

• Reduced dose preoperative radiation to lower target volumes was associated with high rates of tumor necrosis and R0 resection
• These findings support the incorporation of pre-operative radiation in future risk-stratified ES protocols

Children and Adolescents With Localised Non-Rhabdomyosarcoma Soft Tissue Sarcoma: Results of the CWS-96 and CWS-2002P Prospective Trials With Reclassification of the Trial Data Incorporating the Recent Soft Tissue Sarcoma Registry. [3] Heinz AT et al., Pediatr Blood Cancer. 2026 Feb;73(2):e32159. PMID: 41216926.

Primary tumor resection with wide margins remains the mainstay of treatment for non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), with neoadjuvant chemotherapy and/or radiotherapy used in select cases depending on tumor characteristics and risk group. However, the role of adjuvant chemotherapy and radiotherapy in NRSTS remains uncertain.

The CWS-96 and CWS-2002P trials used a risk-adapted strategy to evaluate whether chemotherapy and radiotherapy could be safely limited in children with localized NRSTS. A total of 872 risk-stratified patients were included (128 low-risk, 99 standard-risk, and 645 high-risk). Complete surgical resection was the strongest predictor of outcomes, with EFS by margin status of 75% and 78% for R0 resections, 65% and 68% for R1 resections, and 41% and 46% for R2 resections in CWS-96 and CWS-2002P, respectively. Low-risk patients who underwent surgery alone experienced 5-year EFS and OS of 82% and 93%, respectively. Intensified anthracycline dosing in high-risk patients did not improve survival outcomes.

Key Findings:

• R0 resection is the strongest predictor of survival in pediatric NRSTS (5-year EFS 75–78% for R0 vs. 41–46% for R2 resections).
• Low-risk patients had excellent 5-year EFS (82%) and OS (93%) with surgery alone. Intensification of anthracycline dosing did not improve survival among high-risk patients (matched analysis showed no difference in EFS, p = 0.23, or OS, p = 0.73).

Enhanced Recovery After Surgery (ERAS) Improves Length of Stay and Decreases Complications After Resection of Abdominal Neuroblastoma. [4] Mansfield SA et al., Pediatr Blood Cancer. 2025 Nov;72(11):e31971. Epub 2025 Aug 8. PMID: 40781829.

The ERAS Society promulgates Enhanced Recovery After Surgery guidelines. This society developed from an adult colorectal surgery working group but expanded to include multiple specialties, including in pediatrics. Decreased complications and/or lengths of stay have been shown across many areas of surgery using standardized preoperative, intraoperative, and postoperative protocols. In pediatric surgery, these principles have been successfully demonstrated in pediatric colorectal surgery (Short et al., JPS, 2017) and pediatric surgical oncology (Mansfield et al., JPS, 2025), neonatal ERAS guidelines have been developed (Pilkinton et al., JAMA Surgery, 2024), and the ENRICH-US multicenter randomized pediatric surgery ERAS trial is ongoing (Raval et al.).

This study extends a previously published pediatric surgical oncology ERAS framework (Mansfield et al., JPS, 2025) to a specific set of the most complex abdominal tumors – abdominal, retroperitoneal, and pelvic neuroblastoma. The authors prospectively protocolized care and collected data on 23 patients, comparing them to 24 historic controls. ERAS protocols included multimodal pain control with blocks and non-opioid analgesia, euvolemia with preoperative high-carbohydrate clear liquids and intraoperative fluid minimization, increased use of laparoscopy, avoidance of postoperative nasogastric decompression, and early resumption of a regular diet, among other interventions. These patients had complex tumors – only one in each group did not have any image-defined risk factors. Complications were markedly lower in the ERAS group – 39% vs. 96% (p< 0.001), and length of stay was cut from 6.9 days down to 3.7 days after ERAS implementation (p=0.004). While surgeons may have previously felt comfortable implementing ERAS measures in less complex cases, this study demonstrates that these principles can be applied safely and effectively even in the most complex cases, to the substantial benefit of our patients.

Implementation of Comprehensive Surgical Guidelines for Hepatoblastoma: Analysis of the Children’s Oncology Group AHEP0731 Phase III Trial. [5] Kastenberg ZJ et al., Ann Surg. 2025 Sep 25. Epub ahead of print. PMID: 40996219.

The treatment of hepatoblastoma requires multidisciplinary care with definitive surgical resection a cornerstone to achieving a cure. Prior studies have focused on optimizing chemotherapeutic strategies with resection at the discretion of each individual institution. The PRETEXT staging system was developed as a framework to guide surgical decision making. In the United States, the current standard recommends upfront resection of PRETEXT I or II lesions and delayed resection after biopsy and chemotherapy for PRETEXT III or IV lesions or tumors with positive annotation factors.

A retrospective review of surgical guideline adherence was performed for patients with hepatoblastoma enrolled in AHEP0731 from 2009-2018 using PRE- and POST-TEXT groups and annotation factors. Retrospective assessment of surgical guideline adherence was performed after completion of the study and categorized as adherent or nonadherent based on radiographic central review. There was an overall 65% (133/205) adherence within the guideline proposed timeframe. 133/205 (65%) had their operations within the guideline-proposed timeframe. Nonadherence included 15% (30/205) tumors resected at diagnosis that did not meet criteria for upfront resection, 7% (14/205) tumors resected after only 2 cycles of chemotherapy despite continued major vascular involvement, and 13% (28/205) tumors resected or transplanted late after 6 or more cycles of chemotherapy. There was 91% (128/140) adherence with surgical guidelines for partial hepatectomy verses liver transplant for Intermediate and High-Risk groups. Nonadherence included 9% (12/140) who underwent transplant while central imaging review did not meet recommended transplant criteria. These 12 patients represent 26% (12/46) of patients undergoing liver transplant during the trial. The implementation of comprehensive surgical guidelines in the AHEP0731 trial significantly improved the rate of definitive tumor resection in children with hepatoblastoma. Nonadherence led to potentially unnecessary liver transplants in some cases.

Key Findings:

• Implementation of surgical guidelines increased the rate of definitive tumor resection compared to historical trials.
• Nonadherence to guidelines led to liver transplants in some patients for whom partial hepatectomy might have been an option.
• There were no significant differences in EFS, OS, or complication rates between adherent and nonadherent groups.

Surgical Lymph Node Staging in Extremity Rhabdomyosarcoma: The EpSSG RMS 2005 Trial Experience. [6] Terwisscha van Scheltinga S et al., Ann Surg Oncol. 2025 Oct;32(10):7751-7761 Epub 2025 Jul 24. PMID: 40705262.

Accurate staging of regional lymph nodes is critical in extremity rhabdomyosarcoma (RMS), as lymph node metastasis (N1) is a major prognostic factor. The Intergroup Rhabdomyosarcoma Study (IRS) IV showed 17% of clinically negative nodes were found to have disease when biopsied, resulting in upstaging that would have otherwise been missed. This is of particular importance in extremity RMS as relapse occurs in about 40% of cases and about 63% of those relapses are locoregional.

This study aimed to analyze the European pediatric soft tissue Sarcoma Study Group (EpSSG) RMS 2005 trial data to report on 1) the types of lymph node sampling strategies used 2) the outcomes of patients undergoing different nodal staging techniques. Patients with non-metastatic extremity RMS between 2005 – 2016 were included. There was a total of 198 patients. 144 (~73%) had clinically/radiologically node negative (cN0) disease. 54 (~27%) had radiologically malignant/suspicious appearing nodes. The 5-year overall survival rates of patients with N0 and N1 disease were 82.5% (95% CI 74.7 – 88.0) and 46.5% (95% CI 32.2-59.7) respectively, highlighting the importance of accurate staging.

Key Findings:

• Nodal sampling (NS) was performed in only 111/198 (~56.1%) of patients, suggesting that further advocacy for appropriate NS in extremity RMS is necessary
• NS resulted in upstaging (cN0 to pN1) in 15.3% of cases (23% after sentinel node biopsy, 11% after random NS)
• 26.5% of radiologically malignant/suspicious nodes were found to be node-negative after NS, which allows for omission of local treatment and intensified systemic therapy
• ~9.3% (n = 5) of patients with radiologically malignant/suspicious appearing nodes (cN1) underwent sentinel node biopsy, which is contraindicated in radiologically positive nodes due to potential false negative. An involved node can alter lymph drainage resulting in a false negative sentinel node, which did occur in 3 out of 5 of cases. Patients with radiologically involved nodes should instead undergo targeted nodal biopsy.
• Although interpretation is limited by a small n, patients with N1 disease that underwent nodal biopsy had a significantly longer overall survival in months compared to those that were staged solely by imaging.

Additional Resources:

[7]van Scheltinga CEJ, et al. Lymph Node Staging and Treatment in Pediatric Patients with Soft Tissue Sarcomas: A Consensus Opinion From the Children’s Oncology Group, European Paediatric Soft Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe. Pediatric Blood & Cancer. 2025. PMID: 39844722.

[8]Abdelhafeez A, et al. Evidence-Based Surgical Guidelines for Treating Children With Rhabdomyosarcoma. Pediatric Blood & Cancer. 2025. PMID: 39870584.

Reappraisal of liver resection as an alternative to transplantation in locally advanced hepatoblastoma: A systematic review and analysis of pooled individual patient data. [9] Fuchs J et al., Pediatr Blood Cancer. 2024 Dec;71(12):e31339. Epub 2024 Sep 27. PMID: 39334537.

Hepatoblastoma is the most common primary pediatric liver cancer, and its treatment typically involves complete surgical resection along with chemotherapy. For locally advanced hepatoblastoma (LAHB), liver transplantation (LT) has been the standard treatment when the tumor is considered unresectable. Current guidelines from the Children’s Oncology Group (COG) and the European Childhood Liver Tumor Study Group (SIOPEL) define unresectability based on PRETEXT and POST-TEXT staging criteria, which consider tumor location, vascular involvement, and response to chemotherapy. Historically, LT has shown excellent outcomes, and modern 5-year survival rates exceed 80%. LT comes with significant drawbacks, however, including lifelong immunosuppression, increased chemotherapy toxicity, organ shortages, and high postoperative morbidity. Some studies have reported successful liver resection (LR) in cases where LT would traditionally be deemed necessary based on standard criteria. This observation challenges the concept of primary LT for LAHB, particularly as current guidelines are based on limited evidence. This study aimed to comprehensively review and compare the outcomes of LT and LR for LAHB.

This study systematically reviewed and analyzed individual patient data from 55 studies, including 189 children with LAHB, to compare the outcomes of LT and LR. It found that overall survival (OS) and event-free survival (EFS) were similar between both approaches → 5-year OS: 75.3% for LT vs. 87.6% for LR, p = 0.140 → 5-year EFS: 68.5% for LT vs. 71.1% for LR, p = 0.700

Key Findings Include

• Local recurrence was more common after LR (14% vs. 3% in LT, p = 0.008), but distant recurrence was more frequent after LT (16% vs. 5% in LR, p = 0.035).
• Despite higher local recurrence, salvage LT for patients who relapsed after LR had promising outcomes, with most patients surviving long-term (6 of 7 patients at median follow-up of 55 months).

This study suggests that in select cases, LR can be a viable alternative to LT in patients with LAHB meeting traditional criteria for transplant evaluation, potentially reducing the need for transplantation and its associated complications. Careful patient selection and further studies focusing on identifying patient subgroups that derive the greatest benefit from resection or transplantation are needed.

Current Surgical Approach to Pulmonary Metastasectomy. [10] Corkum KS et al., Pediatr Blood Cancer. 2024 Dec 9:e31468. Epub ahead of print. PMID: 39654090.

The frequency of pulmonary metastases at the time of diagnosis for children with solid tumors is dependent on the tumor histology. Certain tumors, such as those within the abdomen, pelvis, and genitourinary system, more commonly have pulmonary metastases. Pulmonary metastasectomy plays a critical role in the management of these tumors and may serve diagnostic or therapeutic purposes. This paper presents the preoperative evaluation and surgical techniques necessary for successful pulmonary metastasectomy.

This study explores the role of pulmonary metastasectomy in pediatric solid tumors, focusing on the factors that influence the success of surgical intervention. The authors provide detailed guidelines for preoperative workup, surgical planning and tumor localization and the use of minimally invasive techniques. Lastly, the paper discusses the follow-up necessary for this patient population.

Key Recommendations:

• Preoperative Imaging: Chest CT is recommended for detecting pulmonary metastases. Non-contrast CT is adequate for pulmonary metastatic disease. Contrasted CT is needed for primary pulmonary masses, lymph nodes, and mediastinal anatomy.
• Localization Techniques: Methods, such as hook wire or microcoil insertion, methylene blue tattooing, and fluorescence-guided surgery are vital for identifying small pulmonary metastases. These techniques aid in pulmonary nodule identification when using a minimally invasive approach.
• Surgical Approach: Most pulmonary nodules can be removed by wedge excision, but central nodules may require an anatomic resection. The minimally invasive approach has benefits of smaller incisions and the ease to perform repeat pulmonary resections. Muscle-sparing thoracotomy may reduce the complications of scoliosis and chest wall deformities and allow for palpation of small pulmonary lesions not visible on CT. Intercostal nerve cryoablation has shown benefit for pain control after thoracotomy.
• Postoperative Follow-up: Continuous monitoring through CT scans and lung function testing, if symptomatic, is essential for assessing potential recurrence. In summary, pulmonary metastasectomy is a critical adjunct in the management of pediatric metastatic tumors. This study highlights the importance of precise surgical planning, advanced imaging techniques, and careful postoperative care to optimize outcomes for these pediatric patients.

Evaluation and Surgical Management of Pediatric Cutaneous Melanoma & Atypical Spitz Tumors A Report from the Children’s Oncology Group. [11] Sargen MR et al., J Clin Oncol. 2024 Oct 4: PMID: 39365959.

Pediatric cutaneous melanoma (CM) and atypical Spitz tumors (AST) are rare but increasingly recognized entities that require specialized evaluation and treatment strategies. Unlike adult melanoma, pediatric cases often present diagnostic challenges due to overlapping histological features between benign and malignant melanocytic tumors. The lack of pediatric-specific surgical trials has led to variability in management approaches. This study aims to provide standardized recommendations to enhance classification accuracy and optimize treatment decisions for young patients.

This report, developed by a multidisciplinary panel from the Children’s Oncology Group Rare Tumor Committee, presents consensus recommendations on the evaluation, histologic diagnosis, and surgical management of pediatric CM, AST, and non-Spitz melanocytic tumors. The study synthesizes expertise from 33 specialists across dermatology, oncology, pathology, and surgery, supported by data from 87 peer-reviewed publications. It provides updated surgical guidelines, diagnostic techniques, and molecular insights to ensure better alignment of treatment with patient-specific pathology.

Key Recommendations:

• Excisional Biopsy First: Clinically suspicious melanocytic neoplasms should undergo excisional biopsy with 1-3 mm margins when feasible, or punch/incisional biopsy to ensure accurate histopathologic assessment and prevent sampling errors. Shave biopsies should be avoided.
• Surgical Treatment Guidelines: Pediatric CM should be managed according to National Comprehensive Cancer Network guidelines, incorporating wide local excision and sentinel lymph node biopsy where appropriate.
• Tumor Classification: Immunohistochemistry and next-generation sequencing play a crucial role in differentiating benign from malignant AST. These tools help identify molecular markers that indicate aggressive behavior, guiding appropriate intervention.
• Standardized Margins for ASTs: Spitz tumors of uncertain malignant potential should be excised with 5 mm margins to ensure complete removal while minimizing overtreatment. Those classified as likely benign require 1-3 mm margins if transected on biopsy, reducing unnecessary re-excision.
• SLNB Use Criteria: Sentinel lymph node biopsy should not be performed for Spitz tumors unless a melanoma diagnosis is strongly favored based on clinicopathologic and molecular evaluation. This approach helps avoid unnecessary surgical morbidity in cases where malignancy is unlikely.

This report underscores the importance of precise diagnostic evaluation and adherence to standardized surgical management for pediatric patients with melanocytic tumors. By integrating molecular diagnostics, histopathologic assessment, and multidisciplinary expertise, clinicians can improve tumor classification accuracy, minimize treatment variability, and optimize outcomes for affected children.

Multimodality detection of tumor rupture in children with Wilms Tumour [12] Dzhuma K et al., Pediatr Blood Cancer. 2024 Nov;71(11):e31226. Epub 2024 Aug 8. PMID: 39118247.

Preoperative Wilms tumor rupture (TR), whether preoperatively or intraoperatively identified, increases the risk of local recurrence. In both the SIOP and COG frameworks, this results in disease upstaging, resulting in either flank or whole abdominal radiotherapy (WART). WART is associated with decreased fertility and an increased risk of secondary malignancy. Given the risks of WART, the definition and diagnosis of TR must be clearly defined. While intraoperative identification of TR has clearly defined criteria based on macroscopic appearance, preoperative TR is based on clinical and radiographic findings that are vaguely defined and are not validated. Moreover, pathologic evaluation of TR may not be confirmed after neoadjuvant chemotherapy because of the formation of a pseudocapsule that covers the site of rupture.

This study aims to describe associations between radiological, surgical, and pathology-detected TR with the goal of refining patient selection and therefore upstaging. Patients with TR that occurred during surgery (spill) were excluded from analysis. This is a retrospective evaluation of a prospectively-collected database as part of the IMPORT (Improving Population Outomes for Renal Tumours of Childhood) study. Of 141 eligible patients, TR was present on both central radiology review (CRR) and surgical reports in 29 patients. TR was present on CRR only in 69 patients. TR was present on the surgical report only in 43 patients. Central pathology review (CPR) was performed for all patients meeting study criteria. Diagnostic imaging for the detection of preoperative TR had both high false-positive and high-false negative rates (48% and 47%, respectively). Nine patients were upstaged based on the preoperative diagnosis of tumor rupture and received WART despite stage I or II diagnoses on pathologic staging. The authors state that imaging alone should not be relied upon to make treatment decisions involving TR. The authors suggest that the term “tumor rupture” is a misleading term from a radiology standpoint, and consideration should be made to replacing this with more specifically descriptive terms.

Principles of Pediatric Palliative Surgical Oncology: A Guide to Palliative Care for Pediatric Surgeons [13] Halix SJ, et al., Ann Surg. 2024 May 8. Epub ahead of print. PMID: 38727141.

Pediatric surgical oncologists have a central role in managing the complex care of children with cancer. Pediatric cancer care is increasingly incorporating principles of palliative care, which emphasizes improving quality of life by addressing pain, distressing symptoms, and facilitating communication about serious illness. These services can improve end-of-life experiences, reduce the need for invasive procedures, and better align treatment with the family’s goals. However, despite clear benefits, many pediatric surgeons delay palliative care consultations due to concerns that they might be perceived as surrendering the patient’s care. Integrating palliative care principles into pediatric surgical oncology is vital for improving holistic patient outcomes. Historically, the focus has been on technical interventions, but now the role of surgeons is expanding to include communication of prognoses, emotional support, and shared decision-making with families.

This paper introduces seven guiding principles for integrating primary palliative care into pediatric surgical oncology, developed by the American Pediatric Surgical Association’s Cancer Committee. These principles are intended to help pediatric surgeons deliver comprehensive care that aligns with patient and family values.

1. Respecting Values: Pediatric surgeons should prioritize understanding the values, hopes, and fears of the patient and family, ensuring that care aligns with their beliefs and definitions of acceptable outcomes.
2. Effective Communication: Pediatric surgeons should deliver honest, empathetic, and clear communication. By aligning recommendations with patient and family goals, surgeons help alleviate the decision-making burden.
3. Expert Symptom Management: Pediatric surgeons must manage distressing symptoms, including pain and discomfort, through both medical and surgical interventions to improve quality of life.
4. Commitment to Longitudinal Care: Surgeons should remain involved in the care continuum, fostering trust and ensuring continuity, even when curative surgery is not possible.
5. Collaborative Practice: Surgeons should work within multidisciplinary teams to ensure care is goal-concordant, respecting the input of various specialists.
6. Access to Subspecialty Palliative Care: Surgeons should recognize when specialized palliative care services are needed and make timely referrals for optimal patient care.
7. Enhanced Provider Resilience: Pediatric surgeons must also focus on their well-being by adopting resilience practices, such as team debriefings and reflection, to sustain high-quality care. These principles offer a roadmap for integrating palliative care into pediatric surgical oncology practice, enhancing both patient and family experiences during their treatment journey. By emphasizing value-based care and communication, surgeons can ensure that the care provided is both compassionate and technically appropriate.

