Children's Oncology Group's 2023 blueprint for research: Germ cell tumors.

Extracranial germ cell tumors (GCT) are a biologically diverse group of tumors occurring in children, adolescents, and young adults. The majority of patients have excellent outcomes, but treatment-related toxicities impact their quality of survivorship. A subset of patients succumbs to the disease. Current unmet needs include clarifying which patients can be safely observed after initial surgical resection, refinement of risk stratification to reduce chemotherapy burden in patients with standard-risk disease, and intensify therapy for patients with poor-risk disease. Furthermore, enhancing strategies for detection of minimal residual disease and early detection of relapse, particularly in serum tumor marker-negative histologies, is critical. Improving the understanding of the developmental and molecular origins of GCTs may facilitate discovery of novel targets. Future efforts should be directed toward assessing novel therapies in a biology-driven, biomarker-defined, histology-specific, risk-stratified patient population. Fragmentation of care between subspecialists restricts the unified study of these rare tumors. It is imperative that trials be conducted in collaboration with national and international cooperative groups, with harmonized data and biospecimen collection. Key priorities for the Children's Oncology Group (COG) GCT Committee include (a) better understanding the biology of GCTs, with a focus on molecular targets and mechanisms of treatment resistance; (b) strategic development of pediatric and young adult clinical trials; (c) understanding late effects of therapy and identifying individuals most at risk; and (d) prioritizing diversity, equity, and inclusion to reduce cancer health disparities and studying the impacts of social determinants of health on outcomes.

Validation of a Wound Tool for Assessment of Surgical Wounds in Infants.

BACKGROUND: Wound assessment is a critical part of the care of hospitalized infants in neonatal intensive care. Early recognition and initiation of appropriate treatment of wounds are imperative to facilitate wound healing and avoid complications such as secondary infection and wound dehiscence. There are, however, no validated tools for assessing surgical wounds in infants. PURPOSE: The aim of this study was to develop and interrogate a tool for the assessment of surgical wounds. Specific aims for the tool included interrater reliability (give a consistent and dependable result independent of user) and test criterion validity (give an accurate assessment of the wound compared with an expert). METHODS: This was an exploratory cohort study involving a structured wound tool applied by nursing staff to 40 surgical wounds. The wounds were also assessed by wound experts (a pediatric wound care nurse and a pediatric surgeon). Comparisons were made to elucidate estimates of reliability and validity. RESULTS: The wound tool demonstrated interrater reliability with intraclass correlation coefficient of 0.775 (95% CI, 0.665-0.862) as well as criterion validity with rank correlation coefficient of 0.55 (95% CI, 0.34-0.76) to 0.71 (95% CI, 0.53-0.88). To obtain 100% sensitivity to distinguish mild from moderate-severe wounds, a low cutoff score was needed. IMPLICATIONS FOR PRACTICE AND RESEARCH: Wound assessment continues to be a subjective exercise, even with the utilization of a tool. Additional research is needed for strategies to support the assessment of surgical wounds in infants. Such tools are needed for future research, particularly when multiple institutions are involved.

Gonadal dysgenesis is associated with worse outcomes in patients with ovarian nondysgerminomatous tumors: A report of the Children's Oncology Group AGCT 0132 study.

PURPOSE: In this report, we characterize the timing and behavior of malignant ovarian germ cell tumors (GCTs) in pediatric patients with dysgenetic gonads compared to those with normal gonadal development. PATIENTS AND METHODS: Patients from the Children's Oncology Group AGCT0132 with malignant ovarian GCTs were included. Within this population, we sought to identify patients with gonadoblastoma, streak ovaries, or other evidence of gonadal dysgenesis (GD). Patients with malignant GCTs containing one or more of the following histologies-yolk sac tumor, embryonal carcinoma, or choriocarcinoma-were included. Patients were compared with respect to event-free survival (EFS) and overall survival (OS). RESULTS: Nine patients with GD, including seven with gonadoblastoma (mean age, 9.3 years), were compared to 100 non-GD patients (mean age, 12.1 years). The estimated 3-year EFS for patients with GD was 66.7% (95% CI 28.2-87.8%) and for non-GD patients was 88.8% (95% CI 80.2-93.8%). The estimated 3-year OS for patients with GD was 87.5% (95% CI 38.7-98.1%) and for non-GD patients was 97.6% (95% CI of 90.6-99.4%). CONCLUSION: Patients presenting with nongerminomatous malignant ovarian GCTs in the context of GD have a higher rate of events and death than counterparts with normal gonads. These findings emphasize the importance of noting a contralateral streak ovary or gonadoblastoma at histology for any ovarian GCT and support the recommendation for early bilateral gonadectomy in patients known to have GD with Y chromosome material. In contrast to those with pure dysgerminoma, these patients may represent a high-risk group that requires a more aggressive chemotherapy regimen.

