Current surgical approach: Extracranial malignant germ cell tumors.

Germ cell tumors (GCT) are a complex, heterogeneous collection of tumors that may present in either gonadal or extragonadal sites. They consist of a variety of benign and malignant histologies that can occur at several locations throughout the body. An important component of treatment is surgical resection, and while the key components of resection are site specific, the universal goals of GCT resection include the complete resection of tumor without violating the tumor capsule, while preserving function of surrounding organs, minimizing morbidity, and assessing for regional spread.

Critical elements of pediatrics sacrococcygeal germ cell tumor surgery.

Sacrococcygeal teratoma is the most common extragonadal germ cell tumor in the pediatric population, and accounts for approximately 70% of all teratomas in childhood.1,2 They present in two distinct phases, with most cases seen in neonates with large predominately exophytic tumors, often detected in utero on prenatal sonography or at birth. A smaller cohort presents in older infants and children with primarily hidden tumors in the pelvis which have a much higher rate of malignancy. The primary surgical objective is complete tumor resection without compromise to critical structures or function. Herein we outline the critical elements of tumor resection and management of sacrococcygeal germ cell tumors with a focus on the technical aspects of this tumor across a range of presentations.

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.

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.

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.

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.

Clinicopathologic predictors of outcomes in children with stage I testicular germ cell tumors: A pooled post hoc analysis of trials from the Children's Oncology Group.

BACKGROUND: Patients with clinical stage I (CS I: cN0M0) testicular germ cell tumors (TGCT) exhibit favorable oncologic outcomes. While prognostic features can help inform treatment in adults with CS I TGCT, we lack reliable means to predict relapse among pediatric and adolescent patients. OBJECTIVE: We sought to identify predictors of relapse in children with CS I TGCT. STUDY DESIGN: We performed a pooled post hoc analysis on pediatric and adolescent AJCC CS I TGCT patients enrolled in 3 prospective trials: INT-0097 (phase II), INT-0106 (phase III), and AGCT0132 (phase III). Pathology was centrally reviewed. Patient demographics, pT stage, serum tumor markers, margin status, histology, relapse, and survival were compiled. Cox regression analyses were used to identify predictors of events, defined as relapse, secondary malignant neoplasm, or death. RESULTS: 106 patients were identified with outcomes data available. Most patients were pT1-2 stage. Among patients with evaluable histopathology, yolk sac tumor elements were present in all patients and lymphovascular invasion in 51% of patients. Over a median follow-up of 56 months, no patients died, and 25 patients (24%) experienced an event (median event-free survival not reached). Independent predictors of events on multivariable analysis included age ≥12 years at diagnosis (HR 8.87, p < 0.001) and higher pT stage (pT2 HR 7.31, p = 0.0017; pT3 HR 13.5, p = 0.0043). DISCUSSION: Although our study population reflects the largest pooled prospective cohort of CS I pediatric and adolescent TGCT to our knowledge, the relatively low event rate limits our multivariable analysis, and longer follow-up duration would help further characterize the natural history of these patients. Centralized pathologic review was also unable to be performed for several patients. CONCLUSION: Pediatric and adolescent CS I TGCT patients exhibit remarkable 5-year survival. Using combined data from multiple prospective trials, our study identifies clinicopathologic features that predict relapse and inform personalized treatment for these patients by potentially guiding surveillance versus adjuvant treatment strategies.

'Teratoid' Hepatoblastoma: An Intriguing Variant of Mixed Epithelial-Mesenchymal Hepatoblastoma.

Liver neoplasms are quite rare in childhood. They often involve 6.7 cases per 10 million children aged 18 years or younger. Hepatoblastoma (HB) is the most frequent tumor, but this neoplasm's rarity points essentially to the difficulty of performing biologic studies and large-scale therapeutic trials. On the pathological ground, HB is separated into an entirely epithelial neoplasm or a mixed neoplasm with epithelial and mesenchymal components. This last category has been further subdivided into harboring teratoid features or not. The 'teratoid' HB includes a mixture of components with heterologous origin. The heterologous components include neuroectoderm, endoderm, or melanin-holding cells with or without mesenchymal components. The most important criterium for the teratoid component is neuroepithelium, melanin, and, more recently, a yolk-sac-like component and neuroendocrine components. The mesenchymal components include muscle, osteoid, and cartilage, which are most often observed mainly in 'teratoid' neoplasms. The teratoid component or mesenchymal components are diagnosed with biopsies. They appear more prominent after chemotherapy due to the response and shrinkage of epithelial elements and non- or low-responsive components of mixed HB. This review focuses on the clinical, radiological, and pathological findings of HB with teratoid features.