Tracking changes in image-defined risk factors during neoadjuvant chemotherapy and their predictive value for surgical outcomes based on the International Neuroblastoma Surgical Report Form [14] Liu T et al., Pediatr Blood Cancer. 2024 Oct;71(10):e31161. Epub 2024 Jul 10. PMID: 38987989.

Image-defined risk factors (IDRFs) are essential in staging and surgical planning for neuroblastoma (NB). The International Neuroblastoma Risk Group Staging System (INRGSS) classifies patients with localized disease without IDRFs as L1 and those with IDRFs as L2. Often, patients with L2 tumors undergo biopsy followed by neoadjuvant chemotherapy to enable safer and more complete resection. This study evaluated changes in IDRFs during neoadjuvant chemotherapy and explored how pre-surgical IDRFs predict surgical outcomes. Study design: This single-center retrospective analysis from Shanghai, China, reviewed 53 neuroblastoma patients treated between 2014 and 2020. Data collection followed the International Neuroblastoma Surgical Report Form (INSRF). IDRFs and tumor volumes were assessed at diagnosis, after two cycles, and after four cycles of neoadjuvant chemotherapy, with percentage reductions calculated. Surgical outcomes were categorized as complete resection, minimal residual disease (< 5 cm³), incomplete resection (>5 cm³), or biopsy only. IDRFs were divided into seven subgroups based on their relationship to vital structures.

The study found tumor volume reductions of 54% and 69% after two and four chemotherapy cycles, respectively. Significant improvements were observed in the “compression of airway,” “intraspinal tumor extension,” and “two body compartments” subgroups after two cycles (p = 0.001), with further reduction in the “intraspinal tumor extension” subgroup after four cycles (p = 0.034). Overall, 43% of IDRFs resolved following chemotherapy, with the median number decreasing from four to one. Patients with more preoperative IDRFs had a higher risk of incomplete resection, and the persistence of "infiltration of vital structures" IDRFs was significantly associated with surgical extent (p = 0.010). While overall surgical complication rates were similar between groups, “renal vessel contact” IDRFs were linked to higher complication rates (p = 0.023). These findings can help surgeons better understand the importance of neoadjuvant therapy on improving IDRFs and help guide surgical decision making. Limitations include the study’s single-center design, small sample size, variability in chemotherapy regimens, and non-standardized surgical timing. In summary, the type and number of preoperative IDRFs, beyond their mere presence, can predict surgical outcomes in NB patients. Future studies should prospectively refine IDRF definitions to optimize surgical management.

Central Venous Catheter Consideration in Pediatric Oncology: A Systematic Review and Meta-analysis From the American Pediatric Surgical Association Cancer Committee [15] Christison-Lagay ER et al, J Pediatr Surg. 2024 Aug;59(8):1427-1443. Epub 2024 Mar 27. PMID: 38637207

The use of long-term central venous catheters in pediatric oncology patients is common. However, the adverse events associated with their use are poorly researched leaving a gap in the literature. There is a need to establish best practices to minimize CVC-related complications in order to optimize care for children with cancer. Questions often arise on four topics related to central venous catheter management in pediatric oncology patients, including catheter composition, thrombocytopenia, neutropenia, and CLABSI management.

The study design was a systematic review and meta-analysis that included a mix of retrospective, single-institution studies; prospective cohort studies; and randomized controlled trials. The study population included pediatric patients with cancer undergoing placement of long-term central venous catheters with a focus on patients with thrombocytopenia and neutropenia. The methodology used in this study was a systematic literature review following PRISMA guidelines, with a comprehensive search of multiple databases, separate searches for each of the four key questions, and updated searches over time to capture the most recent literature. The four key questions are 1. To determine if catheter composition (polyurethane vs silicone) influences the incidence of complications 2. To identify a minimum platelet count below which catheter placement poses an increased risk of complications 3. To identify a minimum absolute neutrophil count (ANC) below which catheter placement poses an increased risk of complications 4. To identify best practices for managing central line-associated bloodstream infections (CLABSIs). The main findings of the study center around the lack of high-quality data to establish best practice algorithms and opportunities to conduct further studies to improve the quality of care for children with cancer. The study finds that there is no preferred catheter composition (polyurethane vs silicone) in terms of complication rates. The authors go on to conclude that thrombocytopenia below 50,000 platelets/uL is not associated with increased major bleeding risk and there is limited evidence that ANC below 500 cells/uL increases CLABSI risk. Lastly, catheter salvage can be attempted in lower-risk patients despite the high recurrence rates. High-risk patients or those with extended bacteremia greater than 72 hours should undergo catheter removal. In conclusion, the authors point to the lack of high-quality data suggesting opportunities to improve the quality of care in children with cancer.

Prognostic impact of lymph node involvement and loss of heterozygosity of 1p or 16q in stage III favorable histology Wilms tumor: A report from Children’s Oncology Group Studies AREN03B2 and AREN0532[16]Evageliou N et al, Cancer. 2024 Mar 1;130(5):792-802. Epub 2023 Oct 30. PMID: 37902955.

Treatment of favorable histology Wilms tumor (FHWT) has approximately 90% cure rate with current protocols. A key factor to this success has been the refinement of clinical and biological prognostic markers, that allows protocols to focus on risk-stratified directed therapy. For stage I/II, singular loss of heterozygosity (LOH) at 1p or 16q was associated with increased risk of relapse and these patients have been shown to benefit from therapy intensification Patients with stage III FHWT due to positive lymph nodes (LN+) have worse outcomes compared to those with LN-. The additive impact of LN positivity combined with adverse biology (LOH) is poorly understood. These patients are classified as stage III because of their LN positivity and therefore receive at least 3-drug chemotherapy and radiation. Stage III FHWT with singular LOH 1p or 16q have historically been treated with DD4A regimen; only those with Stage III FHWT and positive for combined LOH were treated with more a more intensified regiment (i.e. Regimen M)., In the primary analysis of stage III FHWT children treated on AREN0532, event free survival (EFS) was significantly inferior in patients with LOH of 1p and 16q combined with LN+. This study aimed to investigate the relationship between LOH (both single and combined) and lymph node status, and whether there is role for further therapeutic intensification aimed at improving EFS in these children with stage III FHWT.

A total of 1189 patients with stage III FHWT enrolled on AREN0532 or AREN03B2 had outcome data, and among these patients, 714 had LOH testing. This study defined four groups by possible combinations of LN status (positive or negative) and singular LOH 1p or 16q status (positive for one or negative for both), and a significant difference in EFS across the groups was observed (log-rank p< .0001). Compared with patients with negative LN and singular LOH, the other groups each had increased risk in EFS, though overall survival (OS) did not reach statistical significance. Therefore, this group with singular LOH in addition to LN+ are candidates for investigation for therapeutic intensification aimed at improving EFS. Conversely, stage III FHWT patients negative for both LN and LOH have very high EFS and could potentially be candidates for therapy reduction. While prognostic effects of LN and LOH status (alone or combined) were not statistically different on OS, there is potential to reduce medical and psychological burdens of relapse. Parent advocates prefer upfront risks of intensified therapy to avoid risk of relapse. Improved risk stratification can not only help identify which patients would benefit from intensified therapeutic protocols, but also provide an opportunity to avoid unnecessary toxicities of initial therapy. Findings from this study are helping to guide risk stratification on the upcoming COG FH Wilms Tumor trial.

The results of concentration of care: Surgical outcomes of neuroblastoma in the Netherlands[17] van der Steeg AFW et al, Eur J Surg Oncol. 2023 Feb;49(2):505-511. Epub 2022 Oct 18. PMID: 36307270

Centralization of care for rare diagnoses has been widely discussed and shown to improve outcomes and reduce complications. In adults, several studies have shown inverse relationships between mortality and hospital volume for complicated surgical procedures. Furthermore, the incidence of complications was less with high-volume surgeons compared to low-volume surgeons in a high-volume hospital setting. While volume standards have been set for adults (ex. ten esophagectomies per year for a high-volume surgeon), there are no standards for pediatrics. The feasibility and potential benefit of centralization of care has been demonstrated in a few systems, including biliary atresia care in the UK, though applications in decentralized systems such as the US are lacking. Although rare, neuroblastoma is the most common pediatric extra-cranial solid tumor. High-risk neuroblastoma requires complex, technically-challenging surgical management. In the Netherlands the annual incidence is approximately 25 cases which were historically treated in 5 different academic centers, resulting in approximately 3-6 surgeries per center annually.

This study is a retrospective multicenter review comparing the outcomes before and after centralization of care for neuroblastoma patients in the Netherlands. The historical cohort (1998-2014) included all neuroblastoma cases who underwent resection in the Netherlands by a pediatric surgeon (a total of 40 surgeons). The centralized cohort included all neuroblastoma cases at the Princess Máxima Center, performed by five surgeons (2015-2021). All patients were treated using SIOPEN protocol. Complications were assessed using the Clavien Dindo Classification (CDC). There were no statistically significant patient characteristic differences in the cohorts except age at diagnosis was older for the centralized cohort. Intraoperative outcomes showed statistically significant improvement with a shorter surgical time, decreased blood loss, fewer unplanned nephrectomies, and fewer major vascular complications in the centralized cohort (p< 0.001). Total complications in the first 30 days were the same between cohorts. However, the historical cohort had significantly more CDC 3/4/5 complications than the centralized cohort (p=0.005). Long term complications showed no difference between cohorts. EFS and ‘relapses only’ were not statistically different between cohorts. Estimated OS was significantly better in the centralized cohort (log rank p=0.022). In summary, centralization of care with high volume surgeons for neuroblastoma patients in the Netherlands led to a decrease in intraoperative and short-term complications, with an increase in overall survival.

Management and Outcomes of Wilms Tumor With Suprarenal Intravascular Extension: A Pediatric Surgical Oncology Research Collaborative Study[18]. Naik-Mathuria B, et al. Ann Surg. 2024 Mar 1;279(3):528-535. Epub 2023 Jun 2. PMID: 37264925

Tumor thrombus can be seen in up to 10% of patients with Wilms tumor. Extension into the inferior vena cava (IVC) adds surgical complexity and risk of incomplete resection. Patients with extension at or above the level of the hepatic veins should receive neoadjuvant chemotherapy prior to surgical resection. Previous data were variable regarding the degree of tumor thrombus regression following neoadjuvant therapy. This paper evaluated outcomes in children with IVC tumor thrombus from 19 Pediatric Surgical Oncology Collaborative (PSORC) centers.

A total of 124 children treated between 2009-2019 were included. Upfront nephrectomy was performed in 19 children. Neoadjuvant chemotherapy was given to the remaining 102 children followed by delayed nephrectomy. Tumor thrombus regressed in 45% of children with intracardiac thrombi and 62% of suprahepatic thrombi. It was estimated that cardiopulmonary bypass was avoided in 67% of these children by using neoadjuvant chemotherapy. Intrahepatic thrombi regressed in 50% of cases, and neoadjuvant chemotherapy can be considered selectively in these patients. The majority of infrahepatic thrombi did not demonstrate any regression, reinforcing recommendations for upfront nephrectomy for these children, barring other contraindications. Viable tumor cells were identified in 36/99 (36%) of patients following neoadjuvant chemotherapy. Neither incomplete resection of thrombus nor viable cells within the thrombus affected EFS or OS. Therefore, it may be acceptable to leave thrombus intact or perform incomplete thrombectomy for FH tumors if there is prohibitive surgical risk. This study also reaffirms that anticoagulation is not routinely recommended for patients with IVC tumor thrombus.

Do children with Osteosarcoma benefit from Pulmonary Metastasectomy? - A Systematic Review Of Published Studies and ’Real World’ Outcomes[19]. Boam T, et al. Ann Surg. 2024 Feb 20. Online ahead of print. PMID: 38375639

Osteosarcoma (OS) is the most prevalent bone cancer in children, with a significant proportion presenting with or later developing lung metastases. Current standard treatment protocols include pulmonary metastasectomy (PM), often involving multiple surgeries to prolong survival and increase the chance of cure. While the introduction of multi-agent chemotherapy has improved survival rates for metastatic disease since the 1970s-80s, outcomes remain suboptimal. The efficacy of PM versus the impact of modern chemotherapy and other treatments remains unclear, especially in light of recent trials like PulMiCC for colorectal cancer, which showed no significant survival benefit from PM.

This is a systematic review of the outcomes of PM in pediatric (< 18 years of age) OS, analyzing data from 11 studies (9 retrospective and 2 prospective with no randomization of treatments) that met inclusion criteria. A total of 357 patients underwent PM, and 164 did not. The study found improved overall survival for patients receiving PM with 3-year survival of 0-54% (PM) vs 0-16% (no PM) in the 7 patient cohorts where this was calculable. No studies looked at quality of life or pulmonary health function metrics. The authors highlighted the methodological limitations of the existing studies, such as selection bias towards patients with more favorable prognoses. Recognizing the challenges and ethical dilemma concerning consent in the current standard of care, the authors suggest that high-quality, randomized controlled trials are still needed to determine PM’s efficacy conclusively. The authors note the difficulty in isolating the survival benefit of PM from other treatments like chemotherapy.

Cumulative burden of late, major surgical intervention in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS) cohort[20]. Dieffenbach BV, et al. Lancet Oncol. 2023 Jun;24(6):691-700. Epub 2023 May 11. PMID: 37182536

Childhood cancer survivors undergoing multimodal cancer therapy are at increased risk of subsequent malignancies, chronic health conditions and premature mortality. A subset of these late-onset health conditions requires surgical treatment, creating a burden on both the individual and the healthcare system. Previous studies showed that childhood cancer survivors have increased rates of specific late surgical procedures, including cholecystectomy, limb amputation, and solid organ transplantation. However, this study is the first to investigate the cumulative burden of late, major surgical interventions across the spectrum of childhood cancer survivors.

This is a retrospective cohort analysis of the Childhood Cancer Survivor Study (CCSS), which collects longitudinal prospective follow-up data on 5-year survivors of childhood cancer (diagnosed before age 21) from 31 USA institutions, with a comparison of nearest-age siblings. Between 1970-1999, 25,656 survivors with median follow-up of 21.8 years and median age 6.1 years at diagnosis were compared with nearest-age siblings, with a primary outcome of any self-reported late major surgical intervention (defined as requiring anesthesia and occurring > 5 years from primary cancer diagnosis) and cumulative burden assessed with mean cumulative counts (MCC). The 35-year MCC of a late, major surgical intervention was 206.7 per 100 survivors (95% CI 202.7-210.8) and 128.9 per 100 siblings (95% CI 123.0-134.7). The likelihood of late, major surgical intervention was higher in survivors versus siblings (adjusted RR 1.8, 95% CI 1.7-1.9) and female versus male survivors (RR 1.4, 95% CI 1.4-1.5). Survivors diagnosed in the 1990s had increased likelihood of late surgery compared to those diagnosed in the 1970s. Survivors of Hodgkin lymphoma, Ewing sarcoma, and osteosarcoma had the highest cumulative burden. This study improves understanding of which subpopulations of survivors are more likely to need late surgical intervention and the common types of surgical procedure performed. This information should influence informed consent to multimodality treatment, therapeutic choice in pediatric cancer patients, and screening of survivors for anticipated surgical issues.

Comparison of Outcomes between Surveillance Ultrasound and Completion Lymph Node Dissection in Children and Adolescents with Sentinel Lymph Node Positive Cutaneous Melanoma[21]. Scoville SD, et al. Ann Surg. 2024 Mar 1;279(3):536-541. Epub 2023 Jul 24.

In patients with cutaneous melanoma, regional lymph nodes are the primary site for metastatic disease, and positive lymph nodes are more frequently found in children than adults. The use of sentinel lymph node biopsy (SLNB) is based mainly on adult guidelines and is recommended in patients with clinically negative nodes and intermediate or high-risk primary melanoma. Completion lymph node dissection (CLND) had been routinely used in adults for clinically or radiologically positive nodes or those with positive SLNB. However, recent prospective trials showing equivalent survival rates for observation versus immediate CLND in adults with positive SLNB have led to a change in practice. However, the prognostic value of SLNB and completion lymph node dissection in the pediatric and adolescent population remains unknown.

This is a multi-institutional retrospective study from 14 centers participating in the Pediatric Surgical Oncology Research Collaborative (PSORC). Patients ≤ 18 years with cutaneous melanoma were included. Patients with atypical spitz lesions were excluded. 252 patients were identified with a median age of 11.0 years. 90% of patients underwent SLNB with 50.9% having a positive SLN. 67 patients underwent CLND, 97% were after a positive SLNB. A median of 20 lymph nodes were removed and 20.6% of those who underwent CLND had further positive nodal disease identified. 46 patients underwent surveillance nodal basin ultrasound, 78.3% after positive SLNB, most commonly at 3 month intervals (84.8%). Of note, there was a decreased rate of performing CLND after 2017 when the large adult trial was published. 8.9% of all patients had recurrent disease, 28.6% at regional nodal basins. Those with recurrence were more likely to have a positive SLNB. There was no significant difference in outcomes, including recurrence or death from disease, in the ultrasound observation vs CLND groups. Of note, among patients who underwent CLND, there was no difference in recurrence between those who had additional positive nodes vs those who did not. Given these data, the authors conclude adult guidelines can be applied to pediatric patients with melanoma and positive SLNB as the use of surveillance ultrasound in this cohort is both feasible and safe in the appropriate patient population.

Lymph node metastases in paediatric and young adult patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS): Findings from Children’s Oncology Group (COG) study ARST0332 [22]. Alvarez E, et al. Eur J Cancer. 2023 Feb;180:89-98. Epub 2022 Nov 25.

Children and young adults with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) have variable degree of lymph node (LN) involvement depending on the specific histologic subtype. The recent COG study ARST0332 required regional LN sampling for those with epithelioid sarcoma, clear cell sarcoma or clinically/radiographically enlarged LNs. It is not known whether lymph node sampling of clinical unenlarged nodes identifies a significant number of occult LN metastases and/or impacts survival.

Twenty of 529 patients with NRSTS had LN metastases; epithelioid sarcoma had the highest incidence (18%, 5 of 28). Pre-treatment imaging identified LN enlargement in 19 of 20 patients; 1 had no pre-treatment LN imaging. 5-year overall survival was 85.7% for isolated LN metastases and 15.4% for patients with LN and distant metastases. LN recurrence occurred in only one patient without LNs sampled at initial diagnosis. The authors concluded that LN metastases occur in about 4% of at-risk histologic subtypes. Unlike in rhabdomyosarcoma where lymph node sampling identifies a significant number of occult LN metastases, the vast majority of LN metastases in NRSTS are associated with clinical or imaging evidence of lymphadenopathy. Therefore routine lymph node sampling with sentinel lymph node biopsy is likely not required, even for at-risk histologic subtypes. If enlarged nodes are removed and treated appropriately outcomes are similar to patients without nodal disease. Patients with isolated LN metastases should be treated with curative intent.

Lifetime Burden of Psychological Symptoms, Disorders, and Suicide Due to Cancer in Childhood, Adolescent, and Young Adult Years. A Systematic Review and Meta-analysis[23]. Lee ARYB, et al. JAMA Pediatr. 2023;177(8):790-799.

With advances in cancer treatment, survival rates for pediatric cancers have significantly improved. As a result, there is increased attention on long-term outcomes such as psychosocial consequences of a cancer diagnosis. Across all age groups, it is well established that a cancer diagnosis and treatment can be traumatizing, particularly for younger patients in their formative years. This may put pediatric, adolescent, and young adult cancer patients at increased risk for adverse psychosocial outcomes.