Gastrostomy Tube Feeding after Neonatal Complex Cardiac Surgery Identifies the Need for Early Developmental Intervention.

OBJECTIVE: To compare the proportion of developmental delay in early complex cardiac surgery (CCS) survivors with and without gastrostomy tube feeding (GTF). To explore acute care predictors of GTF that might help improve care in CCS survivors. STUDY GROUP: This comparison study of 2 groups within an inception cohort included 334 CCS survivors after cardiopulmonary bypass at ≤6 weeks of age (2005-2012) who did not require extracorporeal membrane oxygenation or heart transplantation. Children were assessed at 21 ± 3 months with the Bayley Scales of Infant and Toddler Development-Third Edition and the Adaptive Behavior Assessment System-Second Edition: general adaptive composite score. Delay was determined by scores >2 SD below mean. The χ(2) test compared groups. Predictors of GTF were analyzed using multiple logistic regression analysis, results expressed as OR with 95% CI. RESULTS: Of the survivors, 67/334 (20%) had GTF any time before the 21-month assessment. Developmental delays in children with GTF were cognitive in 16 (24%), motor in 18 (27%), language in 24 (36%) vs without GTF in 7 (3%), 8 (3%), and 32 (12%), respectively (P < .001). Gastrostomy group had almost 8 times the number of children delayed on the general adaptive composite score. Independent OR for GTF are presence of a chromosomal abnormality, OR 4.6 (95% CI 1.8, 12.0) (P = .002), single ventricle anatomy, OR 3.4 (95% CI 1.7, 6.8) (P < .001), total postoperative days of open sternum, OR 1.15 (95% CI 1.1, 1.3) (P = .031), and total number of hospital days at CCS, OR 1.03 (95% CI 1.1, 1.04) (P = .002). CONCLUSIONS: GTF identifies CCS survivors at risk for delay, who would benefit from early developmental intervention. The described mostly nonmodifiable predictors may guide counseling of these children's families.

Bedside to bench: The risk of bleeding with parenteral omega-3 lipid emulsion therapy.

Our clinical experience led us to reassess the effect of sole omega-3 lipid therapy on hemostasis. We compared thromboelastography platelet mapping in neonatal piglets given sole omega-3 lipid. We identified abnormalities in reaction time (P = .025) and the arachidonic acid pathway (P = .025). The potential for bleeding complications from parenteral omega-3 lipid emulsion therapy in high-risk infants with liver disease has been dismissed but, on the basis of this data, should be reconsidered.

Pediatric patient-specific three-dimensional virtual models for surgical decision making in resection of hepatic and retroperitoneal tumors.