The Genetics of Postoperative Recurrence in Crohn Disease: A Systematic Review, Meta-analysis, and Framework for Future Work.

Background: Recurrence following abdominal surgery in Crohn disease is over 50%. The impact of genetics on postoperative recurrence is not well defined. Methods: A literature search was conducted where inclusion required an assessment, by genotype, of postoperative recurrence. The primary endpoint was odds of surgical recurrence. Results: Twenty-eight studies identified a total of 6715 patients. Thirteen loci were identified as modifying the risk of recurrence. NOD2 was identified as a risk factor for recurrence by multiple works (cumulative odds ratio: 1.64, P = 0.003). Conclusions: A NOD2 risk allele is associated with recurrence following surgery in Crohn disease. Progress in this area will require standardized reporting in future works.

Imaging Appearance of Nongerminoma Pediatric Ovarian Germ Cell Tumors Does Not Discriminate Benign from Malignant Histology.

STUDY OBJECTIVE: Pediatric ovarian neoplasms with imaging appearance suggestive of teratoma are often presumed to have low risk of malignancy. We assessed the pre-operative imaging appearance of pediatric malignant ovarian germ cell tumors (MOGCT) and the presence of associated teratoma in a series of MOGCT. DESIGN: Retrospective review of clinical and pathology data. SETTING: Multicenter trial for extracranial malignant germ cell tumors in young female individuals by the Children's Oncology Group (COG study AGCT0132) that included yolk sac tumor, embryonal carcinoma and choriocarcinoma. PARTICIPANTS: Female individuals 0-20 years of age at enrollment with ovarian primary nonseminomatous malignant germ cell tumors. INTERVENTIONS: Review of data forms, including prospectively collected surgical checklist documenting imaging characteristics of the tumor, and review of pathology reports. MAIN OUTCOME MEASURES: Description of imaging appearance and frequency of mixed histology with benign teratoma elements. RESULTS: A total of 138 female individuals (11 months to 20 years of age) had primary ovarian tumors. Imaging appearance and pathology information were available for 133 patients. Among the 133 patients, tumor appearance was solid (10.5%), solid with calcification (3.0%), mixed cystic and solid (58.7%), mixed cystic and solid with calcification (24.8%), and unknown (3.0%). In all, 54% had elements of teratoma in addition to malignant histology. CONCLUSION: Mixed cystic and solid appearance with or without calcification was seen in 83.5% of pediatric ovarian malignant germ cell tumors. Associated benign teratoma was common. The presence of a mixed cystic and solid appearance on preoperative imaging should not dissuade the surgeon from obtaining preoperative serum markers and undertaking complete surgical staging.

Heterotaxy Syndrome and Intestinal Rotation Abnormalities.

BACKGROUND: Infants with heterotaxy syndrome (HS) have abnormal lateralization of organs along the right-left body axis. Intestinal rotation abnormalities (IRAs) are a potential source of morbidity and mortality. For this study, our objective was to prospectively observe a cohort of infants with HS and determine the incidence and natural history of IRA. METHODS: Infants ≤6 months of age with HS were enrolled in this prospective observational study. Exclusion criteria were other congenital abnormalities that necessitated abdominal surgery. HS was defined as any arrangement of organs that was not situs solitus or situs inversus along with associated congenital heart disease. The investigation for IRA was at the discretion of each participating center. RESULTS: Infants were recruited from January 2012 to December 2016. Thirty-eight infants from 7 institutions were included; 22 infants had right isomerism and 16 infants had left isomerism. Twenty-nine infants (76%) were evaluated for IRAs; 21 of 29 evaluations (72%) were abnormal. Eight infants were investigated because of symptoms, and 21 infants were evaluated routinely. The median age at symptom presentation was 46 days (range: 5-171 days). Seven infants had a Ladd procedure; 4 were prophylactic, with 3 as part of a combined procedure, and 3 were emergent. No child suffered acute midgut volvulus over a median follow-up of 1.6 years (range: 0.06-4.93 years). CONCLUSIONS: IRAs are common in infants with HS. Infants with symptoms presented by 6 months of age. There was no failure of expectant management resulting in midgut volvulus during a median follow-up of 1.6 years.

Endospore forming bacteria may be associated with maintenance of surgically-induced remission in Crohn's disease.