This is a systematic review and meta-analysis of 52 studies that reviewed childhood, adolescent, and young adults with cancer (CYACs) and considered the outcomes of depression, anxiety, psychotic disorders (including schizophrenia), and suicide mortality. The review included 2 distinct groups of CYACs with a diagnosis of any solid or hematologic cancer. First, patients up to 25 years old who were receiving or planning to receive treatment with curative intent. The second cohort was cancer survivors, diagnosed before age 25 years, and who were in remission at the time of study. Meta-analyses revealed that CYACs were at increased lifetime risk of severe symptoms or a disorder of depression (RR, 1.57; 95% CI, 1.29-1.92), anxiety (RR, 1.29; 95% CI, 1.14-1.47), and psychotic disorders (RR, 1.56; 95% CI, 1.36-1.80) relative to both matched controls and their siblings. Overall suicide mortality was not significantly elevated (RR, 1.63; 95% CI, 0.78-3.40). The mean severity of depression was found to be elevated in CYACs receiving treatment (SMD, 0.44; 95% CI, 0.13-0.74) and long-term survivors (SMD, 0.18; 95% CI, 0.02-0.33). The mean severity of anxiety was found to be elevated only during treatment (SMD, 0.16; 95% CI, 0.03-0.20) Long into survivorship, CYACs may be at increased risk of developing depression, anxiety, psychotic disorders, and schizophrenia after remission of cancer compared with their siblings and controls without cancer. Pediatric surgeons caring for cancer patients and families must be informed about the short and long-term psychosocial outcomes. Appropriate access to supportive resources and treatment will enhance any multi-disciplinary cancer care model.

Blood Transfusion is Associated with Adverse Outcomes in Pediatric Solid Tumor Oncology Patients Following Tumor Resection[24]. Acker SN, et al. J Pediatr Hematol Oncol. 2023 Apr 1;45(3):137-142. Epub 2022 Aug 22.

Transfusion of packed red blood cells (PRBC) can be a necessary and life-saving intervention across medical settings. However, transfusion of packed red blood cells has also been associated with pro-inflammatory states, immunosuppressive effects, and potential poor outcomes. Adults with malignancies who receive PRBC transfusions in the perioperative period have been found to have worse outcomes, with increased infectious complications, and decreased event free (EFS) and overall survival (OS). Little, however, is known about these potential impacts in children with cancer undergoing surgical intervention.

This study compared outcomes between children undergoing surgical resection of a malignancy who did and did not receive perioperative PRBC transfusions between 2002 and 2013. Three hundred and sixty children were studied retrospectively and just over half (54%) received blood perioperatively. Patients who received blood transfusion had higher rates of postoperative infectious complications, shorter EFS, and higher rates of tumor recurrence. There was a dose effect for infectious complications, with an increase in risk of post-operative infections for each unit of blood transfused.

Management and outcomes of chest wall rhabdomyoscarcoma: A report from the Children’s Oncology Group Soft Tissue Sarcoma Committee[25]. Lautz TB, Xue W, Luo LY, et al. Pediatr Blood Cancer. 2023 Jul;70(7):e30357. Epub 2023 Apr 18.

Local control of chest wall rhabdomyosarcoma (RMS) tumors is challenging due to the potential morbidity, most commonly development of scoliosis, of resections involving multiple ribs. The presence or absence of metastatic disease is the most significant predictor of overall outcomes. Local control can be achieved with a combination of surgery and/or radiotherapy (RT). The ability to achieve a complete R0 resection for RMS, either through upfront resection or with delayed primary excision (DPE) after induction chemotherapy, has been associated with improved outcomes.

This study focuses on chest wall RMS, including patients across a wide range of risk-stratification scenarios, and with the aim of identifying predictors of local failure and survival, including the influence of local control modalities. Forty-four patients from Children’s Oncology Group (COG) low-risk (8), intermediate-risk (19), and high-risk (17) RMS studies with primary tumors of the chest wall and intrathoracic region were included. Disease was localized in 57% and metastatic in 43%. Five-year local failure-free survival, event-free survival, and overall survival were 72.1%, 49%, and 58.5% respectively. Kaplan-Meier analysis showed significant differences in local failure free survival based on clinical group, surgical completeness, tumor size, and tumor depth. No local recurrence occurred in patients who had DPE, nor in those who achieved R0 or R1 resection (upfront or DPE). However, 70% of R0 resections were for tumors involving only the superficial musculature. Kaplan-Meier analysis of overall survival found significant differences based on clinical group and surgical completeness. This study updates the literature by showing that with modern protocols, complete surgical excision of chest wall RMS (either upfront or with DPE) is associated with improved outcomes, but is also usually only possible for smaller tumors confined to the superficial musculature. If a patient would require resection of more than three ribs, particularly in the posterior position, the benefits of DPE vs. definitive RT should be weighed against potential morbidity.

Survival of Patients With Neuroblastoma After Assignment to Reduced Therapy Because of the 12- to 18-Month Change in Age Cutoff in Children’s Oncology Group Risk Stratification[26]. Bender HG, et al. J Clin Oncol. 2023 Jun 10;41(17):3149-3159.

Older patients with neuroblastoma have long been known to have worse oncologic outcomes. From 2000-2006, 12 months of age was chosen in the COG biology protocol ANBL00B1 as the cutoff for intermediate vs. high-risk disease, whereby patients below 12 months of age were intermediate-risk, and patients between 12 and 18 months were high-risk. There were two specific subsets of toddlers in this schema: 1) MYCN not amplified (MYCN-NA), favorable International Neuroblastoma Staging System (INSS) stage 4, favorable International Neuroblastoma Pathology Classification (INPC), hyperdiploid tumors; and 2) INSS Stage 3, MYCN-NA, unfavorable INPC. Several studies reported excellent outcomes in the 12-18 month age groups for these two subsets. In 2006, patients in these cohorts aged 12-18 months were reclassified from high-risk to intermediate-risk as an addendum to COG ANBL00B1. Outcomes subject to this change in risk stratification and therefore therapy intensity reduction have yet to be validated.

This study compares outcomes from patients aged 12-18 months who were in the two specific subgroups listed above from the pre-2006 cohort to the post-2006 cohort, whose therapy intensity decreased after this time. 105 toddlers were studied retrospectively. The 5-year overall survival and event-free survival was similar in both subsets before and after 2006. The newly classified intermediate-risk patients (age 12-18 months) had similar outcomes to patients of all ages also assigned intermediate risk. Additionally, the patients receiving intermediate-risk therapy had less short-term and long-term toxicity/morbidity compared to those receiving therapeutic regimens aimed at high-risk neuroblastoma.

Relapse after Non-Metastatic Rhabdomyosarcoma: The impact of routine surveillance imaging on early detection and post-relapse survival [27]. Casanova M, et al. Pediatr Blood Cancer. 2023 Feb;70(2):e30095. Epub 2022 Nov 21.

Rhabdomyosarcoma recurrences have a poor prognosis with median overall survival of around 10 months and 5-year overall survival of 13-17%. Thus, surveillance imaging has been implemented to improve post-relapse outcomes with the paucity of literature suggesting most recurrences are diagnosed related to clinical symptoms, but surveillance could detect relapses earlier. However, none of the evidence shows that earlier detection has resulted in improved outcomes.

This manuscript presents a prognostic score to identify a subgroup of rhabdomyosarcoma survivors in whom surveillance screen resulted in improved outcomes. The prognostic scores were calculated by one point for each risk factor: early relapse, no radiotherapy, no response to chemotherapy, and failure to achieve a second remission (remission for at least 6 months after treatment). This study showed that patients with 0-1 prognostic factors had better survival rates when detected on surveillance imaging (5-year OS 75.0% vs. 33.0%, p =0.047).

Clinical and Biological features prognostic of survival after relapse or progression of INRGSS stage MS pattern neuroblastoma: A Report from the International Neuroblastoma Risk Group (INRG) project [28]. Campbell K, et al. Pediatr Blood Cancer. 2023 Feb;70(2):e30054. Epub 2022 Oct 31.

Patients with neuroblastoma stage 4S (INSS staging system) or MS (INRGSS) have been found to have a more favorable prognosis compared to other subtypes of neuroblastoma, with a documented overall survival (OS) of 84%. However, patients with MS disease who have MYCN amplification or chromosome 1p or 11q aberrations may have less favorable outcomes. MS disease has also been associated with a potential for spontaneous regression. After the introduction of INRGSS, a 2011 retrospective study of patients less than 18 months with metastatic disease found tumor biology to be more important than age or metastatic pattern for risk stratification.

The study aimed to investigate the clinical and biological factors associated with survival after relapse or progression of patients with neuroblastoma MS disease and to compare OS for those diagnosed before 2001 vs. after 2001 (to differentiate patients that likely received more modern therapy). This study analyzed data from the INRG Data Common, which had over 1,500 patients worldwide diagnosed with neuroblastoma MS. Of the 209 patients who met study eligibility, the authors found that 47% had known data on the pattern of their first relapse or progression. Of these patients, 25% had their first relapse at the primary site, 48% at a metastatic site, and 27% at both primary and metastatic sites. In addition, the median time from diagnosis to the first event was 8.16 months, and the 5-year post-event OS was 53%. Patients diagnosed in 2001 or later had a higher post-event OS than those diagnosed before 2001. Univariate survival analyses showed that factors associated with inferior post-event OS included age at initial diagnosis (365-547 days, HR = 3.85), MYCN amplification (HR = 5.81), 1p loss/aberration (HR = 3.86), diploidy (HR = 4.69), high Mitotic Karyorrhexis Index (HR = 3.48), LDH ≥1400 U/L (HR = 3.58), unfavorable International Neuroblastoma Pathology Classification histology (HR = 2.66), and 12 or more months from the initial diagnosis to first event (2.09). Of the above factors, MYCN amplification, non-White race, and diploidy were independently prognostic of lower post-event overall survival.

Type I and Ir pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry [29]. Nelson AT, et al. Cancer. 2023 Feb 15;129(4):600-613. Epub 2022 Dec 20.

The multidisciplinary and multi-modality treatment for children with pleuropulmonary blastoma has suffered because of the rarity of the disease and the lack of large data sets. The International PPB/Dicer1 Registry was formed to address this problem. This paper investigates those children who can be cured through surgery alone. Although historically, children with type 1 PPB were thought to be cured by surgery alone, recent data suggest that the size of the cystic lesions, pathology (primitive small cells with or without rhabdomyoblastic features) and number of residual lesions even if type I, can impact EFS and OS.

This paper describes which children can be cured by surgery alone and which children benefit from surgery and chemotherapy, while at the same time maximizing EFS and OS. It clearly delineates the difference between type 1 and type 1r PPB and provides critical preliminary data that will be used for an upcoming COG study for children with PPB. This is one of the largest collections of well-characterized children with PPB. The strength of the paper is that central review was used for pathology, radiology and surgical procedure (albeit retrospectively).

Utility of Frozen Section in Pediatric and Adolescent Malignant Ovarian Nonseminomatous Germ Cell Tumors: A report from the children’s oncology group [30]. Dicken BJ, et al. Gynecol Oncol. 2022 Sep;476-480. Epub 2022 Jun 22.

Intra-operative frozen section has been shown to be accurate and valuable in guiding surgical staging for adult patients with epithelial ovarian tumors. It is not known whether this is also true for frozen section in malignant ovarian germ cell tumors. This study therefore aimed to assess the concordance between intra-operative frozen section and final diagnosis in an effort to understand if frozen section can be used to guide extent of surgical staging in malignant ovarian germ cell tumors in the pediatric and adolescent population.

Of 131 eligible patients, 60 patients had both frozen section and final paraffin section available for analysis. There were similar results found between those in the low risk (stage 1) vs intermediate risk (stage 2 or 3) patients. Frozen section agreed with the final pathology of a malignant tumor in 61.7% of patients. Immature teratoma without malignancy was identified on frozen section in 16.7% of patients. In 2 patients, frozen section did not reveal any diagnosis and 3 patients were identified as having germ cell tumor not otherwise specified on frozen section analysis. 13.3% of patient were deemed to have benign disease on frozen section. Overall, frozen section provided an incorrect diagnosis in 38.3% of patients.

Given this inaccuracy of almost 40%, the authors conclude that intra-operative frozen section is not reliable to inform the extent of surgical staging in pediatric and adolescent malignant ovarian germ cell tumor.

Sacrococcygeal Teratoma: Long-term Outcomes. A UK CCLG Surgeons Group Nationwide Study [31]. Braungart S, et al. Pediatr Blood Cancer. 2023 Jan;70(1):e29994. Epub 2022 Oct 13.

Sacrococcygeal teratoma (SCT) has an estimated incidence of 1:40,000 live births. Most tumors are benign and surgical resection is considered the standard therapy to achieve lifelong cure. There have been limited studies examining the long-term outcomes of intestinal and urological function in patients undergoing SCT resection. These outcomes may have important implications for survivorship and quality of life measures.

This is a multi-institutional study across 14 centers in the United Kingdom Children’s Cancer and Leukemia Group (CCLG) that examined long-term functional outcomes in patients undergoing resection of an SCT. There were 165 patients including both neonates and late presenting index cases. Median age at operation was 10 days [IQR 4-150 days]. The distribution of Altman type was as follows: Type I (21%), II (38%), III (24%), IV (17%), and most neoplasms were mature teratoma biology (69%, n =114 cases). Follow-up data were available in 83% of index cases and median length of follow-up was 5 years [IQR36.75-92.75 months]. One third of patients had urological or bowel dysfunction. Twenty two patients (13.3%) in the study cohort required clean intermittent catheterization, with a 2.5 relative risk increase for patients who underwent resection for Altman type III or IV tumors. Nearly one third of patients had documented constipation with or without fecal soiling and 15% of patients required further operations for bowel management and continence control (e.g. antegrade continence enema appendicostomy or diversion colostomy). There was no statistically significant risk for subsequent functional bowel problems between patients with type I-II versus type III-IV tumors.

Surgical Factors Influencing Local Relapse and Outcome in the Treatment of Unilateral Nephroblastoma [32]. Meier CM, et al. Ann Surg. 2022 Aug 26. Online ahead of print.

Children with Wilms tumor (WT) have excellent survival rates greater than 90% due to multi-modal therapy including surgery, chemotherapy, and radiation therapy in some settings. Unfortunately, when relapse occurs it is quite challenging to treat. This study aimed to investigate various factors of the tumor and surgical procedure, and the impact of such factors on local relapse.

This is a retrospective analysis of the most recently completed clinical trials of the German Society of Pediatric Oncology and Hematology (GPOH) that enrolled patients between 1989 and 2020. Patients were included if they were less than 18 years of age, and had received neoadjuvant chemotherapy as part of the standard GPOH/SIOP protocols for WT. 2386 patients with preoperatively treated unilateral WT were included with a median follow up time of 14.6 years. Local recurrence occurred in 116 patients (4.9%). The control group included the 2270 patients who did not locally relapse. Increased risk of local relapse was noted in older children (age >48 months, hazard ratio 3.10, p< 0.001, CI 1.74-5.52), larger tumor volume at the time of surgery (>500ml hazard ratio 2.14, p=0.002, CI 1.33-3.45), and increasing stage (stage III compared to stage I hazard ratio 2.39, p< 0.001, CI 1.54-3.69). Importantly, when evaluating completeness of nodal sampling, local relapse was significantly more frequent if no lymph nodes were sampled (hazard ratio 1.85, p=0.012, CI 1.45-2.97). Furthermore, for the 771 patients with known number of nodes sampled, patients with fewer than 5 nodes removed had a significant increased risk of local relapse (4.2% vs 1.6%, p=0.04). Intraoperative tumor rupture and unfavorable histology were also associated with an increased risk of local relapse.

The findings of this study highlight that certain operative factors, namely adequate sampling of lymph nodes within the ipsilateral renal drainage system and avoidance of intraoperative tumor capsule violation/rupture, are in the control of the surgeon and directly impact local recurrence risk.

Incidence and Management of Pleural Effusions in Patients with Wilms Tumor: A pediatric Surgical Oncology Research Collaborative Study International [33]. Al-Hadidi A, et al. Int J Cancer. 2022 Nov 15;151(10):1696-1702. Epub 2022 Jul 14.

Wilms tumor (WT) is the most common renal malignancy in children, with overall excellent survival rates for those with favorable histology. The presence of a pleural effusion for patients with WT may be noted on diagnostic imaging, but the exact incidence and prognostic significance is unknown.

This is a multi-institutional retrospective review including 1259 children with WT from 21 North American hospitals involved in the Pediatric Surgical Oncology Research Collaborative. In this review, a pleural effusion was noted to be present on diagnostic chest computed tomography in 7.5% of patients. Only 36.7% of the effusions were visible on plain chest x-ray. Effusions were ipsilateral to the tumor in 68.5%. Compared to children without an effusion, children with a pleural effusion were significantly older (median age 4.3 years vs 3.5 years, p=0.004), were more likely to present with advanced staged tumors (local stage III 83% vs 51.6%, p< 0.0001; overall stage III 43.6% vs 26.6%, p< 0.0001; overall stage IV 38.3% vs 25.5%, p< 0.0001), and more likely to have preoperative tumor rupture (36.2% vs 9%; p< 0.0001). There were no significant differences noted in sex, race, histology, or molecular features of the tumor (LOH 1p/16q or 1q gain) (all p>0.05). The management strategy among the various hospitals for patients with pleural effusions in the setting of WT was not standardized. Of the 94 patients with an effusion, only 14 underwent thoracentesis, and of these 14, only 3 had malignant cytology. Given the low incidence of known malignant pleural effusions, the authors conclude that current evidence does not support a change in management of children with WT who present with a pleural effusion. The use of select thoracentesis at the discretion of the treating surgeon should be employed, but routine thoracentesis is not currently recommended.

Thoracoscopy vs Thoracotomy for the Management of Metastatic Osteosarcoma: A Pediatric Surgical Oncology Research Collaborative Study [34]. Lautz TB, et al. Int J Cancer. 2021 Mar 1;148(5):1164-1171. Epub 2020 Aug 31.

Osteosarcoma is the most common bone tumor in the pediatric population. The most common site of metastases in the lungs. Previous studies have shown that pulmonary metastases are a negative prognostic factor, and complete resection and clearance of the pulmonary metastases improve overall survival. Thoracotomy allows for manual palpation and tactile sensation to identify and remove pulmonary nodules that were not detected on imaging even with improved quality of cross-sectional imaging techniques in recent years. However, a thoracotomy has increased morbidity related to pain and longer hospital stay compared to thoracoscopy. The authors aim to compare the overall survival and pulmonary disease-free survival between thoracotomy and thoracoscopy approaches in removing pulmonary metastatic nodules from patients with osteosarcoma.

This is a retrospective study from 15 North American pediatric hospitals that participate in the Pediatric Surgical Oncology Research Collaborative. Charts from 1996 to 2018 were reviewed and 202 pediatric patients with pulmonary metastases who either underwent thoracotomy (n=154) or thoracoscopy (n=48) for metastasectomy were identified. The median number of nodules resected was 5 in the thoracotomy group and 1 in the thoracoscopy group (p< 0.001). The total number of nodules resected was greater than the number of nodules seen on CT scan in 49% of thoracotomy patients versus 10% of thoracoscopic patients. Kaplan -Meier survival analysis showed comparable 5-year overall survival and pulmonary disease-free survival between the two groups. Subset analysis showed better survival in patients with oligometastatic disease, compared to those with 5 or more lesions, but no difference between thoracotomy vs thoracoscopic approaches. On multivariate analysis, thoracoscopy had a significantly increased risk of mortality (HR 2.11, p=0.027) but not pulmonary recurrence (HR 0.96, p=0.9). When looking only at oligometastatic disease, thoracoscopy was not associated with increased mortality or recurrence. In conclusion, thoracotomy and thoracoscopic approaches had no difference in overall and pulmonary disease-free survival for patients with oligometastatic pulmonary disease secondary to osteosarcoma.