PURPOSE: Typically, preoperative imaging is viewed in two dimensions (2D) only, but three-dimensional (3D) virtual models may improve viewers' anatomical perspective by permitting them to interact with the imaging through manipulating it in space. Research into the utility of these models in most surgical specialties is growing rapidly. This study investigates the utility of 3D virtual models of complex pediatric abdominal tumors for clinical decision making, particularly the decision to proceed with surgical resection or not. METHODS: 3D virtual models of tumors and adjacent anatomy were created from CT images of pediatric patients scanned for Wilms tumor, neuroblastoma or hepatoblastoma. Pediatric surgeons individually assessed the resectability of the tumors. First, they assessed resectability using the standard protocol of viewing imaging on conventional screens and then reassessed resectability after being presented with the 3D virtual models. Inter-physician agreement on resectability for each patient was analyzed using Krippendorff's alpha. Inter-physician agreement was used as a surrogate for correct interpretation. Participants were also surveyed afterward on the utility and practicality of the 3D virtual models for clinical decision making. RESULTS: Inter-physician agreement when using CT imaging alone was "fair" (Krippendorff's alpha α = 0.399), while inter-physician agreement when using 3D virtual models increased to "moderate" (Krippendorff's alpha α = 0.532). When surveyed about model utility, all 5 participants considered them helpful. Two participants felt the models would be practical for clinical use in most cases, while 3 felt they would be practical for select cases only. CONCLUSION: This study demonstrates the subjective utility of 3D virtual models of pediatric abdominal tumors for clinical decision making. The models are an adjunct that can be particularly useful in complicated tumors that efface or displace critical structures that may impact resectability. Statistical analysis demonstrates the improved inter-rater agreement with the 3D stereoscopic display over the 2D display. The use of 3D displays of medical images will increase over time, and evaluation of their potential usefulness in various clinical settings is necessary.

Characterizing Lymphovascular Invasion in Pediatric and Adolescent Malignant Ovarian Nongerminomatous Germ Cell Tumors: A Report from the Children's Oncology Group.

BACKGROUND: Lymphovascular invasion (LVI) has been identified as a poor prognostic factor for a variety of tumors; however, its significance in malignant ovarian germ cell tumors (MOGCT) in pediatric and adolescent patients is not well described. We aim to clarify the significance of LVI in the subset of patients with nongerminomatous MOGCT. METHODS: Records of patients 0-20 years of age with MOGCT enrolled on Children's Oncology Group study AGCT0132 were reviewed. Patients with documented presence or absence of LVI in either institutional or central review pathology reports were included. RESULTS: Of 130 patients with MOGCTs, 83 patients had of the presence or absence of LVI documented in their pathology report. 42/83 patients (50.6%) were found to have LVI present. The estimated odds of having LVI was higher in patients with stage II and III disease, 11 years and older and with the presence of choriocarcinoma. Event-free survival (EFS) and overall survival (OS) remained high in patients with LVI. Approximately 50% of patients with a documented LVI status in either institutional pathology report or central review were found to have LVI. CONCLUSIONS: The presence of LVI was higher in tumors with adverse risk factors including higher stage and age greater than 11 years. While LVI was not associated with EFS or OS in the intermediate risk group, further work is necessary to determine the effect of LVI on long-term disease-free survival. We, therefore, recommend routinely incorporating LVI status into institutional pathology reports for pediatric and adolescent patients with MOGCT. LEVEL OF EVIDENCE: III.

Critical elements in the operative management of pediatric malignant ovarian germ cell tumors.

Performance of the appropriate operation is highly important to ensure that any patient with a suspected ovarian germ cell tumor receives optimal therapy that prioritizes cure while simultaneoulsy minimizing risk of short and long-term toxicities of treatment. The following critical elements of any operative procedure performed for a suspected pediatric or adolescent ovarian germ cell tumor are reviewed: 1. Complete resection of the tumor via ipsilateral oophorectomy while avoiding tumor rupture and spillage, and 2. Performance of complete intraperitoneal staging at the time of initial tumor resection.

Predicting node positivity in gastric cancer from gene expression profiles.

Lymphovascular invasion (LVI) in gastric cancer is readily demonstrated pre-operatively by mucosal biopsy during endoscopy, which can also provide samples for gene expression profiling. We have examined gene expression associated with lymphovascular invasion in a cohort of gastric cancer patients and have developed a 28-gene predictor of tumor aggressiveness for forecasting risk of node positivity (N+), which could potentially be useful pre-operatively. The resulting model's ranking of increasing tumor aggressiveness correlated positively with N+ status, reaching statistical significance, and was three times the correlation of LVI with N+ status.

Pneumonectomy in a Child with Multilobar Pneumatocele Secondary to Necrotizing Pneumonia: Case Report and Review of the Literature.