A Novel Standard for Systematic Reporting of Neuroblastoma Surgery: The International Neuroblastoma Surgical Report Form (INSRF): A Joint Initiative by the Pediatric Oncological Cooperative Groups SIOPEN∗, COG∗∗, and GPOH∗∗∗ [35]. Matthyssens LE, et al. Ann Surg. 2022 Mar 1;275(3):e575-e585.

Neuroblastoma (NBL) accounts for 6% of all childhood cancer and 12-15% of cancer-related deaths under the age of 15 years. Its clinical, biological, and anatomic features are very broad as are its behavior and prognosis. Robust risk assignment and preoperative staging systems have been devised with international consensus and are widely utilized. However, it has been difficult to study select surgical issues related to NBL because surgical reporting has not been standardized. Experts from COG, SIOP, and the German cooperative collaborated to create an “International NBL Surgical Report Form (INSRF)” as a structured and uniform reporting tool for NBL surgery documenting aspects of the procedure as well as intraoperative and 30-day postoperative complications. It is known that cancer surgery operative reports are inaccurate, especially for complicated NBL resections. Therefore, the objective of this study was to standardize reporting, with the aim of improving the ability to critically evaluate the surgical treatment of NBL.

The INSRF was created as a 5 section, 5-page document, with the first 4 to be completed by the surgeon directly after the operation, and the 5th dealing with postoperative complications to be completed 30 days after the surgery. The requested operative details are extensive including choice of incision, operative specifics, vital structures involved, and management of intraoperative complications. This document will be implemented into clinical practice by the surgeons of the participating cooperative groups with plans for an electronic version to increase ease and compliance of completion. Pediatric surgeons treating NBL will become familiar with this reporting system, and its utilization will ultimately serve to improve the study of surgical factors as they relate to NBL outcomes.

Risk of bacterial bloodstream infection does not vary by central-line type during neutropenic periods in pediatric acute myeloid leukemia [36]. Elgarten C, et al. Infect Control Hosp Epidemiol. 2022 Apr 25;1-8.

Pediatric patients with AML undergo treatment with myelosuppressive chemotherapy, leading to periods of severe neutropenia. These neutropenic periods put AML patients at increased risk for developing bloodstream infections (BSIs), which can result in significant morbidity and mortality. Given that most patients with AML undergo placement of a central venous access device (CVAD) for chemotherapy administration, this further increases their risk of developing a BSI. The author’s goal was to determine if one of three CVAD types (PICC lines, ports, or tunneled externalized catheters [TECs]) was associated with an elevated risk of developing a BSI during neutropenic periods in patients with AML.

This is retrospective review of pediatric patients with AML who received chemotherapy from January 2011 through July 2018 at 17 children’s hospitals in the US. Neutropenia was defined as an absolute neutrophil count below 500 cells/µL. For every patient, the development of a BSI was recorded, as was what type of CVAD the patient had. In total, the analyzable cohort consisted of 560 patients who underwent 1828 chemotherapy courses. The median duration of neutropenia was 19 days (IQR 14-25). TECs were the most frequently employed CVAD type, accounting for 65.1% of courses, while PICCs were employed 27.5% of time and ports accounted for 7.3% of cases. BSIs occurred in 444 (22.5%) courses, of which 395 (89%) developed while the patient was neutropenic. Univariate analysis did not reveal any difference in the rates of BSI based on the type of CVAD used—21.2% for TECs, 23.3% for PICCs and 18.7% for ports. Univariable analysis did identify several covariates that were associated with an increased rate of BSI, including course, age, receipt of antibiotic prophylaxis and hospital-level prophylactic practices. Multivariate analysis confirmed that the incident rate ratio for the development of a BSI while neutropenic was statistically similar for TECs, PICCs and ports. In conclusion, the risk of developing a BSI in neutropenic AML patients did not differ based on CVAD type. Thus, other factors such as the type of chemotherapy being delivered and patient-specific needs, rather than the relative risk of a BSI, should be used to determine which CVAD is placed in children with AML.

Value of the Sentinel Node Procedure in Pediatric Extremity Rhabdomyosarcoma: A Systematic Review and Retrospective Cohort Study [37]. Jeremiasse B, et al. Ann Surg Oncol. 2021. Epub 2021 May.

Rhabdomyosarcoma is the most common soft tissue sarcoma in children. Significantly poorer survival is noted in the presence of regional lymph node involvement, requiring escalation of therapy. Radiological and clinical assessment alone, however, is insufficient in accurate identification of involved nodes. Previous studies have focused on random lymph node sampling with small series examining the utility of sentinel lymph node (SLN) procedures.

This study is the first meta-analysis of SLN biopsy for pediatric rhabdomyosarcoma. In this study, 55 patients undergoing SLN biopsy with pathological classification were compared to radiological classification alone. The authors found SLN procedures changed the nodal classification for 17% of patients, demonstrating the value of targeted SLN procedures for extremity RMS to determine accurate staging and subsequent risk stratification. The conclusions from this meta-analysis are that pathological assessment of a lymph node or nodal basin is preferable to radiological evaluation alone, and that SLN procedures offer a more rational approach to a nodal basin with fewer complications than random node sampling.

Unresectable Thoracic Neuroblastic Tumors: Changes in image-defined risk factors after chemotherapy and impact on surgical management [38]. Delforge X, et al. Pediatr Blood Cancer. 2021:68e29260 Epub 2021 Jul 24.

High risk neuroblastoma is treated with multimodal therapy. Image-defined risk factors (IDRF), obtained via cross sectional imaging, are used to assess primary operative resection. Tumors considered resectable at diagnosis are defined as L1 and treated with upfront surgical resection, while those that are unresectable are defined as L2 and treated with neoadjuvant chemotherapy. Changes in IRDF’s with neoadjuvant chemotherapy for neuroblastic tumors have not been well defined for primary tumors within the thoracic cavity.

In this retrospective review of 27 patients from 6 institutions, spanning the years 2000-2019, IDRFs and tumor volume were defined pre and post chemotherapy. The most common IDRF identified was vascular encasement, followed by local structure infiltration, and represented the IDRF most likely to respond to chemotherapy. In total, 78 IDRFs were initially identified of which 25 (32%) persisted at the time of operative intervention. This contrasts with abdominal neuroblastic tumors, which are generally responsive 50% of the time with vascular encasement least likely to change with chemotherapy. Tumor volume correlated with resolution of IDRFs and, as expected, more likely to undergo a minimally invasive resection. The authors give a possible explanation for the difference within the thoracic cavity in that tumors within the thoracic cavity arise from the paravertebral sympathetic chain instead of perivascular sympathetic tissue, and thus shrinkage of the tumor will result in resolution of the vascular IDRF. Further studies are needed to determine what tumor factors are more likely to lead to resolution of IDRF and therefore benefit the most from neoadjuvant chemotherapy.

Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology clinical practice guideline update [39]. Wong SL, et al. Ann Surg Oncol. 2018 Feb;25(2):356-377. Epub 2017 Dec 13.

Melanoma in the pediatric population is uncommon, and pediatric surgeons likely less familiar with contemporary management when compared with adult colleagues. While there are many high-quality studies in the adult population there are minimal data in children due to the rarity of the diagnosis. Thus, pediatric surgeons frequently rely on adult data to guide management for children with melanoma. There are over 80,000 new cases of melanoma in the adult population per year, yet only 500 in infants, children, and adolescents (1). In 2012 the American Society of Clinical Oncology and the Society of Surgical Oncology published a clinical practice guideline on sentinel lymph node (SLN) biopsy in melanoma (2). This practice guideline recommended SLN biopsy for intermediate thickness melanoma (Breslow thickness 1 to 4 mm). Sentinel lymph node biopsy for thin (< 1 mm) melanomas was not recommended due to insufficient evidence, although it could be considered in patients with high-risk disease. Completion lymph node dissection was recommended for all patients with a positive sentinel lymph node.

The current article updates the 2012 recommendations by including nine new observational studies, two systematic reviews, an updated randomized controlled trial of SLN biopsy, and two randomized controlled trials of completion lymph node dissection (CLND) after positive SLN. The clinical practice guideline was written to answer two questions. First, what are the indications for SLN biopsy, and second, what is the role of CLND? The key recommendations are as follows. Routine SLN biopsy is not recommended for thin (T1a, < 0.8 mm nonulcerated lesions) melanoma. SLN biopsy may be considered for T1b lesions (0.8 mm- 1 mm or < 0.8 mm ulcerated lesions). Intermediate thickness lesions (1 -4 mm) should undergo SLN biopsy. Thick lesions (> 4 mm) should also undergo SLN biopsy in the absence of clinically positive nodes. The strength of recommendation for all the above was moderate. Additionally, either CLND or careful observation may be offered to patients with low risk micrometastatic disease. Higher risk patients may also be offered careful observation only after a thorough discussion of the risks and benefits of foregoing CLND. Higher risk patients were defined as those with extracapsular spread/extension, concomitant microsatellitosis of the primary tumor, more than three involved lymph nodes, more than two involved nodal basins in an immunocompromised patient. Of note, careful follow-up involved frequent serial nodal ultrasound which may limit the applicability of these recommendations for certain populations. The strength of recommendation for CLND was strong.

Late-onset kidney failure in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study [40] , European Journal of Cancer 2021 Aug 10;155:216-226.

This is a paper from the Childhood Cancer Survivor Study (CCSS) that looked across disease at late-onset kidney failure in childhood cancer. Several of the authors are APSA members who have a focus on pediatric oncology. This paper is important because while the 5-year event-free survival and overall survival for childhood cancer have improved but the 10-year EFS and OS have not. This is primarily due to the late effects of treatment. It has now been shown by late effects study groups in North America/Europe that childhood cancer survivors have significant health concerns such as premature heart disease, pulmonary restriction, reduced reproductive capacity/ premature labor, and second malignancies all factors that can reduce life expectancy. Furthermore, while some diseases have published specific renal failure rates that look as far as 20 -25 years there is little data for survivors greater than 35 years out. This is also important to study because there may be factors that could be altered through early detection that could potentially reduce the risk of certain late effects.

The CCSS is a multi-institutional, retrospective cohort with prospective follow-up of 5-year survivors of childhood cancer treated at one of 31 institutions in North America and includes a comparison group of nearest-age siblings selected by random sampling. This study adds several things to the literature. First, these are 35-year outcomes for renal failure in children. Second, this study includes multiple diseases and the data on the treatment is well known. Third, it identifies several potential targets to mitigate the risk of late-onset kidney failure. Specifically, diabetes and hypertension are two factors that were identified that can be monitored and modified, and aggressively treated. Fourth while anthracyclines (doxorubicin) have been known to affect cardiac disease this study shows that these drugs play a greater role in late-onset renal failure than was previously known. We have known that radiation therapy has been associated with renal failure the specific dosing of greater than 15 Gy was shown to be a particularly strong risk factor. For pediatric surgery practice, these results have two direct implications. First, we should make sure all our cancer patients are followed in long-term clinics from youth through to young adulthood, aggressively treating hypertension and watching for risk factors that predispose to diabetes (obesity). Finally, for those pediatric surgeons actively involved in the Children’s Oncology Group, we should lobby to have a protocol that reduces late effects in patients.

Revised Neuroblastoma Risk Classification System: A Report from the Children’s Oncology Group [41], Irwin et al. J Clin Oncol. 2021 Jul 28; JCO2100278.

The authors validated a revised risk stratification using the International Neuroblastoma Risk Group Staging System (INRGSS) that incorporated segmental chromosome aberrations (SCA) as an additional genomic biomarker and used overall survival instead of event-free survival as the outcome endpoint to create the new risk classification system. They used 4,832 patients with neuroblastoma enrolled on COG studies from 2007-2017. Outcomes for patients with locoregional tumors with no image-defined risk factors (L1) or locoregional tumors with image-defined risk factors (L2) had excellent outcomes (approximately 95% 5-year overall survival). Exceptions to this great outcome were those L2 with MYCN amplification (80% OS) or patients age ≥ 18 months, MYCN nonamplified tumors, with unfavorable histology (majority with SCA) (82% OS). The OS outcome for metastatic patients was 59% but was worse for MYCN amplified tumors (51%). However metastatic patients < 12 months with MYCN nonamplified was better than amplified (91% vs 45% respectively). Outcomes remain excellent for MS patients (92% OS) except for MYCN amplified tumors (64%).

The revised 2021 COG neuroblastoma risk classification (version 2) that incorporates INRGSS and biomarkers including SCA will enable more accurate risk stratification and appropriate treatment assignment. Furthermore, version 2 will enable better international collaboration to harmonize data collection and comparisons across patient subsets and trials as well as provide the foundation for future evaluations of novel biomarkers and treatments. This new risk classification system does not radically change surgical therapy for these patients, but it is important for us to be aware of these changes and how they impact our patient’s care.

Treatment of Pediatric Adrenocortical Carcinoma with Surgery, Retroperitoneal Lymph Node Dissection, and Chemotherapy: The Children’s Oncology Group ARAR0332 Protocol [42], Rodriguez-Galindo et al. J Clin Oncol 2021 Apr 6.

Childhood adrenocortical carcinoma (ACC) is very rare in the United States (25 cases per year), and management has traditionally followed adult protocols. Low stage and complete resection are good prognostic factors and recurrence are as high as 50% in large tumors. The role of retroperitoneal lymph node dissection (RPLND) is not understood.

This article reports the results of COG protocol ARAR0332 in which stage I patients had tumor resection, stage II (>200cc or 100g) had resection and RPLND, and stage III and IV received chemotherapy and mitotane plus surgery. The results of 77 patients were described. Older patients had higher-stage tumors. Hormonal hypersecretion was present in 90%/ Germline TP53 variation was more common in the Brazilian cohort vs North American (95% vs 50%) and was associated with the lower stage. Normal germline P53 function and mutations in ATRX are associated with a higher stage and a worse outcome. Five-year event-free survival was: stage I 86%, stage II 53%, stage III 81%, and stage IV 7%. Five-year overall survival was: stage I 95%, stage II 79%, stage III 95%, and stage IV 16%. What this study adds is that surgical resection for stage I disease and chemotherapy plus surgery for stage III disease lead to good outcomes and warrant adoption. However, RPLND for stage II disease does not add a clear advantage. Stage IV patients are older and have a poor outcome despite chemotherapy. Furthermore, the mitotane and chemotherapy regimen was poorly tolerated, with one-third of advanced patients being unable to complete the regimen. An optimal regimen requires further evaluation.

Indeterminate Pulmonary Nodules in Osteosarcoma are associated with increased risk of pulmonary metastasis [43], Seher et al. J Pediatr Hematol Oncol. 2021 Mar 3.

The most common site of metastasis in osteosarcoma is the Lung. Approximately 15-20% of patients have pulmonary metastasis at the time of diagnosis. CT is the main imaging modality for diagnosing pulmonary metastases. Nodules above 5 mm with calcified characters are more likely to be metastatic lesions.  As per EURAMOS (European and American osteosarcoma protocols), Single nodules >10mm or >=3 nodules of 5-9mm are consistent with pulmonary metastasis. However, nodules that don’t meet these criteria are considered indeterminate pulmonary nodules (IPN) with unclear prognostic significance.

This manuscript by Seher et al. is a retrospective cohort study of osteosarcoma patients under age 18, between Jan 2005 to Dec 2018. Of 155 patients 31.6% had IPN. 43% of IPN patients developed pulmonary metastatic disease compared with 26% without IPN (p< 0.001, Relative risk 1.6). This study found that 3 or more IPN almost doubles the risk of subsequent pulmonary mets (p=0.013) and they have lower overall and event-free survival (58% and 35%, and 72% and 46%, respectively) although this was not significant. Most developed metastasis within 2 years. This manuscript illustrates the association between IPN and the increased risk of subsequent pulmonary metastatic disease and these findings are supported by other studies published this year. Further investigations will be required to determine if there is any benefit to biopsy of IPN or if changes in therapy for these patients would be beneficial.

Pleuropulmonary Blastoma in Pediatric Lung Lesions [44], Kunisaki et al. Pediatrics. 2021 Mar 24:e2020028357.

Congenital lung lesions, though rare, are frequently diagnosed on prenatal imaging. There is consensus that congenital lung lesions causing symptoms (respiratory compromise or infection) should be removed. There is no consensus on the management of asymptomatic lesions. There is a smaller subset of patients with congenital lesions who present postnatally. When counseling these families on the need for potential surgical removal, indications for removal may be the future risk for infection or malignancy, but these true risks are unclear. Pleuropulmonary blastoma (PPB) is thought to exist on a continuum with Type II (cystic) progressing to Type II (solid/cystic) and Type III (solid). Early diagnosis and treatment of pleuropulmonary blastoma is important as survival is significantly lower in Type II and Type III PPB.

This multi-institutional retrospective review included all patients undergoing surgery for primary lung lesions (n = 521) at 11 tertiary pediatric centers. It is the practice at all participating institutions to resect all symptomatic and asymptomatic lung lesions. The primary focus of the analysis was to evaluate the postnatally diagnosed patients. Lung lesions diagnosed postnatally were also compared to the lesions diagnosed prenatally. The authors found there were significantly lower APGAR scores and significantly more respiratory distress in the postnatally diagnosed lung lesions. The most common pathologic diagnoses in prenatally diagnosed patients were congenital pulmonary airway malformation (CPAM), bronchopleural sequestration (both intra- and extra-lobar), and CPAM with a feeders vessel. There were no malignancies in lung lesions diagnosed prenatally. In contrast, the most common pathologic diagnoses in postnatally diagnosed lung lesions were CPAM, congenital lobar emphysema, intra-lobar sequestration, and malignancy in 8.7%. Bivariate analysis showed malignancy was associated with suspicion of malignancy on pre-operative imaging, lack of a feeding vessel, and bilateral disease. Eight of 14 patients with pleuropulmonary blastoma (PPB) were positive for DICER 1. Finally, the diagnostic accuracy of preoperative imaging was examined and while sensitivity and positive predictive value were low (33.3% and 71.4% respectively), specificity and negative predictive value were high (98.8% and 94.1% respectively). The authors conclude there is a higher rate of malignancy in postnatally diagnosed lung lesions than previously thought. Furthermore, pediatric surgeons may wish to use DICER 1 testing to help determine the malignant potential of cystic lung lesions diagnosed postnatally given the low sensitivity of cross-sectional imaging.

Thoracoscopy vs thoracotomy for the management of metastatic osteosarcoma: A Pediatric Surgical Oncology Research Collaborative Study [34], Lautz et al. Int J Cancer 2021; 148(5): 1164-1171.

Osteosarcoma is the most common bone tumor in children and young adults. Fifteen to twenty percent present with metastases at diagnosis with the lung being the most common site. Complete surgical clearance of pulmonary disease is critical for long-term survival and has traditionally been approached via thoracotomy to allow for palpation of lesions. This open approach with palpation has resulted in the resection of more nodules compared to those detected by computerized tomography (CT). Thoracotomy is associated with increased pain, longer hospitalizations, potential long-term morbidity, and increased risk of complications compared to thoracoscopy.

This multi-institutional study retrospectively reviewed 202 pediatric patients with metastatic osteosarcoma who underwent pulmonary metastasectomy by thoracotomy (n=154) versus thoracoscopy (n=48) to assess for a survival advantage. A significant difference in the number of total nodules resected was seen between thoracotomy (5) and thoracoscopy (1). The number of pathologically malignant lesions resected via thoracotomy was higher than the number seen on CT in 27% of patients, compared to 2% in thoracoscopy. Mean chest tube duration (three versus one day) and postoperative length of stay (five versus two days) were longer in the thoracotomy patients. Complication differences between the two groups were not statistically significant. Pulmonary relapse was seen in 135 patients (67.5%). There was no significant difference in five-year pulmonary disease-free survival or overall survival between thoracotomy and thoracoscopy. Regardless of approach, survival was superior in oligometastatic disease. In a subset analysis of patients with oligometastatic disease, thoracoscopy had comparable risks of mortality and recurrence.
This large series pooled from multiple institutions suggests that comparable outcomes may be achieved with thoracotomy or thoracoscopy for resection of pulmonary metastatic disease in patients with metastatic osteosarcoma and limited pulmonary disease. The study does have some serious limitations including significant selection bias. Rather than adopt thoracoscopy, surgeons are encouraged to enroll patients in an upcoming recently approved randomized study.

A nomogram of clinical and biologic factors to predict survival in children newly diagnosed with high-risk neuroblastoma: An International Neuroblastoma Risk Group project [45], Moreno et al. Pediatr Blood Cancer. 2021 Mar;68(3):e28794.

High-risk neuroblastoma, despite improvements with multimodal therapy, continues to have a low overall survival (OS, 50% at five years). An international consensus has broadly defined high-risk as all patients greater than or equal to 18 months of age with metastatic neuroblastoma. This heterogeneous group of patients has a wide range of OS outcomes and yet they are all assigned to receive the same intensive multimodal treatment. There are members of this high-risk group with very poor outcomes (ultra-high-risk) who would potentially benefit from new innovative therapies at an earlier time in their disease process. Previous attempts have been made to stratify ultra-high-risk patients but this has not resulted in treatment modifications.

This study is the first to create and validate a nomogram of high-risk neuroblastoma risk factors and identify those with ultra-high-risk of treatment failure. The nomogram identified MYCN status, elevated lactate dehydrogenase, and the presence of bone marrow metastases as validated prognostic factors to identify ultra-high-risk patients. This nomogram allows pediatric surgeons and oncologists to better determine prognosis at diagnosis as well as identify patients with the highest mortality risk. The nomogram allows differentiation of patients with a 30% OS at three years (nomogram score greater than 82) compared with 58% OS for those with a score less than 82. This article produced an effective nomogram that could potentially identify children unlikely to respond to current treatment strategies who have a terrible prognosis and may benefit from alternative experimental therapies. This article will hopefully impact and alter the clinical practice and treatment of high-risk neuroblastoma.

Survival Impact of Anti-GD2 Antibody Response in a Phase II Ganglioside Vaccine Trial Among Patients With High-Risk Neuroblastoma With Prior Disease Progression [46]. Cheung et al. J Clin Oncol. 2021 Jan 20;39(3):215-226.

Patients with high-risk neuroblastoma frequently have a poor prognosis. Adding anti-GD2 monoclonal antibodies to the treatment of high-risk neuroblastoma patients has helped achieve long-term survival in 50 to 60% of patients. Further innovations in immunotherapy offer a promising avenue both to manage patients with disease that is refractory to chemotherapy and to provide effective treatments that are associated with minimal morbidity. Additionally, it has been speculated that the generation of an antitumor antibody response to tumor antigen by the patient could produce a more durable response than bolus administration of the antibody. Beta-glucans are a heterogeneous group of polysaccharides abundant in the cell walls of yeasts, bacteria, and fungi that reportedly induce a trained immunity and are effective vaccine adjuvants. Previously, a small phase I GD2/GD3 vaccine trial described long-term survival and a favorable safety profile among patients with a history of disease progression.

The study described in this manuscript was the Phase 2 prospective trial employing the same GD2/GD3 vaccine used in the Phase 1 study plus oral beta-glucan in a larger sample of 102 high-risk neuroblastoma patients who achieved remission, after salvage therapy, following at least one period of disease progression. The primary endpoint was progression-free survival (PFS), while secondary endpoints were quantification of anti-GD2 and anti-GD3 antibody response and correlation of antibody response with PFS and overall survival (OS). Patients had a history of one (63%), two (21%) or three to six (16%) episodes of disease progression. 82% of them progressed following anti-GD2 monoclonal antibodies. The PFS was 32% ± 6%, and the OS was 71% ± 7% at 5 years. No grade 3, or higher, morbidities were observed in any patients administered GD2/GD3 vaccine. Combining subcutaneous GD2/GD3 conjugate vaccine with oral β-glucan adjuvant was found to be safe and effective in inducing antibody response. Multivariable analyses showed that anti-GD2 antibody titer ≥ 150 ng/mL by week eight was associated with favorable PFS and OS while having fewer prior episodes of PD and the time from the last PD to the vaccine were associated with PFS. This is especially interesting given that most of these patients had disease progression after already being treated with anti-GD2 monoclonal antibodies. Given the safety profile of this vaccine, the correlation with antibody response titers and PFS/OS of high-risk neuroblastoma patients, and the expression of GD2 and GD3 among many other tumors, GD2/GD3 vaccination remains an intriguing treatment that clearly warrants further investigation.

A prospective study of pediatric and adolescent renal cell carcinoma: A report from the Children’s Oncology Group AREN0321 study [47], Geller et al Cancer 2020 Dec 1;126(23):5156-5164.

Renal cell carcinoma (RCC) is rare in the pediatric and adolescent population but is the second most common solid malignancy of the kidney, after Wilms Tumor, in this age group. Very little is known about this tumor and most published information comes from small retrospective case series or from extrapolation of adult data. It has been reported that RCC tumors are quite distinct biologically from those seen in adults and act differently clinically. Data has been lacking and this has created difficulty for pediatric surgeons and oncologists in treatment planning and discussions with patients and families.
This study’s importance lies in its prospectively and centrally (Children’s Oncology Group) gathered data with a rigorous review of pathology, radiology, and surgery. The article represents the first such study in the literature on this particular tumor in this group of patients and thus fills an important gap in knowledge in pediatric solid tumors. Most of these tumors were found to contain the TFE3 gene translocation. Overall, the study shows that favorable four-year outcomes can be achieved without adjuvant therapy in children and adolescents with completely resected RCC - independent of lymph node status (event-free and overall survivals in the 80 to 90% range). This differs from adult RCC outcomes. Metastatic disease portends a much poorer survival. The article provides new and important insights into treatment, outcomes, and prognostic factors. It will likely be the most referenced article on this subject for a long time.

Benefit of delayed primary excision in rhabdomyosarcoma: a report from the Children’s Oncology Group (COG) [48], Lautz et al Cancer 2020

Treatment for pediatric rhabdomyosarcoma (RMS) includes chemotherapy plus surgery and/or radiation therapy (RT) for local control. The majority of patients with RMS have the gross disease at the start of chemotherapy and are considered intermediate risk (group III) disease. Delayed primary excision (DPE) after neoadjuvant chemotherapy may allow for reduced doses of adjuvant radiation therapy but may increase surgical morbidity in this high-risk population.

Children with group III RMS of bladder/prostate, intrathoracic, retroperitoneal, trunk and extremity primary sites enrolled in COG studies D9803 and ARST0531 were compared (n=369). All children underwent upfront chemotherapy. In D9803, patients underwent DPE after 12 weeks of chemotherapy if the primary tumor appeared resectable. In ARST0531, definitive RT was the preferred mode of local control while DPE was permitted but not encouraged. Surgical morbidity of DPE resulted in loss of organ/function in 22% of cases. However, children who underwent DPE received lower radiation dose in 81% of patients; 51% were reduced to 36 Gy and 30% were reduced to 42 Gy with no difference in local failure rates. Importantly, children who underwent DPE had equivalent or improved overall survival. This is the first study to demonstrate the positive impact of DPE in the surgical treatment of pediatric RMS. While DPE poses a risk of surgical morbidity, the long term benefits of reduced RT dose and potential survival benefits highlight the need for careful consideration of risks and benefits when developing treatment plans for patients with group III RMS.

Optimization of percutaneous biopsy for diagnosis and pretreatment risk assessment of neuroblastoma [49], Overman et al Pediatr Blood Cancer 2020 May;67(5):e28153.

The treatment of neuroblastoma relies on accurate and complete biopsy results. In addition to histology, assessment of ploidy, MYCN amplification, and loss of heterozygosity are variables considered critical in the pathologic evaluation. Biopsy of suspected neuroblastoma has traditionally been performed via an open approach in order to guarantee adequate specimen procurement. In the past decade, however, several institutions have reported on the feasibility and adequacy of percutaneous biopsy. These reports also suggested a lower complication rate and less associated pain.

The study reported a collective retrospective chart review from 12 participating institutions comprising 243 cases of pediatric neuroblastoma. Of the 164 cases that were diagnosed by biopsy (as opposed to excision), 70 were performed percutaneously using core biopsies. Comparing open to percutaneous approaches, the authors found no difference in the ability to establish a principle diagnosis or evaluate for MYCN amplification. The percutaneous biopsy group had a statistically significantly lower rate of ability to identify loss of heterozygosity (56% versus 91%) and tumor ploidy (58% versus 89%), but these differences were diminished when a pediatric pathologist was present during the biopsy to assess the adequacy of specimens. Blood transfusion and opiate utilization were higher in the open biopsy compared to the percutaneous group but major complications did not differ. The authors concluded that percutaneous biopsy is a viable alternative to traditional open incisional biopsy and that protocolization vis-a-vis pediatric pathologist involvement, needle core size, and core biopsy pass attempts would further increase its accuracy and utility.

Predicting Acute Ovarian Failure in Female Survivors of Childhood Cancer: a Cohort Study in the Childhood Cancer Survivor Study (CCSS) and the St Jude Lifetime Cohort (SJLIFE) [50], Clark et al Lancet Oncol 2020 Mar;21(3):436-445.

Survivors of pediatric cancer are at risk for a number of chronic health conditions including infertility. The major risk factors for impaired ovarian function include chemotherapy (alkylating agents, and to a lesser extent cisplatin), radiation (pelvis and pituitary) and stem cell transplant. The effect of therapy on ovarian function can range from reduced ovarian reserve manifesting as infertility and/or premature menopause up to acute ovarian failure with complete loss of ovarian function. Prior efforts have helped to establish threshold doses of these therapies which place patients at an increased risk for infertility but further work is needed to identify the six percent of females who have acute ovarian failure, or complete loss of ovarian function, within five years of treatment.

5800 females from the Childhood Cancer Survivor Study comprised the primary data source and 875 in the St Jude Lifetime Cohort were used for validation. Six percent of survivors in the CCSS cohort were diagnosed with acute ovarian failure. A logistic regression model to determine the risk of acute ovarian failure had high diagnostic accuracy with an area under the curve (AUC) of 0.94. This model has been incorporated into a web-based model available for calculating an individual patients risk of acute ovarian failure.
https://ccss.stjude.org/tools-and-documents/calculators-and-other-tools/cc.... In applying this tool, it should be remembered that the model is designed to predict early, complete loss of ovarian function; patients can still have infertility and impaired ovarian function at lower doses of chemotherapy and radiation. A fertility preservation consultation with discussion and risk assessment should be offered to every patient undergoing cancer therapy and many families will opt for fertility preservation procedures at thresholds much lower than those expected to cause acute ovarian failure.

Prevalence and Predictors of Frailty in Childhood Cancer Survivors and Siblings: A Report From the Childhood Cancer Survivor Study [51], Hayek et al J Clin Oncol 2020 Jan 20;38(3):232-247.

Maintaining Outstanding Outcomes Using Response- And Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report From the Children’s Oncology Group Study ANBL0531 [52], Twist et al J Clin Oncol 2019 Dec; 37(34), 3243-3255.

Understanding the Value of Tumor Markers in Pediatric Ovarian Neoplasms [53], Lawrence et al J Pediatr Surg 2020;55(1):122–125.

The diagnostic accuracy and reliability of tumor markers for malignancy in girls with ovarian neoplasms is unknown. The role of tumor markers requires further clarification. Efforts are being made to promote ovary sparing surgery in the appropriate setting. However, one of the challenges facing surgeons is how best to preoperatively risk stratify the patient who presents with an ovarian neoplasm. Elements of the history, physical exam and imaging must be considered but tumor markers may also provide important information.

This study evaluated a large cohort of over 400 patients. It concluded that tumor marker testing is helpful in preoperative risk stratification of ovarian neoplasms for malignancy. Given the variety of potential tumor types no single marker provides enough reliability and therefore a panel of tumor marker testing is recommended if there is concern for malignancy. Prospective studies may help further elucidate the predictive value of tumor markers in a pediatric ovarian neoplasm population.

The Role of Surgery in High-risk Neuroblastoma [54], Ryan et al J Pediatr Hematol Oncol 2020 Jan;42(1):1-7.

The extent of surgical resection for high risk neuroblastoma has been the subject of debate among surgeons and oncologists with contrasting correlations to survival outcomes.

This review article summarizes the most recent articles on the implication of surgery for the treatment of high risk neuroblastoma and addresses many of the relevant surgical questions. The authors address the extent of surgical resection, describe the timing of surgical intervention and highlight potential complications from surgery as described in the literature and in most recent cooperative group protocols. The authors conclude that the objectives for surgical resection of neuroblastoma may differ from surgical resection goals in other various solid tumors treated by pediatric surgeons. Surgery is beneficial in high risk neuroblastoma although the extent of resection remains controversial. Further prospective trials that are currently collecting data including postsurgical resection data, image defined risk factors and induction response may help guide future surgical treatment.

Lymphatic Leakage after Surgery for Neuroblastoma: A Rare Complication? [55], Froeba-Pohl et al Eur J Pediatr Surg 2020 Jan 20.

Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients with High-Risk Neuroblastoma: A Randomized Clinical Trial [56], Park et al JAMA 2019. 27; 322: 746-755.

Evaluation of the diagnostic biopsy approach for children with hepatoblastoma: A report from the Children’s Oncology Group AHEP0731 Liver Tumor Committee [57], Weldon et al J Pediatr Surg 2019. May 11

Biopsies of unresectable liver tumors are currently being done by open, laparoscopic or percutaneous approaches with no prospective studies comparing their outcomes. Correct histopathological and molecular diagnosis is essential for effective treatment for children with solid organ tumors. For many tumors an open biopsy has been the standard of care. Alternatively, the development of interventional radiology techniques are attractive but raise questions about safety (e.g. bleeding) and diagnostic accuracy (e.g. obtaining enough tissue for molecular studies) compared to the traditional open biopsy.

This study reviewed children with hepatoblastoma enrolled in the Children’s Oncology Group study AHEP0731 who underwent biopsy of the primary tumor for initially unresectable patients. A total of 121 patients were included in the analysis of which 36 (30%) were PRETEXT II, 60 (50%) PRETEXT III and 25 (21%) PRETEXT IV. There were no PRETEXT I patients. Open biopsies were the most commonly performed (63%), followed by percutaneous (23%) and laparoscopic (14%), with no difference in biopsy type by age, PRETEXT group or time to initiating treatment.

Postbiopsy hemorrhage requiring blood transfusion occurred significantly more frequently in the open (36%) and laparoscopic (24%) biopsies compared with percutaneous (0%) (p< 0.01). The six-year cumulative incidence of tumor relapse was 19% (standard error (SE) 10%) in the open group, 19% (SE 10%) in laparoscopic, and 14% (SE 7%) in the percutaneous. Evaluation of the quality of the tumor tissue was not evaluated in this study although all biopsy approaches yielded a pathologic diagnosis.

This is the first analysis to prospectively compare biopsy techniques among children enrolled in a study for advanced stage hepatoblastoma. In the currently active trial AHEP1531 (Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT)), the type of biopsy is left to the discretion of the treating institution but the image guided percutaneous core needle biopsy is preferred. This study adds to our knowledge of the safety of the percutaneous biopsy approach compared to open or laparoscopic biopsy. Further study is required to further define the optimal approach to obtain diagnostic and pathologic material as well as material for biological studies in pediatric liver tumors.

Refinement of risk stratification for childhood rhabdomyosarcoma using FOXO1 fusion status in addition to established clinical outcome predictors: A report from the Children’s Oncology Group [58], Hibbitts et al Cancer Med 2019 Oct.

The classification and staging of children with rhabdomyosarcoma (RMS) is complex. Histology has traditionally been a major factor in determining risk stratification and treatment. However, identifying better prognostic markers are needed. FOXO1 fusion status is now recognized as a biological marker of disease severity in children with RMS. Recent studies suggest that it is more important prognostic factor than histology with fusion positive status seen in 80% of alveolar rhabdomyosarcomas and rarely seen in embryonal. FOXO1 status has replaced histology for classification in future treatment protocols.

This study pools data from six Children’s Oncology Group clinical trials – two studies each for low, intermediate and high risk patients with RMS. Using event free survival (EFS) as the primary endpoint, a survival tree regression was performed to determine the prognostic impact of risk factors (FOXO1 status, age, clinical group, histology, node status, number of metastatic sites, primary site, sex, tumor size, presence of metastasis at specific sites). The most significant associated factor on EFS for all patients was extent, with five-year EFS of 73% for localized and 30% for metastatic disease. However, within each subset (e.g. localized, metastatic), the tumor’s FOXO1 fusion status was the strongest prognostic factor. For local disease five-year EFS was 78% for fusion negative tumors versus 52% for fusion positive tumors. For metastatic disease the five-year EFS was 46% for fusion negative tumors versus six percent for fusion positive tumors. The overall results of the survival tree analysis allowed proposal of new risk group definitions using FOXO1 status in risk classification and treatment.

Treatment of Stage IV Favorable Histology Wilms Tumor With Lung Metastases: A Report From the Children’s Oncology Group AREN0533 Study [59], Dix et al J Clin Oncol 2018 Jun 1;36(16):1564-1570.

Patients with favorable histology Wilms tumor and lung metastases have a four-year event free survival (EFS) of 74.5% and overall survival (OS) of 86%. These patients were all treated with three-drug chemotherapy (DD4A) and lung radiation (RT). Experience in Europe reported by the International Society of Pediatric Oncology (SIOP) has suggested that complete response of pulmonary nodules following six weeks of three-drug chemotherapy allows for omission of lung RT with maintenance of similar outcomes (five-year EFS 77%; OS 87%). The implications of this are important, because chest radiotherapy is associated with an increased risk of cardiac dysfunction and breast cancer. A subgroup of these patients were further analyzed by SIOP and those with incomplete response, stable disease or progression had a significantly worse prognosis [five-year EFS 17% (stable or progression); EFS 67% (incomplete response)].

This study by Dix uses the response to the first six weeks of chemotherapy to determine subsequent treatment. In this study, patients that had a rapid complete response (RCR), defined by resolution of all lung disease on chest computerized tomography after six weeks of DD4A chemotherapy would then omit lung RT and continue with the same chemotherapy. This represented 45% of all patients and the authors show an improvement in outcomes despite omission of lung RT (four-year EFS to 80%; OS 96%). Incomplete response after six weeks of DD4A was thought to signify more aggressive disease so these patients wound receive lung RT as well as an intensified chemotherapy regimen (Regimen M). This group also showed a significant improvement in outcomes (three-year EFS 88%; OS 92%).

Wilms tumor with lung metastases

Visual abstract courtesy of Celeste Hollands

Factors Associated With Management of Pediatric Ovarian Neoplasms [53], Lawrence et al Pediatrics. 2019 Jul;144(1).

This is a multicenter retrospective review of 819 girls and women aged two to 21 years who underwent surgery for an ovarian mass at 10 children’s hospitals between 2010 and 2016. The two primary objectives of the study were to identify risk factors for malignancy and identify characteristics associated with oophorectomy in patients with benign pathology. They found that the overall rate of malignancy was 11% and that younger age, abdominal bloating, presence of lymphadenopathy, solid components on imaging and increased size were independently associated with malignancy. For each one-cm increase in lesion size there was an associated 12% increased odds of malignancy. Patients with torsed ovaries and those with solid components on imaging were more likely to undergo oophorectomy for benign disease. In addition, pediatric surgeons and adult gynecologists had significantly increased odds of performing oophorectomy (OR 2.68 CI 1.12-6.41; OR 4.23 CI 2.08-8.62, respectively) for benign disease compared to pediatric gynecologists. For each 1-cm increase in lesion size, there was an associated eight percent increased odds of oophorectomy for benign disease.

pediatric ovarian neoplasms

Visual abstract couretsy of Sarah Walker

Nationwide Overview of Survival and Management of Appendiceal Tumors in Children [60], Parikh et al J Pediatr Surg 53 2018 1175-1180.