BACKGROUND: Community-acquired pneumonia (CAP) is common within pediatrics and contributes disproportionately to morbidity and mortality. Necrotizing pneumonia is a well-documented complication of CAP. It is thought to be caused by necrosis and liquefaction of consolidated lung and can result in damage to lung parenchyma, including pneumatocele development. Management of necrotizing pneumonia with pneumatocele may include hospitalization, intensive care unit admission, and lengthy antibiotic courses. Severe cases may need invasive procedures. CASE PRESENTATION: We present a case of severe necrotizing pneumonia requiring prolonged venovenous extracorporeal membrane oxygenation (V-V ECMO) with development of persistent pneumatoceles, requiring pneumonectomy while on ECMO support to allow for decannulation and extubation. CONCLUSIONS: In critically ill patients with extensive unilateral necrotizing pneumonia with pneumatocele development, surgical intervention can be considered when attempts to wean ventilation have been unsuccessful. This case provides evidence that V-V ECMO and pneumonectomy is a viable salvage therapy in the most critically unwell children.

Reduced and Compressed Cisplatin-Based Chemotherapy in Children and Adolescents With Intermediate-Risk Extracranial Malignant Germ Cell Tumors: A Report From the Children's Oncology Group.

Purpose To investigate whether event-free survival (EFS) can be maintained among children and adolescents with intermediate-risk (IR) malignant germ cell tumors (MGCT) if the administration of cisplatin, etoposide, and bleomycin (PEb) is reduced from four to three cycles and compressed from 5 to 3 days per cycle. Patients and Methods In a phase 3, single-arm trial, patients with IR MGCT (stage II-IV testicular, II-III ovarian, I-II extragonadal, or stage I gonadal tumors with subsequent recurrence) received three cycles of PEb. A parametric comparator model specified that the observed EFS rate should not be significantly < 92%. As recommended for trials that test a reduction of therapy, a one-sided P value ≤ .10 was used to indicate statistical significance. In a post hoc analysis, we also compared results to the EFS rate of comparable patients treated with four cycles of PEb in two prior studies. Results Among 210 eligible patients enrolled from 2003 to 2011, 4-year EFS (EFS4) rate was 89% (95% confidence interval, 83% to 92%), which was significantly lower than the 92% threshold of the comparison model ( P = .08). Among 181 newly diagnosed patients, the EFS4 rate was 87%, compared with 92% for 92 comparable children in the historical cohort ( P = .15). The EFS4 rate was significantly associated with stage (stage I, 100%; stage II, 92%; stage III, 85%; and stage IV, 54%; P < .001). Conclusion The EFS rate for children with IR MGCT observed after three cycles of PEb was less than that of a prespecified parametric model, particularly for patients with higher-stage tumors. These data do not support a reduction in the number of cycles of PEb from four to three. However, further investigation of a reduction in the number of cycles for patients with lower-stage tumors is warranted.

Surgical management of pulmonary and gastrointestinal complications in children with cystic fibrosis.

PURPOSE OF REVIEW: Cystic fibrosis is a common disorder, affecting as many as 1:2500 Caucasian live births. Despite improved medical management, disease-specific complications are common and are responsible for substantial morbidity and ultimately mortality. Both pulmonary and gastrointestinal complications of cystic fibrosis are well known; however, the complications requiring surgical intervention in the pediatric population are infrequent. We provide a detailed review of the cystic fibrosis-associated pulmonary and gastrointestinal complications and potential surgical options for management in children with cystic fibrosis. RECENT FINDINGS: Recent operative approaches are described that include application of minimally invasive surgical techniques primarily for intrathoracic disease. Novel medical therapies are also presented. Finally an attempt is made to put in perspective those surgical care advances that have had a benefit on disease outcomes. SUMMARY: This report will provide the physician caring for the child with cystic fibrosis an understanding of those disease complications that will require surgical consultation and potential operative intervention.

Factors associated with neonatal ostomy complications.