Anterior Mediastinal Masses – A Multidisciplinary Pathway for Safe Diagnostic Procedures [61], Malik et al J Pediatr Surg. 2019 Feb; 54(2):251-254.

Appendicitis in a Neutropenic patient: A Multicentric Retrospective Study [62], Scarpa et al J Pediatr Hem Onc 2017 39:365-369.

Current and Emerging Roles of Whole-Body MRI in Evaluation of Pediatric Cancer Patients [63], Gottumukkala et al Radiographics 2019 Jan 25:180130.

Diagnostic Performance of 18F-FDG PET/CT and Whole-Body Diffusion-Weighted Imaging with Background Body Suppression (DWIBS) in Detection of Lymph Node and Bone Metastases from Pediatric Neuroblastoma [64], Ishiguchi et al Ann Nucl Med 2018, 32:348-362.

Microscopically Positive Resection Margin after Hepatoblastoma Resection: What is the Impact on Prognosis? A Childhood Liver Tumours Strategy Group (SIOPEL) Report [65]
Aronson et al Eur J Cancer 106: 126-132, 2019.

In this article, Aronson retrospectively reviewed the patients from SIOPEL 2 (1994 to 1998) and 3 (1998 to 2006) trials and evaluated the impact of microscopically positive resection margins on outcomes. All patients, regardless of tumor size, received multiple cycles of preoperative cisplatin based chemotherapy. There were 312 SIOPEL standard risk patients and 117 SIOPEL high risk patients. Of the 371 patients who achieved a gross complete surgical resection, 58 had microscopically positive margins. An additional 11 had gross residual tumor. Fifty-one patients underwent complete hepatectomy and liver transplantation. With a mean followup of 67 months, local tumor recurrence was 3/58 (5.1%) for patients with microscopically positive resection margins versus 23/371 (6.1%) for tumors that with negative microscopic margins. The five-year event free and overall survival rates were 86% versus 86%, and 91% versus 92% for patients with microscopically positive resection margins and patients with complete resections, respectively. No statistically significant differences in event free and overall survival were observed with subgroup analysis with standard risks and high risks patients. The goal of surgical resection in hepatoblastoma is a complete resection however this retrospective analysis shows that microscopic positive margins seem to have similar outcomes when patients have received postoperative chemotherapy. According to the study reports, no additional measures were taken in the treatment of the patients who had positive microscopic margins.

2017 PRETEXT: radiologic staging system for primary hepatic malignancies of childhood revised for the Paediatric Hepatic International Tumour Trial (PHITT) [66], Towbin et al Pediatr Radiol 48:536-554, 2018.

Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children’s Hepatic tumors International Collaboration [67], Meyers et al Lancet Oncol 18:122-131, 2017.

Characterization of Pulmonary Metastases in Children With Hepatoblastoma Treated on Children’s Oncology Group Protocol AHEP0731 (The Treatment of Children With All Stages of Hepatoblastoma): A Report From the Children’s Oncology Group [68], O’Neill et al J Clin Oncol 35:3465-3473, 2017.

Minimal Treatment of Low-Risk, Pediatric Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the Children’s Oncology Group [69], Appel et al J Clin Oncol 2016 Jul 10;34(20):2372-9.

Children and Adolescents with Marginal Zone Lymphoma have an Excellent Prognosis with Limited Chemotherapy or a Watch-and-Wait Strategy after Complete Resection [70], Ronceray et al Pediatr Blood Cancer 2018 Apr;65(4).

Temporal Trends in Treatment and Subsequent Neoplasm Risk Among 5-Year Survivors of Childhood Cancer, 1970-2015 [71], Turcotte et al JAMA. 2017 317:814-824.

This report studies the long term risk of secondary neoplasms. Briefly, patients who were younger than 21 years of age at time of diagnosis and with an initial diagnosis of leukemia, Hodgkin lymphoma, nonHodgkin lymphoma, central nervous system tumor, Wilms tumor, neuroblastoma, rhabdomyosarcoma or bone cancer were included in the study. The study included patients treated in the United States or Canada between 1970 and 1999. The primary outcome was the cumulative incidence of subsequent neoplasms after treatment and by treatment decades. The most common primary cancers were acute lymphoblastic leukemia, Hodgkin lymphoma and astrocytoma. The most frequently observed subsequent malignancies were breast and thyroid cancers. During the three decades, radiation therapy decreased and the doses of anthracyclines and alkylating agents decreased – even though the number of children treated with these chemotherapeutic agents increased. At 15 years after their initials diagnosis, patients in this cohort had an incidence of subsequent neoplasms of 2.9%, 2.4% and 1.5% if treated during the first, second and third decade respectively. Survivors treated with radiation had the highest cumulative incidence of secondary neoplasm. Female survivors had a relative risk of 1.7 for subsequent malignant neoplasms compared to their male counterparts. Radiation at any dose and alkylating agents were associated with increased risks of malignant neoplasms. The incidence of subsequent neoplasms decreased over five year increments and was associated most significantly with a decrease in the dose of radiation therapy.

Long-term outcomes in survivors of neuroblastoma: a report from the Childhood Cancer Survivor Study [72], Laverdière et al J Natl Cancer Inst 2009 101:1131-40.

Risk of Adverse Health and Social Outcomes Up to 50 Years After Wilms Tumor: The British Childhood Cancer Survivor Study [73], Wong et al J Clin Oncol 2016 34:1772-9.

Breast Cancer After Chest Radiation Therapy for Childhood Cancer [74], Moskowitz et al J Clin Oncol 2014 32:2217-23.

Chronic Health Conditions in Adult Survivors of Childhood Cancer [75], Oeffinger et al N Engl J Med 2006 355:1572-82.

Final Report of Sentinel Node Biopsy versus Nodal Observation in Melanoma [76], Morton et al N Engl J Med 2014;370:599-609

This report describes a randomized phase 3 clinical trial, the Multicenter Selective Lymphadenopathy Trial (MSLT-I), in which adult patients with intermediate thickness or thick primary localized melanoma were randomized to undergo wide local excision with sentinel lymph node biopsy or wide local excision and nodal observation. The purpose of this trial was to determine whether sentinel lymph node biopsy could be used to identify occult nodal metastases. The 10-year disease free survival rates were significantly improved in the sentinel lymph node biopsy group compared to the observation group for both intermediate thickness and thick melanomas. This pivotal trial validated the prognostic value of sentinel lymph node biopsy for localized intermediate thickness and thick melanomas and identified patients who may benefit from immediate completion lymphadenectomy. Biopsy based management led to improved disease-free survival in this trial.

Completion Dissection of Observation for Sentinel Node Metastasis in Melanoma [77],Faries et al N Engl J Med 2017; 376:2211-2222.

This second Multicenter Selective Lymphadenopathy Trial (MSLT-II) built upon the foundation of MSLT-I, which had validated the prognostic utility of sentinel lymph node biopsy for patients with intermediate thickness and thick localized melanoma. This phase 3 clinical trial randomized patients with cutaneous melanoma and sentinel node metastases to either immediate completion lymph node dissection or nodal observation with ultrasonography, with the primary end point of melanoma-specific survival. In both intention-to-treat and per-protocol analyses, immediate completion lymph node dissection was not associated with improved melanoma-specific survival. The 3-year melanoma specific survival in both groups was 86% (p=0.42). The rate of disease-free survival was slightly improved in the immediate dissection group (68%) compared to the observation group (63%) (p=0.05). The rate of lymphedema was 24% in the dissection group compared to 6.3% in the observation group. This trial demonstrated that immediate completion lymph node dissection increased the rate of regional disease control but did not improve melanoma specific survival among patients with melanoma and sentinel lymph node metastases.

Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update [39], Wong et al Ann Surg Oncol 2018; 25:356-377.

The purpose of this report was to provide expert panel recommendations for guidelines regarding sentinel lymph node biopsy and the need for completion lymph node dissection in adult patients with melanoma. A systematic review of the literature was conducted which included nine observational studies, two systematic reviews and three randomized controlled trials. Recommendations based upon the included relevant studies included indications for sentinel lymph node biopsy for T1b, T2, T3 and some T4 lesions. The panel concluded that for positive sentinel lymph node biopsy, completion lymph node dissection or nodal observation are reasonable options following careful consideration of tumor- and patient-specific clinicopathological factors.

Pediatric Patients with Cutaneous Melanoma: A European Study [78], Brecht et al Pediatr Blood Cancer 2018 Jan

The authors report results from a multinational retrospective study performed by EXPeRT (European Cooperative Study Group for Pediatric Rare Tumors) on pediatric cutaneous melanoma. A registry was used to prospectively collect data from certified multinational centers between 2002-2012. Inclusion criteria were as follows: histologically confirmed diagnosis of cutaneous melanoma, age less than 18 years, a follow up of longer than three months and time of diagnosis between 2002 and 2012. 219 patients were included. Data was collected on clinical findings (Clark level, Breslow thickness, ulceration and nodal status) and all patients were reclassified according to the adult American Joint Committee on Cancer (AJCC) staging system. Overall 112 patients underwent SLNB (51%), SLNB was positive in 42 patients (37.5% of those with SLNB). Adjuvant therapy was used in only 33 patients (61% of patients with advanced disease- AJCC stage III/IV). Adjuvant therapies included: interferon alpha (19 patients), immunotherapy (four patients), chemotherapy plus interferon alpha (2 pts), and chemotherapy and Vemurafenib (one patient). There was no significant difference in disease free survival (DFS) or overall survival (OS) between groups treated with adjuvant therapy and those not treated with adjuvant therapy. For all patients, the OS and DFS at 3 years was 91.4% and 84% respectively at median follow up of 41.8 months. Tumor site, ulceration status, tumor size, nodal status and AJCC stage all had a significant influence on DFS which is similar to adult outcome trends. Age at diagnosis did not correlate with survival. The significance of this study is it suggests that pediatric melanomas may behave similar to adult melanomas.

Spitz Nevi and Other Spitzoid Neoplasms in Children: Overview of Incidence Data and Diagnostic Criteria [79], Dika et al Pediatr Derm. Vol. 34 No. 1 25-32, 2017.

The authors conducted a PubMed and Cochrane database search to review the current literature on the clinical, dermatoscopic, genetic and histopathologic aspects of spitzoid tumors. While the authors did not adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, they provide a well written summary of an often confusing topic for pediatric surgeons: Spitzoid tumors in children. Spitzoid neoplasms usually affect young patients (less than 20 years of age), are typically solitary lesions and most often occur on the head and neck and extremities. Spitz nevi are benign melanocytic neoplasms characterized by epithelioid or spindle melanocytes or both. Atypical spitz tumors (ASTs) are characterized by atypical histologic features (asymmetric and poorly circumscribed shape, thicker and deeper extension, ulceration, lack or absence of Kamino bodies and the presence of more than 6 mitoses/mm²) and include cases of positive sentinel lymph node(s); however, sentinel lymph node positivity has not been associated with a bad prognosis in ASTs as is the case with malignant melanoma. The article also summarizes the immunohistochemical and cytogenetic similarities and differences between Spitz nevi, ASTs and malignant melanoma. Spitz nevi may spontaneously involute in up to 80% of cases and conservative management with periodic clinical and dermatoscopic follow-up is recommended. Surgical excision is reserved for children with suspicious lesions including those with atypical features (large lesions, ulceration, asymmetry, rapid growth). If the pathologic diagnosis after excision is benign Spitz nevus, no follow-up is required except annual exams. If the pathologic diagnosis is AST, annual clinical exams with periodic nodal ultrasonagraphy is usually sufficient. The utility of sentinel lymph node biopsy in cases of AST is still debated. It is important that highly skilled dermatopathology and molecular characterization be used in the study of spitzoid tumors.

Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer [80], Francis et al Thyroid 2015:25, 716-760.

This manuscript is the result of an independent task force commissioned by the American Thyroid Association Guidelines Task Force on Pediatric Thyroid Cancer to develop recommendations for the treatment of pediatric thyroid nodules and cancers based on an extensive review of the existing literature (405 references). This extensive review provides 34 rated and referenced recommendations and algorithms for the preoperative evaluation, surgical intervention, postoperative treatment and long term care of children and adolescents with thyroid nodules and differentiated (papillary and follicular) thyroid cancer.

Prophylactic Thyroidectomy in Multiple Endocrine Neoplasia Type 2A [81], Skinner et al N Engl J Med. 2005 Sep 15;353(11):1105-13.

The authors evaluate the timing of total thyroidectomy to prevent medullary thyroid carcinoma in 50 children know to have inherited a mutated RET allele characteristic of MEN2a. All patients underwent preoperative calcitonin testing, total thyroidectomy and long term evaluation for persistent or recurrent disease five years or more after total thyroidectomy by calcitonin testing (with pentagastrin or calcium stimulation). Older children were more likely to have elevated preoperative calcitonin levels (median age 11years) and microscopic and/or macroscopic evidence of medullary thyroid cancer (median age 10 years) at operation. In 88% of patients, there was no evidence of persistent or recurrent medullary thyroid cancer by calcitonin testing at five years or longer postoperatively. No child who had resection prior to eight years of age and had no nodal involvement showed evidence of recurrent or persistent disease by calcitonin testing or exam. While this work is one of the initial publications demonstrating the efficacy of early total thyroidectomy for the kindred of MEN2a families with RET oncogene mutation in prevention of medullary thyroid cancer, subsequent work has refined the recommended age of resection be based on the particular RET codon mutation identified as summarized in Wells et al Thyroid; 2015:25, 567-610 (Recommendations 33-36).

Predictors of Nodal Metastasis in Pediatric Differentiated Thyroid Cancer [82], Kim et al J Pediatr Surg 2017 Jan;52(1):120-123.

The authors present a SEER database review of 1,075 children with differentiated thyroid cancer to assess for clinical findings associated with nodal involvement. Their data suggest nodal metastasis in children with differentiated thyroid cancer is associated with larger tumor size (greater than 1.1cm OR 2.02, 95% CI 1.22-3.34, p=0.006), extrathyroidal disease (OR 7.28, 95% CI 4.04-13.01, p< 0.001) and multifocal disease (OR 1.94, 95% CI 1.33-2.84, p=0.001). Follicular thyroid carcinoma and Hürthle cell carcinoma were associated with lower risk of nodal involvement compared to papillary (OR 0.05, 95% CI 0.02-0.19, p< 0.001). Age, sex and race were not associated with increased risk of nodal involvement in differentiated pediatric thyroid cancers.

18F-Fluorodeoxygludose Positron Emission Tomography/Computed Tomography May Exclude Malignancy in Sonographically Suspicious and Scintigraphically Hypofunctional Thyroid Nodules and Reduce Unnecessary Thyroid Surgeries [83], Ruhlmann et al Thyroid 2017 Oct;27(10):1300-1306.

This paper out of Germany is a retrospective study specifically looking at an adult population (65 patients) that had a thyroid nodule that was ultrasound suspicious (TIRAD 4a or greater), Tc-99 negative (cold nodule) and refused, for a variety of reasons, to undergo an fine needle aspiration (FNA). Instead all patients underwent a PET/CT. In 18/65 the PET/CT was positive and patients underwent lobectomy or total thyroidectomy with malignancy detected in 11 of the 18. Of the remaining 47 patients that were PET/CT negative, ultrasound was used for a minimum of five years of follow up and all showed no growth. Thus the PPV was 61% and the NPV was 100%. The significance of this paper, especially in the pediatric population, is that it provides another potential avenue of work up for patients besides an FNA to reliably exclude a thyroid nodule as being malignant and potentially avoid an unnecessary operation. Another potential advantage would be in patients that undergo an FNA and have indeterminate pathology.

Validation of American Thyroid Association Ultrasound Risk Assessment of Thyroid Nodules Selected for Ultrasound Fine-Needle Aspiration [84], Tang et al Thyroid 2017 Aug;27(8):1077-1082.

In 2015, the American Thyroid Association produced the inaugural guidelines for the management of thyroid nodules and differentiated thyroid cancer in children and updated the adult guidelines. Within both, ultrasound is recommended to both determine size and appearance of the nodule with certain sonographic features associated with a malignancy including microcalcifications, taller-than-wide shape, marked hypoechogenicity and irregular margins. Features associated with benign pathology include purely cystic and spongiform appearance. Depending upon size and characteristics, the risk of malignancy is broken down into high (70 to 90%), intermediate (10 to 20%), low (5 to 10%), very low (less than 3%), and benign (less than 1%). In this study, from March of 2015 to May of 2016, 211 nodules were prospectively evaluated with ultrasound (US) and fine needle aspiration. The proportion of nodules that were cytologically malignant or suspicious of malignancy correlated with the US risk pattern: high (77%), intermediate (6%), low (1%) and very low (0%). Also of note within the study, there were 71 nodules with “indeterminate” cytology. Of those that eventually underwent removal, if the US findings were categorized as high, there was a 100% incidence of malignancy. The significance of this study is that it validates the ATA guidelines and will be useful for providing reliable data in discussions with families about risks assessment for thyroid nodules and treatment recommendations.

Pancreaticoduodenectomy for malignancies in children [85], d’Ambrosio et al J Pediatr Surg 2014 Apr;49(4):534-8.

This case series examined five patients who underwent pancreaticoduodenectomy (PD) for malignant tumors. Pathologic diagnoses varied with two patients with pancreatic acinar cell carcinomas, one with a solid pseudopapillary tumor and two patients with rhabdomyosarcoma (RMS) of bile ducts. The patients with RMS of bile ducts also required hepatic resection. Pyloric preservation was performed when possible. Reconstruction of the pancreatic stump was done with intussusception into the roux loop. They noted that four of five patients were on full feeds by second week postoperatively and did not note any dumping syndrome symptoms. Pancreatic enzymatic supplementation was required in three of five children. Two patients developed strictures of the pancreaticojejunal anastomosis and required reoperative surgery. Two patients who underwent surgery for RMS of bile ducts died of disease - the rest are alive and free of disease.

Pancreaticoduodenectomy outcomes in the pediatric, adolescent, and young adult population [86], Mansfield et al J Surg Res 2016 Jul;204(1):232-6.

This study examined a single institution outcome of pediatric, adolescent and young adult patients undergoing pancreaticoduodenectomy over a 15-year period. Twenty-two patients were identified with a median age of 25 years. Eighteen patients had a mass of the pancreas with a mean tumor size of 4.0 cm. Of the patients with pancreatic malignancy one patient required reoperation due to stricture of the hepaticojejunostomy. The most common postoperative complication was intra-abdominal abscess (occurring in three patients) and one pancreatic leak. No patients died within the first 30 days and in observational cohort of adults from the same institution was included for qualitative comparison noting that the pediatric population had a favorable side effect profile.

Pancreaticoduodenectomy for pediatric and adolescent pancreatic malignancy: A single-center retrospective analysis [87], Lindholm et al J Pediatr Surg 2017 Feb;52(2):299-303.

A single center review article of all patients less than 18 years of age over a 22 year span who underwent pancreaticoduodenectomy (PD). Twelve patients were identified in this series. Four patients had previous operations and required PD for recurrent disease. Diagnoses included pancreaticoblastoma (3), Solid pseudopapillary toumor (3), neuroblastoma (2), rhabdomyosarcoma (2) and PNET (2). In 8/12 patients a PD was performed as resection of primary disease and four patients underwent PD to treat metastatic disease in the head of the pancreas. 9/12 patients had underwent preoperative chemo- or radiation therapy. Pylorus sparing procedures were performed in all patients. Pancreatic reconstruction varied with the distal pancreas invaginated into posterior stomach (3), end of the jejunum (3) or sewn to jejunal mucosa (4) . Transfusion was required in half of all patients. Mean length of stay was 10.6 days. Immediate postoperative complications included one intraperitoneal abscess and one patient developed a leak. Long term complications included 10/12 patients requiring pancreatic enzyme supplementation. Delayed gastric emptying was reported in two patients. Five patients with solid pseudopapillary tumor or RMS were long term survivors.

A population-based analysis of a rare oncologic entity, malignant pancreatic tumors in children [88], Mylonas et al J Ped Surg 2014 Oct; 49(12): 1730-3.