BACKGROUND: Neonatal ostomies, either temporary or permanent, are created for numerous reasons. Limited attention has been given to understanding what factors might place infants at risk for surgical wound complications. PURPOSE: The purpose of the study is to identify factors associated with risk of significant abdominal wound complications (wound dehiscence and wound infection) following neonatal ostomy creation. METHODS: This is a retrospective chart review of infants undergoing ostomy between January 2009 and December 2013 at the University of Alberta Hospital. MAIN FINDINGS: 66 infants were identified of which 18.2% (12/66) had wound complications. Variables associated with wound dehiscence included: findings of bowel necrosis during laparotomy (7/9 wound dehiscence, 18/57 none, p=0.008), perioperative sepsis (3/9 wound dehiscence, 3/57 none, p=0.006), and perioperative blood transfusion (9/9 wound dehiscence, 30/57 none, p=0.007). Wound infection was not predicted by any variables collected. CONCLUSIONS: Neonates undergoing creation of an ostomy appear to be at substantial risk for wound complications. As wound complications are significant issues for infants undergoing surgery, emerging strategies should be explored to either avoid ostomy creation or promote wound healing.

Central venous catheter repair is not associated with an increased risk of central line infection or colonization in intestinal failure pediatric patients.

PURPOSE: The intestinal failure (IF) population is dependent upon central venous catheters (CVC) to maintain minimal energy requirements for growth. Central venous catheter infections (CVCI) are frequent and an independent predictor of intestinal failure associated liver disease. A common complication in children with long-term CVC is the risk of line breakage. Given the often-limited usable vascular access sites in this population, it has been the standard of practice to perform repair of the broken line. Although widely practiced, it is unknown if this practice is associated with increased line colonization rates and subsequent line loss. METHODS: A retrospective review of our institutional IF population over the past 8years (2006-2014) was performed. Utilizing a prospectively constructed database, all pediatric patients (n=13, ages 0-17 years) with CVC dependency enrolled in the Children's Intestinal Rehabilitation Program with IF were included who underwent a repair and/or replacement procedure of their line. The control replacement group was CVCs that were replaced without being repaired (36), the experimental repair group was CVCs that were repaired (8). The primary outcome of interest was the mean number of days in each group from the intervention (replacement or repair) to line infection/colonization. Mann-Whitney tests for significance were performed with p-values <0.05 being the threshold value for significance. RESULTS: There were no catheter repair associated CVCI. The mean number of days from the replacement or repair of a CVC to its removal owing to infection/colonization was 210.0 and 162.8days respectively. There was no statistically significant difference between these groups in time to removal owing to line infection (p=0.55). CONCLUSION: Repair of central venous catheters in the pediatric population with intestinal failure does not lead to an increased rate of central venous catheter infection and should be performed when possible.

Platelet Arachidonic Acid Deficiency May Contribute to Abnormal Platelet Function During Parenteral Fish Oil Monotherapy in a Piglet Model.

BACKGROUND: Fish oil monotherapy has been an advance for treating intestinal failure-associated liver disease (IFALD). However, such patients are at risk of bleeding complications from liver disease and because fish oil can inhibit thrombosis. We have previously reported abnormal platelet function in neonatal piglets given fish oil monotherapy during parenteral nutrition (PN). The purpose of this study was to determine if abnormal fatty acid composition of the platelets could explain the prior observed antiplatelet effect. METHODS: Neonatal piglets were assigned to 2 treatments: PN with fish oil monotherapy (FO; n = 4) or PN with soy oil (SO; n = 5). On day 14, plasma was collected and platelets isolated by centrifuging. The fatty acid content in plasma and platelet plug were measured using gas liquid chromatography and compared with controls (CON; n = 5). RESULTS: The arachidonic acid (AA) content in the FO group was on average half that of the SO group, in both the platelets (FO, 3.5% vs SO, 7.6%; P = .021; CON, 4.5%-11%) and the plasma (FO, 3.8% vs SO, 9.2%; P = .002; CON, 6.1%-9.5%). No bleeding complications were observed for any piglets during PN treatment. CONCLUSIONS: Using platelet mapping, we have previously shown that neonatal piglets given fish oil monotherapy have abnormal platelet function in the AA pathway. This report demonstrates that such an abnormality can be explained by platelet AA deficiency. Platelet mapping and platelet fatty acid analysis should be undertaken in human infants treated with fish oil monotherapy during PN.