The authors used the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database to identify 114 patients with pancreatic malignancies. Pancreaticoblastomas were most common in children less than 10 years of age while neuroendocrine tumors were the most frequent cell type overall. The overall five-year survival rates for these cell types were 77% and 66%, respectively. Epithelial malignancies were more common in adolescents as were solid pseudopapillary tumors. Controlling for metastatic disease, cancer directed surgery was associated with an improved overall survival.

Solid-pseudopapillary neoplasm of the pancreas in children: Can we predict malignancy? [89], Hwang et al J Ped Surg 2014; 49, 1730-3.

This single institution paper reviews 45 children with solid pseudopapillary neoplasms of the liver who had undergone resection. All children had at least one computerized tomography scan. The median age at treatment was 15 years. Of the cohort, nine had malignant histologic features and three had clinically evident malignant features with peripancreatic soft tissue invasion. Surgical resections included a Whipple variant (27%), distal pancreatectomy (47%) or lesser pancreatic resection (26%). Of the 45 patients, four recurred and were treated aggressively with further surgical resection. Patients with malignant features were larger (10 cm versus 5 cm) and had a higher median solid component ( 88.5% versus 41.5%). Median follow up was 34 months. There were no deaths reported.

Pancreatic tumours in children: diagnosis, treatment and outcome [90], Nasher et al Pediatr Surg Int 2015 Sep;31(9):831-5.

This is a single institution retrospective review over a period of 38 years. There were only 14 patients during this period of whom 12 had complete records. They also reference 41 cases of pancreatic tumors reported to the UK National Registry of Childhood Tumours from 1971 to 2000. The histology of cases in the single center were primarily solid pseudopapillary neoplasms and endocrine pancreatic neoplasms. The diagnoses were very different in the national registry with 11 of 41 (27%) cases being pancreatoblastoma. Specific description of surgical resections and long term outcomes were not provided but it is noteworthy that of 12 with surgical resection, five had an uneventful recovery and there were two pseudocysts, one peripancreatic fluid collection, one hemorrhagic pancreatitis and one death with two unknown outcomes. The conclusion that laparoscopic resection is optimal therapy is not supported by the data presented.

A Prospective, Holistic, Multicenter Approach to Tracking and Understanding Bloodstream Infections in Pediatric Hematology-Oncology Patients [91], Gaur et al
Infect Control Hosp Epidemiol 2017 Apr 12:1-7.

This article reviews and classifies data on 1110 blood stream infections (BSI) from 39 pediatric hematology-oncology units (Childhood Cancer and Blood Disorders Network) collected over 25 months to define the relative contribution of central line associated BSI (CLABSI) to overall BSIs in this population. All centers followed a standardized central line maintenance care bundle for at least two years prior to the study period. BSI events and central line days were tracked monthly. Patients with a positive blood culture and central venous access were assigned to a specific category using National Healthcare Safety Network (NHSN) definitions: CLABSI; secondary BSI; and single positive blood cultures (SPBC). CLABSI infections were further divided into mucosal barrier injury related lab confirmed BSI [MBI-LCBI] and nonMBI-LCBI. 63.8% of all BSIs were designated as CLABSIs, 15.3% were secondary BSIs and 20.9% were SPBCs. 51% of CLABSIs were MBI-LCBI. 65% of non-MBI-LCBI, 91% of MBI-LCBI, 82% of secondary BSI and 75% of SPBC were associated with neutropenia (absolute neutrophil count less than 100 cells/mL). SPBC were associated with Staphylococcus species (54%) and viridans group streptococci (22%). Significantly higher CLABSI rates (88%) and lower secondary BSI rates (12%) were identified over time related to an NHSN update for the definition of BSI.

These data define the contribution of CLABSI to overall BSIs in the pediatric Hematology-Oncology population in a multi-institutional group utilizing a well established standardized central line maintenance care bundle. Identification and removal of MBI-LCBI from CLABSIs appears to reduce the overall CLABSI rate by approximately 50%. The authors suggest "while public reporting of CLABSIs as preventable health-associated infections should continue, the messaging should include the overall context of BSIs and the limits of the definitions used, such that informed interpretations of the reported data can be made."

Preventing CLABSIs among Pediatric Hematology/Oncology Inpatients: National Collaborative Results [92], Bundy et al Pediatr 2014 Dec;134(6):e1678-85.

This study describes implementation a standardized bundle of central venous access care practices and CLABSI surveillance within a 32 Pediatric Hematology/ Oncology collaborative. Pre- and postimplementation rates of central venous line (CVL) infection are documented using Centers for Disease Control and National Healthcare Safety Network (NHSN) surveillance definitions. Baseline CLABSI rate (collected over four years) was 2.85 CLABSIs per 1000 CL-days; by 34 months after adoption the bundle by the collaborative group the mean CLABSI rate was significantly reduced to 2.04 CLABSIs per 1000 CL-days, a reduction of 28% (relative risk: 0.71 [95% confidence interval: 0.55-0.92]). Compliance with CLABSI bundle was initially 38% but increased to 78% within one year. Compliance remained 81% to 86% throughout the remainder of the reporting period without statistically significant changes in CLABSI rates. The odds of a ‘CLABSI-free’ month for any participating unit after implementation of the care bundle were 2.59x the corresponding odds of CLABSI infection during the pre-implementation period when comparing units of similar CVL days. This study demonstrates the feasibility of implementing a standardized CVL maintenance care bundle program in a large collaborative group of pediatric hematology/oncology units and the efficacy of such a program in reducing CLABSIs in the Pediatric hematology/oncology population.

Central Venous Catheter Care for the Patient with Cancer: American Society of Clinical Oncology Clinical Practice Guideline [93], Schiffer et al J Clin Oncol 2013 April 1:31(10);1357-1370.

This paper summarizes the guidelines that were created by the American Society of Clinical Oncology to help practitioners in central venous catheter (CVC) management in patients with cancer including both children and adults. Recommendations were based upon MEDLINE and Cochrane Collaboration Library literature search covering the years 1980 to 2012 and discussions amongst an expert panel. The review included 108 RCT, 25 meta-analyses, and several existing guidelines. The key recommendations include 1) avoidance of femoral vein insertion except for emergencies, 2) CVC’s should be placed by well-trained providers but method of placement (image guided versus landmark) is practitioner dependent, 3) use of a CVC clinical care bundle is recommended to decrease BSI, 4) prophylactic use of systemic antibiotics at the time of insertion is not recommended, 5) if infection is suspected cultures should be obtained prior to starting antibiotics and most BSI’s can be managed with appropriate antimicrobial therapy with catheter removal considered when the infection involves the port or catheter tubing, or if infection with fungi or nontuberculous mycobacteria, or is persistent bacteremia more than 48 to 72 hours after appropriate antimicrobial treatment, 6) routine flushing with saline is recommended, 7) systemic anticoagulation does not appear to decrease CVC related thrombosis and is not recommended, 8) TPA is recommended to restore patency in a nonfunctioning CVC and removal of a CVC in the face of a radiologically confirmed thrombosis that does not respond to three to six months of anticoagulation.

Long-term Central Venous Access in a Pediatric Leukemia Population [94], Fu et al J Surg Res 2016 Oct;205:419-425.

This article is a retrospective review covering all central venous access devices (CVAD) from a single institution over a five year period (2009 to 2014) that were placed in leukemia patients (ALL/AML) and reviewing both perioperative and long term complications associated with the lines with the primary focus being on reasons for removal. This included 292 CVAD’s (240 ports and 52 tunneled lines) for a total of 142,607 catheter days. In the perioperative period 10 catheters were malpositioned and required intervention. No conclusion was reached on how to prevent the malposition but size of the catheter, port versus tunneled line, position of the reservoir on the chest wall, vessel used, or technique were found to be predictors of malposition. With respect to long term complications, 70% had some form of complication with unexplained catheter malfunction (39.7%), infection (31.8%), fibrin sheath (5.1%), and DVT (2.4%) being the top four. A total of 75 lines (25.7%) were removed prematurely as a result of these complications. On multivariate analysis, obesity, preoperative blood transfusion, infection, and unexplained line malfunction were the only factors associated with premature catheter removal. In terms of modifiable factors for the pediatric surgeon, on univariate analysis, port placement below the nipple line (less risk for unexplained catheter malfunction) and delay in placement of the implanted line (use of a PICC first) were associated with less catheters removed prematurely. This study highlights the potential struggles with CVAD in a very fragile population of patients.

Hepatocellular Carcinoma in Children: Does Modified Platinum- and Doxorubicin-Based Chemotherapy Increase Tumor Resectability and Change Outcome? Lessons Learned From the SIOPEL 2 and 3 Studies [95], Murawski et al J Clin Oncol. 2016 Apr 1;34(10):1050-6.

This article reports the results of the two most recent prospective International Childhood Liver Tumor Strategy Group trials (SIOPEL 2 and 3). Of 85 patients with hepatocellular carcinoma (HCC), 13 underwent upfront resection and 72 were treated with intensified platinum- and doxorubicin- based neoadjuvant chemotherapy (NAC) regimens in order to render the tumors resectable. Twenty-nine (40%) of the 72 patients had an objective response, but only in 2 (3%) patients did initially unresectable tumors become resectable with NAC. Including 7 patients who had liver transplants (LTX), 34 (40%) of 85 patients had complete resection with negative margins. Overall 5-year survival was dismal at 22%, but 18 (63%) of 27 patients survived after margin-negative resection, 1 of 7 patients (14%) survived with microscopic residual disease after resection, and 2 of 7 patients (29%) survived after LTX. Complete resection was associated with survival (P=0.035). The authors concluded that patients with resectable HCC should undergo upfront resection, that intensified NAC did not improve the survival in patients with HCC, and that LTX is a suitable option for patients with unresectable, non-metastatic HCC and should be considered early after diagnosis.

Detection of a Recurrent DNAJB1-PRKACA Chimeric Transcript in Fibrolamellar Hepatocellular Carcinoma [96], Honeyman et al Science 2014 Feb 28:343(6174):1010-4.

Fibrolamellar HCC (FL-HCC) is a rare histologic variant of HCC affecting adolescents with no underlying liver disease. Despite its distinct histologic appearance, it shares a poor outcome. This paper documents the discovery of a unique, highly conserved chimeric protein found in all 15 FL-HCC tumors tested. Although there was some variation in the break points, the protein is the product of a 400kb pair deletion on chromosome 19, which joins the promoter and first exon of DNAJB1, a member of the heat shock 40 protein family, to exons 2 to 10 of PRKACA, protein kinase A catalytic subunit alpha. Protein kinase A normally exists in tetramers of catalytic and regulatory subunits. The chimera retains the phosphorylation capacity of PKA, but loses the ability to bind to and be regulated by the regulatory subunit. This retained function, its overexpression in tumor cells compared to wild-type PRKACA, and its presence in 100% of the tumors tested leads the authors to conclude that this is a driving mutation in the development of FL-HCC. The authors also conclude that this distinct DNA, RNA, and protein anomaly may offer a diagnostic and therapeutic target for FL-HCC going forward.

Hepatic Metastasectomy in Children [97], Su et al Cancer 2007 May 15;109(10):2089-93.

While hepatic metastasectomy has proven beneficial in several adult tumors, its use in pediatric solid tumors has been reported much less frequently. This paper reviews the surgical and long-term outcome of 15 patients undergoing hepatic metastasectomy for pediatric solid tumors. The average age at hepatic resection was 6.2 years, 6 of 15 patients had concurrent metastases to other organs, and 12 of 15 resections (80%) were anatomic. There were no intra- or post-operative deaths, and only two minor complications occurred (1 wound infection, 1 biloma). Median survival after hepatic resection was 9 months, only 3 of 15 patients (20%) were long-term survivors, and all deaths were due to disease progression or treatment complications. The authors conclude that, although hepatic metastasectomy in pediatric solid tumors are safe, they must be performed in highly selected patients, preferably with control of the primary site and no evidence of disease outside the liver.

Characteristics and Outcomes in Children with Undifferentiated Embryonal Sarcoma of the Liver: A Report from the National Cancer Database [98], Shi et al Pediatr Blood Cancer 2017 Apr 64(4).

This article is the largest retrospective study of children with undifferentiated embryonal sarcoma of the liver through the National Cancer Database. The authors show a cohort of 103 patients < 18 years. The overall survival (OS) of the group of patients was 86% at 5 years. Children who had combined therapy that included surgical resection and chemotherapy had a 5-year OS of 92%. Best outcomes were associated with tumors smaller than 15cm and surgical resection (with or without chemotherapy). Only 1 of the 22 patients who underwent lymph node sampling was found to have disease within the node. Surgical margins did not correlate with outcome. Metastatic disease was present in 10 patients, and these patients had a 5-year OS of 86% compared to 91% among patients without metastasis. Ten patients underwent liver transplantation as primary treatment and are all alive at 5 years. Of these 10 patients, 9 had chemotherapy in addition to transplant. The multivariate analysis revealed that tumors smaller than 15 cm and combined therapy (surgery and chemotherapy) were independent prognostic indicators associated with the best outcomes.

Widening Spectrum of Liver Angiosarcoma in Children [99], Ackermann et al J Pediatr Gastroenterol Nutr 2011 Dec 53(6): 615-9.

Angiosarcoma of the liver is a rare but very rapidly progressing malignancy seen in children. Due to the relationship with hemangioma and hemangioendothelioma of the liver, which are more commonly seen, it is important to understand scenarios in which patients may be at higher risk of angiosarcoma. This article discusses 3 cases in which children presented with multinodular hemangiomas of the liver that initially responded to nonoperative management including steroid therapy and/or hepatic artery embolization. However, after a period of time, relapse occurred with rapidly progressing metastatic disease and death. These patients were all diagnosed with type 2 hemangioendothelioma or angiosarcoma. The last 2 cases discussed are children presenting after 1 year of age with vascular tumors within the liver. The first patient underwent hemihepatectomy but disease recurred in the liver and lungs and the patient died. The second patient underwent liver transplantation and is alive. Both of these patients also had histologically confirmed angiosarcoma. This paper describes the interesting evolution of hepatic vascular tumors and highlights the potential for multinodular hemangiomas to recur as angiosarcoma, as well as the possibility of tumor sampling error in presumed benign hemangioendothelioma that can miss the angiosarcoma component.

Inflammatory Myofibroblastic Tumor of the Liver in Children [100], Nagarajan et al J Pediatr Gastroenterol Nutr 2013 Sept 57(3): 277-80.

Inflammatory myofibroblastic tumors (IMT) are characterized histologically as spindle cell proliferation with chronic inflammatory infiltrate of plasma cells, lymphocytes, and histiocytes. The tumor is considered benign but in many cases can be locally aggressive. The tumor can arise anywhere in the body and some occur in the liver. The authors present a review of IMT in the liver in children between the ages of 3 months to 15 years, based on data from 35 patients reported in the literature from 1971-2008. Forty percent of patients presented with fever and abdominal pain. Three patients in the published reports experienced resolution of the tumor with NSAID, antibiotic, or no therapy (observation). The majority of patients underwent surgical resection with 6 patients undergoing liver transplantation and all patients surviving without recurrence (minimum follow-up time of 6 months). About 50% of IMT patients are believed to have a gene rearrangement of the anaplastic lymphoma kinase gene, and crizotinib has been used for nonoperative management in these cases with varying results.

Rhabdoid Tumors of the Liver: Rare, Aggressive, and Poorly Responsive to Standard Cytotoxic Chemotherapy [101], Trobaugh-Lotario et al Pediatr Blood Cancer 2011;57:423-8.

This literature review of all published English-language reports from 1970-2010 identified 34 patients with rhabdoid tumor of the liver. The median age at diagnosis was 8 months, the majority of patients had systemic symptoms (fever/lethargy/anorexia/vomiting), and serum AFP was normal or minimally elevated. All 10 tumors tested harbored INI1mutations, now considered necessary for rhabdoid diagnosis. Five (17%) of 29 patients presented with evidence of tumor rupture at diagnosis, and 21 (62%) of 34 patients had metastatic disease at diagnosis. Survival was poor with only 4 (12%) of 34 patients reported surviving. Median time to death from diagnosis was 2 months and nearly all deaths occurred within 1 year of diagnosis. The authors conclude that these tumors are aggressive and poorly responsive to chemotherapy and radiation. They recommend aggressive surgical treatment and intensive chemotherapy to have a chance at cure.

The Evolution of Diagnosis and Management of Pediatric Biliary Tract Rhabdomyosarcoma [102], Curr Pediatr Rev 2016 Jan 17;12:190-98.

This review summarizes decades of reports of this very rare tumor. Although it comprises only 1% of pediatric rhabdomyosarcoma (RMS), biliary tract RMS (BT-RMS) is the most common neoplastic cause of biliary tract obstruction in children. BT-RMS presents at a median age of 3 years, has a slight male predominance, and patients present with jaundice 60-80% of the time. Patients frequently have a conjugated hyperbilirubinemia and an elevated alkaline phosphatase. The diagnosis of BT-RMS is frequently missed due to its rarity and its ability to mimic the more common, benign choledochal cyst in presentation and imaging. The use of CT, MRI, and MRCP can aid in this differential, and any of these showing a soft tissue mass in the porta hepatis should rule out choledochal cyst and raise suspicion for a neoplastic process. Appropriate staging is described, and the importance of biopsy without upfront radical surgery is emphasized. Treatment with RMS-directed chemotherapy and selective radiotherapy and surgery for local control on a case-by-case basis is advocated as the best approach to this rare tumor, which has a good overall survival.

Preserving Fertility in Children and Adolescents with Cancer [103], Children (Basel). 2014 Aug 26;1(2):166-85.

This review paper highlights important concepts regarding approaches to preserving fertility in pediatric oncology patients. The author outlines the importance of fertility preservation programs in the setting of continuously improving survivorship of childhood cancers. Barriers to comprehensive discussion of fertility preservation with pediatric patients and their families by health care professionals are discussed. The author reviews the risks for gonadal toxicity in female patients with oncologic diagnoses, including the concepts of acute ovarian failure and premature menopause. The processes of embryo and oocyte cryopreservation for fertility preservation in post-pubertal females are discussed, as is the approach of ovarian tissue cryopreservation for pre-pubertal females. The importance of monitoring of ovarian function after completion of therapy is outlined. The author reviews the risks for gonadal toxicity in males, as well as the concept of sperm cryopreservation. Algorithms of fertility preservation options for female and for male pediatric patients are presented. The importance of appropriate institutional infrastructure and collaboration between oncologists and reproductive endocrinology experts is discussed in the context of assuring pediatric oncology patients access to fertility preservation programs. An excellent overall review of fertility preservation in children and adolescents with cancer.

Ovarian tissue collection for cryopreservation in pediatric age: laparoscopic technical tips [104], Lima et al J Pediatr Adolesc Gynecol 2014 Apr;27(2):95-7.

This article focuses on surgical technique for collection of ovarian tissue for cryopreservation in the pediatric population. The importance of consideration of approaches to fertility preservation for girls who may sustain chemotherapy- or radiotherapy-induced gonadal toxicity is highlighted. The authors describe their 11-year experience with the use of laparoscopic ovarian tissue collection. They discuss reasoning for their port selection, their rationale for specimen collection from both ovaries, and their technical tips for cutting into the ovaries and achieving hemostasis. They also discuss options for transposition of the ovaries in order to reduce follicle damage in the ovarian tissue left in situ, in cases in which children require pelvic radiotherapy as part of their oncology treatment regimen. A very useful paper to familiarize the pediatric surgeon with the surgical technique for ovarian tissue cryopreservation.

Progress and Prospects for Fertility Preservation in Prepubertal Boys with Cancer [105], Gies et al Curr Opin Endocrinol Diabetes Obes 2015, 22:203-208.

This article is a nice review of what is currently available to the prepubertal boy who is to undergo cancer therapy. According to this paper males have a 46% overall reduction in the likelihood of siring a pregnancy after cancer treatment. The article discusses the option of cryopreservation of spematogonial stem cells (SSC’s) and subsequent autotransplantation. This procedure was first described in mice in 1994. The article goes into detail about the potential cryopreservation techniques available. Of interest is that they discussed the possibility of transplantation of tumor cells into the testis when reimplantation occurs which is an issue with ovarian tissue as well, especially in patients who had leukemia. The authors recommend one large volume biopsy of the testis for preservation which they explained has less risk of devasularization than multiple small biopsies. At this time they also recommend using the technique only for patients at high risk of infertility since there is a small but real risk of the testicular biopsy. They also weighed the options for timing of reimplantation: peripubertal vs as an adult and recommended waiting until adulthood when it is clear the patient is devoid of spermatogenesis and also after they are cured from cancer. This paper was an excellent overview of techniques available and ethical considerations for fertility preservation in the prepubertal male patient.

Fertility Preservation and Reproductive Health in the Pediatric, Adolescent and Young Adult Female Cancer Patient [106], Trudgen et al Curr Opin Endocrinol Obstet Gynecol 2014, 26: 372-380.

One in 530 young adults between the ages of 20-39 is a survivor of childhood cancer so this topic should be in the forefront of those treating these patients. The article details the expected risk to infertility based on treatment. The high risk group are those treated with: cyclophosphamide, ifosphamide, procarbazine, chorambucil, busulfan, melphalan, nitrogen mustard and those undergoing bone marrow ablative chemotherapy for hematopoietic stem cell transplantation (HSCT). The intermediate risk group includes those treated with: cisplatin, carboplatin, doxorubicin. Low risk category are those treated with bleomycin, Actinomicin D, Hodgkin’s protocols with alkylating agents, ABVD, CHOP, CVP and AML/ALL therapies. Very low risk agents are vincristine, vinblastine, methotrexate and 5-FU. The article addressed the fact that not only cancer patients may be at risk for infertility due to these agents since HSCT is being used in other conditions (such as aplastic anemia, Fanconi anemia). These patients are also at risk for infertility and should be counseled accordingly. This article also explained that Anti-Mullerian Hormone (AMH) is a reliable marker to determine ovarian reserve. Also mentioned are some options on the horizon including pharmacologic stimulation of ovarian function with Gonadotropin releasing hormone agonists, mesenchymal stem cell transplantation and egg freezing techniques for patient who have low but present oocyte counts after chemotherapy. They also mentioned when counseling families, discussion should also mention other options available such as donor oocytes or embryos, gestational surrogates and adoption. Very interesting perspective and review of fertility preservation in the young female patient.

The International Pleuropulmonary Blastoma Registry (PPB Registry)

The PPB Registry is an affiliate of the Rare Tumor Sub-Committee of the Children’s Oncology Group (COG). The Registry collects cases of PPB for COG. It is comprised of physicians, scientists, and data analysts from many institutions who have been working together for 20 years to evaluate cases of PPB. The goal of the registry is to collect information on as many cases of PPB as possible. Through this accumulation of information, we have begun to understand some of the biological and treatment issues of this disease. The website provides comprehensive information for families and physicians on this childhood chest tumor, including current treatment recommendations and practices.

Pleuropulmonary Blastoma: A Report on 350 Central Pathology-Confirmed Pleuropulmonary Blastoma Cases by the International Pleuropulmonary Blastoma Registry [107], Messinger et al Cancer 2015;121:276-85.

This is the largest series of PPB cases from the International PPB Registry reporting on 350 centrally reviewed, pathology confirmed cases. The types of PPB were: 33% type I, 35% type II, and 32% type III (or type II/III). The 5 year OS for type I, 91%; type II, 73%; type III, 53%. The strongest predictors of outcome were the type of PPB and presence of distant metastasis. Of the patients tested, 66% were positive for a heterozygous germline DICER1 mutation; however, presence of a DICER1 mutation did not correlate with outcome. PPB is usually found in infants and young children; however, type Ir (regressed) PPB is a cystic lesion without malignant cells found in an older child with a DICER1 mutation or a relative of a PPB patient. About 10% of type I PPB can progress to type II or III. Tumor spillage at surgery, tumor size, or anaplasia did not affect DFS or OS. Interestingly, presence of pneumothorax was associated with a significantly worse DFS and OS in type II and type III patients. Additionally, neoadjuvant chemotherapy significantly improved DFS in type III patients but had no bearing on OS. Nine percent (n=20) of patients presented with metastatic disease. Forty-four patients (19%) had relapse of disease and relapse was the cause of death in 53% of the patients that died.

Type I Pleuropulmonary Blastoma: A Report from the International Pleuropulmonary Blastoma Registry [108], Priest et al J Clin Oncol 2006 Sep 20;24(27):4492-8.

This retrospective study from the International PPB Registry sought to analyze the outcomes of type I PPB patients. Thirty-eight type I PPB cases were identified from the Registry (n=30) and the literature (n=8). Twenty children had surgery alone; eight (40%) experienced recurrence, of whom four died. Eighteen children had surgery and adjuvant chemotherapy; one experienced recurrence and died. All recurrences were type II or III PPB. Recurrence-free survival was higher in the surgery and chemotherapy group. However, overall survival did not differ. Recommended management includes complete surgical resection and adjuvant chemotherapy. Recommended surveillance included CT chest every 3-6 months, for up to three years after type I diagnosis, to age five given the observed rapid recurrence rate and growth of tumors.

Can congenital pulmonary airway malformations be distinguished from Type I pleuropulmonary blastoma based on clinical and radiological features? [109], Feinberg et al J Pediatr Surg 2016 Jan;51(1):33-7.

This is a retrospective study comparing a cohort of 103 cystic congenital pulmonary airway malformation (CPAM) patients from a single institution to 113 type I PPB patients from the International Pleuropulmonary Blastoma Registry. The purpose of the study was to compare clinical and radiographic characteristics of each entity to help guide treatment in these patients. Of the CPAM cohort, none of the patients were found to have PPB. Features most significantly associated with CPAM were prenatal diagnosis, presence of a systemic feeding vessel (PPB cohort did not have any with a feeding vessel), and presence of simple cyst. Features significantly associated with type I PPB were symptomatic lesion, no hyperinflation, absence of a systemic feeding vessel, and complex cyst. This paper suggests that routine DICER1 mutation analysis take place for patients being considered for observation to alleviate concern for PPB. Other data suggests that an asymptomatic lesion, no family history of DICER1familial syndrome, and lack of multifocality or bilaterality can be safely observed.

Great Vessel/Cardiac Extension and Tumor Embolism in Pleuropulmonary Blastoma: A Report from the International Pleuropulmonary Blastoma Registry [110], Priest et al Pediatr Blood Cancer 2011 Apr;56(4):604-9.

This study combined 179 type II and III PPB cases from the International Pleuropulmonary Blastoma registry with 200 cases of type II and III PPB in the literature to focus on cases with great vessel or cardiac extension. Eleven (3%) cases were found and examined in this study. Nine cases (81%) involved the left heart circulation, one case the right heart, and one case involved both circulations. A vascular embolic event occurred in 7 (64%) patients where 5 had a post operative cerebrovascular accident (both hemorrhagic or ischemic), 1 patient had acute paraplegia secondary to descending aorta occlusion from clot, and 1 patient with multiple cerebral infarcts and acute femoral artery occlusion. Six of these events were between 0-17 days post operative. Six (86%) of these 7 children died of vascular related events. Two (18%) out of the 11 patients survived and both of these patients had neoadjuvant chemotherapy with tumor shrinkage of both the primary tumor and vascular component. The one patient that died due to disease progression after neoadjuvant chemotherapy and surgery had primary tumor shrinkage with chemotherapy, however, the vascular component did not respond. Brain metastasis were found in 3 of the 6 patients that experienced a cerebrovascular accident. The authors hypothesize that surgery itself may precipitate embolization of tumor and later cerebral metastasis development since 11% of type II and 54% of type III PPB develop cerebral metastasis. None of the patients that underwent neoadjuvant chemotherapy experienced a vascular related event.

DICER1 Mutations in Familial Pleuropulmonary Blastoma [111], Hill et al Science 2009;325:965.

About 20% of children with PPB have a family history of other solid tumors such as cystic nephroma of the kidney or rhabdomyosarcoma. A heterozygous, germline mutation of DICER1 was found in common among 11 families with PPB. Mutation in DICER1 is a loss of function mutation. Developing mice deficient in DICER1 show cystic airways, disruption of bronchial branching, and cellular expansion similar to PPB. DICER1 gene is found on chromosome 14q.

DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumor predisposition syndrome [112], Slade et al J Med Genet 2011 Apr;48(4):273-8.

This study was undertaken as part of the FACT (Factors Associated with Childhood Tumours) Study in the United Kingdom. The goals of this study were to 1) understand the contribution of DICER1 mutations to non-familial, sporadic PPB; 2) determine if constitutional DICER1mutations predispose to tumors other than PPB; and 3) ascertain if somatic DICER1 mutations contribute to cancer. The authors performed sequencing of over 1600 samples, including constitutional DNA from over 800 patients with broad types of tumors, focusing on tumors associated with PPB, and sequencing of DICER1 in 781 cancer cell lines. 20 cases of PPB were identified through the National Childhood Tumor Registry, none of whom had a family history of PPB. 14 cases were included in this study. A DICER1 mutation was identified in 11 of these cases. This reinforced the knowledge that DICER1 mutation is the major cause of non-familial and familial PBB. When analyzing other tumors commonly associated with PPB, DICER1mutations were seen in 2/3 cases of cystic nephroma and 3/6 ovarian Sertoli-Leydig cell tumors, indicating that these mutations may play a major role in the development of these tumors also. Furthermore, mutational analysis shows that cancer predisposition results from the haplo-insufficiency mechanism. The study also revealed that the majority of patients with DICER1 mutations are well, and that tumor development is variable. This low penetrance and variable phenotype have led the authors to not advocate for the implementation of routine screening of patients with known DICER1 mutations.

Radiographic Screening of Infants and Young Children with Genetic Predisposition for Rare Malignancies: DICER1 Mutations and Pleuropulmonary Blastoma [113], Sabapathy et al AJR Am J Roentgenol. 2015 Apr;204(4):W475-82.

The purpose of this study was to compare the risks of radiation exposure in screening strategies using CXR and CT or CT alone, to detect PPB in DICER-1 positive infants and young children, against the risks of disease and its progression. Given the rarity of such tumors a prospective cohort study of screening strategies is not feasible, thus the authors created a decision analytical model to predict the clinical outcome and cumulative radiation dose for each screening strategy and schedule. This statistics-based model analysis showed that increases in imaging frequency decreased loss of life expectancy for the combined (CXR and CT) screening strategy but increased that for the CT-only strategy. Loss of life expectancy was calculated as a composite of risks of undetected disease and rate radiation induced cancer. Thus, in the combined screening strategy the analysis was largely dominated by risk of undetected disease vs risk radiation induced cancer in the CT only group. For all screening strategies and schedules, overall loss of life expectancy was predicted to be less than that associated with no screening. The current practice of CXR followed by CT in cases with positive findings on CXR is predicted by this model to be the optimal regimen. The study concluded that radiographic screening of infants and young children with cancer-predisposing mutations may result in improved life expectancy compared to an unscreened population, despite the risk of radiation induced cancers in this population.

Translating genomic discoveries to the clinic in pediatric oncology [114], Glade et al Curr Opin Pediatr 2015 Feb;27(1):34-43.

Integrative Clinical Sequencing in the management of refractory or relapsed cancer in youth [115], Mody et al JAMA. 2015 Sep 1;314(9):913-25.

Strategies for the management of adverse events associated with mTOR inhibitors [116], Kaplan et al Transplantation Reviews 28(2014) 126-133.

Risk Stratification for Low and Intermediate Risk Neuroblastoma Advances in Risk Classification and Treatment Strategies for Neuroblastoma [117], Pinto et al J Clin Oncol 2015 Sep 20;33(27):3008-17.

Revised risk estimation and treatment stratification of low- and intermediate-risk neuroblastoma patients by integrating clinical and molecular prognostic markers [118], Oberthuer et al Clin Cancer Res 2015 Apr 15;21(8):1904-15.

Expectant Observation in Very Low Risk Neuroblastoma A prospective study of expectant observation as primary therapy for neuroblastoma in your infants: a Children’s Oncology Group study [119], Ann Surg 2012 Oct;256(4):573-80.

Outcomes After Surgical Resection in Low-risk Neuroblastoma Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children’s Oncology Group study P9641 [120], Strother et al J Clin Oncol 2012 May 20;30(15):1842-8.

Influence of image-defined risk factors on the outcome of patients with localised neuroblastoma. A report from the LNESG1 study of the European International Society of Paediatric Oncology Neuroblastoma Group [121], Monclair et al Pediatr Blood Cancer 2015;62:1536-1542.

Importance of Extent of Resection in High-risk Neuroblastoma Value of surgical resection in children with high-risk neuroblastoma [122], Englum et al Pediatr Blood Cancer 2015 Sep;62(9):1529-35.

Assessment of primary site response in children with high-risk neuroblastoma: an international multicenter study [123], Bagatell et al J Clin Oncol 2016 Mar 1;34(7):740-6.

Minimal Access Surgery in Low-/Intermediate-risk Neuroblastoma Laparoscopic resection of adrenal neuroblastoma without image-defined risk factors: a prospective study on 21 consecutive pediatric patients [124], Mattioli et al Pediatr Surg Int 2014 Apr;30(4):387-94.

High grade osteosarcoma of the extremities metastatic to the lung: Long-term results in 323 patients treated combining surgery and chemotherapy, 1985-2005 [125], Briccoli et al Surg Oncol 2010 Dec;19(4):193–199

Review of long-term survival outcomes of 323 patients with high-grade extremity osteosarcoma with resectable lung metastases either at diagnosis or relapsed. The criteria for resectability were: primary tumor cleared, no pleural/pericardial effusions, no additional distant metastatic disease, and adequate residual pulmonary function after all metastatic lesions removed with clear microscopic margins. Patients were monitored with chest CT and extremity radiographs during chemotherapy every 2 months and after completion of chemotherapy every 3 months for 4 years, and every 6 months for 10 years. Lung resections were approached by lateral thoracotomy with manual palpation of the lungs to detect lesions not identified on chest CT scan. Wedge resection was adequate in most cases to achieve gross and microscopic clear margins. Neoadjuvant or adjuvant chemotherapy was administered according to standard first-line regimens and consisted of combinations of Methotrexate, Cisplatin, Doxorubicin, and Ifosfamide. Relapsed patients were treated with salvage chemotherapy with drugs not previously used or in higher doses. The five-year overall survival was 37% with final outcome related to presence or absence of metastasis/stage at presentation, time of first relapse, and presence of local recurrence. Salvage chemotherapy after relapses did not influence outcome. The best prognosis was seen in patients who underwent only one thoracotomy compared to patients undergoing two or more thoracotomies. There were no differences in survival in patients who underwent two or three versus four or five thoracotomies. Compared to patients who relapsed within 12 months, patients who relapsed after 24 months had higher survival. Lung only metastases had better survival compared to relapse with lung metastases and local recurrence. Thoracotomy should be considered despite the number of lung relapses or the number of secondary pulmonary lesions.

What predicts the risk of recurrent lung metastases? [126], Murrell et al J Pediatr Surg 2013 May;48(5):1020–1024.

The authors conducted a review of patients who underwent resection of lung metastases to determine what factors predict recurrent lung metastatic disease in pediatric cancers. The study found that the majority of pediatric patients with recurrent pulmonary metastases are patients with a primary oncologic diagnosis of osteosarcoma (57%). All nodules were identified on chest CT scans. Smaller lesions (8.7mm) had a higher false negative PET scan rate compared to larger nodules (18.2mm). Of all the variables studied (age, gender, race, tumor type, size, lung lobe involved, location of lung nodule, original tumor margin of resection, solitary vs multiple nodules, procedure performed, PET scan positivity, insurance status), the only significant factors influencing recurrence risk were patients with osteosarcoma and an original PET positive study. Recurrent lung nodules in patients with osteosarcoma and those with PET positive nodules are likely to be malignant necessitating surgical intervention.

Sarcomas [127], HaDuong et al Pediatr Clin N Am 2015 Feb;62(1):179-200.

This article provides a review of the multidisciplinary approach to the multimodal management of sarcomas in children. The pathology and biology of osteosarcoma are described, including several genes implicated in its pathogenesis. The authors review the clinical and imaging features that differentiate osteosarcoma from other childhood sarcomas, and describe the Enneking staging system. Prognostic factors for osteosarcoma are reviewed, the most important of which is the presence or absence of metastatic disease. The authors discuss chemotherapeutic regimens and surgical management of osteosarcoma, including approaches to achieve limb-salvage over amputation. An excellent review of management of sarcomas in children, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and non-rhabdomyosarcoma soft-tissue sarcoma.

Malignant retroperitoneal and abdominal germ cell tumors: an intergroup study [128], Billmire et al J Pediatr Surg 2003 Mar;38(3):315-8.

This randomized study examined survival (S) and event-free survival (EFS) rates using high-or standard-dose cisplatin-based combination chemotherapy and surgical resection for this subset of germ cell tumors. Twenty-five identified for inclusion had abdomen or retroperitoneum as the primary site. Patients had biopsy or resection at diagnosis and randomization to chemotherapy including etoposide, bleomycin, and either standard-dose (PEB) or high-dose cisplatin (HDPEB). 6-year survival rate was 90.0% +/- 11.6% for PEB and 85.7 +/- 14.5% for HDPEB. Study concluded that malignant germ cell tumors arising in the abdomen and retroperitoneum have an excellent prognosis despite advanced stage in most children. Aggressive resection need not be undertaken at diagnosis, but a concerted attempt at complete surgical removal after chemotherapy is important to distinguish viable tumor from necrotic tumor or benign elements that will not benefit from further chemotherapy.

Malignant mediastinal germ cell tumors: an intergroup study [129], Billmire et al J Pediatr Surg 2001 Jan;36(1):18-24.

This secondary analysis of the randomized study Pediatric Oncology Group (POG) 9049/Children’s Cancer Study Group (CCG) 8882, evaluating clinical and operative findings in patients with primary site in the mediastinum. 36 patients were identified for inclusion in the analysis. Overall, 26 of 36 patients survived, with a 4-year patient survival rate of 71%+/-10%, and a 4-year event-free survival rate of 69%+/-10%. Study concluded that tumor resection may be undertaken at diagnosis or after attempted shrinkage with chemotherapy. Aggressive attempt at complete tumor resection should be offered to all patients even if bulky tumor persists after induction chemotherapy with expectation of a significant salvage rate.

Predictors of survival and incidence of hepatoblastoma in the paediatric population [130], Allan et al HPB 2013;15:741-746.

606 patients in the SEER registry were examined in this study. The authors report that HB has increased 2.2% annually from 1973-2009. Multivariate analysis found that surgical resection, Hispanic ethnicity, local disease at presentation and age < 5 to be independent factors associated with improved survival.

The epidemiology of hepatoblastoma [131], Spector et al Pediatr Blood Cancer 2012;59:776-779.

This review article reports the markedly increased rate of HB in patients with Familial Adenomatous Polyposis and Beckwith-Wiedemann Syndromes. These inherited syndromes are rare and only comprise a small amount of HB patients overall. Birth weight is strongly associated with sporadic HB. With a 20-fold increase in HB among children born with very low birth weight (< 1500 g) and 2-fold increase in those born with moderate low birth weight (1500-2500 g).

Is multifocality a prognostic factor in childhood hepatoblastoma? [132], Saetti et al Pediatr Blood Cancer. 2014 Apr 23.

This single center report found that children with multifocal tumors had a lower event free survival (.40 vs. .95), and overall survival (.42 vs .95) when compared with unifocal lesions. The multivariate analysis suggested a hazard ration of 10, p=0.007 for children with multifocal disease. Multifocality is currently being examined by COG in the AHEP 0731 trial and by SIOPEL and is likely to emerge as a major risk factor which will be important in stratifying future trials.

References