Impact of central surgical review in a study of malignant germ cell tumors.

BACKGROUND: Verification of surgical staging has received little attention in clinical oncology trials. Central surgical review was undertaken during a study of malignant pediatric germ cell tumors. METHODS: Children's Oncology Group study AGCT0132 included central surgical review during the study. Completeness of submitted data and confirmation of assigned stage were assessed. Review responses were: assigned status confirmed, assignment withheld pending review of additional information requested, or institutional assignment of stage disputed with explanation given. Changes in stage assignment were at the discretion of the enrolling institution. RESULTS: A total of 206 patients underwent central review. Failure to submit required data elements or need for clarification was noted in 40%. Disagreement with stage assignment occurred in 10% with 17/21 discordant patients reassigned to stage recommended by central review. Four ovarian tumor patients not meeting review criteria for Stage I remained in that stratum by institutional decision. Two-year event free survival in Stage I ovarian patients was 25% for discordant patients compared to 57% for those meeting Stage I criteria by central review. CONCLUSIONS: Central review of stage assignment improved complete data collection and assignment of correct tumor stage at study entry, and allowed for prompt initiation of chemotherapy in patients determined not to have Stage I disease.

Surveillance after initial surgery for Stage I pediatric and adolescent boys with malignant testicular germ cell tumors: Report from the Children's Oncology Group.

PURPOSE: The purpose of this study was to determine prognostic factors correlating with outcome in boys with Stage I malignant testicular germ cell tumors (MTGCT) initially managed with surveillance after surgical resection. METHODS: Between November 2003 and July 2011, 80 boys 0-15 years with Stage I MTGCT were enrolled in Children's Oncology Group Study AGCT0132. Those with residual or recurrent disease were treated with chemotherapy. RESULTS: Characteristics include: age (65, 0-5 years and 15, 11+years), pure YST (93.9%, 0-5 years and 0%, 11+years); and lymphovascular invasion (LVI) (50.6% present vs. 49.4% absent). At median follow-up of 4.94 years, 19 had persistent or recurrent disease, all detected by elevated AFP at a median of 87 days after study enrollment. The outcome from enrollment was 4-year EFS 74% (95% CI: 63%-83%) and 4-year OS 100%. 4-year EFS was improved with younger age (<11 years, 80% vs. 11+years, 48%, p<0.01); pure YST vs. mixed histology (81% vs. 45%, p<0.01), and lack of LVI (84% vs. 62%, p=0.03). CONCLUSIONS: Boys with Stage I MTGCT have excellent overall survival when treated with surgery alone. Age greater than 10 years, mixed histology and presence of LVI are each associated with relapse and may allow identification of high risk boys at time of enrollment.

Heterotaxy syndrome and intestinal rotation abnormalities: a survey of institutional practice.

PURPOSE: Abnormalities of intestinal rotation (IRA) are commonly associated with heterotaxy syndrome (HS). There is controversy whether asymptomatic infants with HS require screening for IRA and if present, whether a prophylactic Ladd procedure is indicated. The objective of this study is to determine institutional practice across North America in the management of asymptomatic infants with HS and IRA. METHODS: We performed an international, multi-institutional web based survey to examine current practice and opinions in the management of IRA in HS patients. RESULTS: Overall response rate was 30%. Of physicians surveyed, 84% believe that HS patients should be screened for IRA in the neonatal period. 61% of general surgeons, 50% of cardiovascular surgeons and 45% of cardiologists feel that all patients with HS and an asymptomatic IRA should have a prophylactic Ladd procedure. 55% of physicians stated they would be comfortable with conservative management for patients with HS and asymptomatic IRA. CONCLUSIONS: The risk of midgut volvulus, morbidity and mortality from elective procedures and cardiovascular prognosis must be considered prior to an elective Ladd procedure on asymptomatic HS patients. There are practice variance among sub-specialists caring for these patients, a lack of expert consensus, and a paucity of evidence-based data for IRA in this population.