Crohn's disease (CD) patients who undergo ileocolonic resection (ICR) typically have disease recurrence at the anastomosis which has been linked with a gut dysbiosis. The aims of this study were to define the mucosa-associated microbiota at the time of ICR and to determine if microbial community structure at the time of surgery was predictive of future disease relapse. Ileal biopsies were obtained at surgery and after 6 months from CD subjects undergoing ICR. Composition and function of mucosal-associated microbiota was assessed by 16S rRNA sequencing and PICRUSt analysis. Endoscopic recurrence was assessed using the Rutgeerts score. Analysis of mucosal biopsies taken at the time of surgery showed that decreased Clostridiales together with increased Enterobacteriales predicted disease recurrence. An increase in the endospore-forming Lachnospiraceae from surgery to 6 months post-ICR was associated with remission. A ratio of 3:1 between anaerobic endospore-forming bacterial families and aerobic families within the Firmicutes phylum was predictive of maintenance of remission. Gut recolonization following ICR is facilitated by microbes which are capable of either aerobic respiration or endospore formation. The relative proportions of these species at the time of surgery may be predictive of subsequent microbial community restoration and disease recurrence.

A BACH2 Gene Variant Is Associated with Postoperative Recurrence of Crohn's Disease.

BACKGROUND: Crohn's disease often requires intestinal resection, which is not considered curative. Repeat surgical intervention is necessary in more than half of patients after their initial operation. Although many genetic loci are implicated in Crohn's disease, few have been associated with post-resection recurrence. STUDY DESIGN: A cohort of patients with Crohn's disease who underwent intestinal resection was analyzed to determine genetic and clinical factors associated with post-resection recurrence. Genotype was assessed at 8 loci associated with adaptive immunity (SMAD3, IL10RB, IL15RA, BACH2, IL12B, IL18RAP, IFNGR2, and JAK2). Univariate and multivariable survival analyses were performed using a log-rank test and Cox-proportional hazard model, respectively. RESULTS: One hundred and ninety-one patients with Crohn's disease and 11.2 years mean postoperative follow-up were included. Forty-six percent experienced a surgical recurrence. Factors associated with increased incidence of recurrence included male sex (p = 0.05) and shortened time to first intestinal operation (5.0 vs 7.3 years; p = 0.03); inflammatory disease behavior was associated with a lower chance of repeat operation (p < 0.01). Of the loci assessed on multivariable analysis, homozygosity for a risk allele at BACH2 (rs1847472) was significantly associated with disease recurrence (hazard ratio 1.54; 95% CI 1.00 to 2.36; p < 0.05). CONCLUSIONS: We identify BACH2 as a susceptibility locus for postoperative recurrence of Crohn's disease in our cohort. BACH2 is critical in the differentiation and function of T cells, as a regulator of B-cell activity, and is associated with several dysregulated immunologic phenomena. Its identification as a risk locus in postoperative Crohn's disease recurrence suggests a potential role for regulatory T cells, effector T cells, humoral immunity, and immunologic memory in the development of this disease process.

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.

The Spectrum of General Surgery Interventions in Pediatric Patients with Ventricular Assist Devices.

Ventricular assist devices (VADs) have positively impacted the management of heart failure. However, they come with a range of complications. Although general surgical complications have been assessed in adults with VADs, there is no study to date that has assessed general surgery intervention in the pediatric population. Fifty-two patients who received VADs from 2005 to 2015 at the Stollery Children's Hospital were assessed for general surgery intervention and anticoagulation status at the time of intervention. Eighteen patients (35%) had general surgery intervention; there were 21 nonemergency procedures and six emergency procedures performed. For nonemergency procedures, 89% of patients had anticoagulation held within 24 hours of surgery and 84% had anticoagulation resumed within 4 hours postoperatively. Antiplatelet therapy was not held perioperatively. In both emergency and nonemergency procedures, anticoagulation status was not a factor in the success of the procedure. This study shows that it is safe to have general surgery intervention on the same admission as a VAD implant provided an appropriate interdisciplinary healthcare team is involved with the perioperative management of the patient.

Prebiotic Supplementation Following Ileocecal Resection in a Murine Model is Associated With a Loss of Microbial Diversity and Increased Inflammation.

Background: Individuals with Crohn's disease frequently require ileocecal resection (ICR), and inflammation often recurs in the neoterminal ileum following surgery. Fructooligosaccharide (FOS) is a fermentable prebiotic that stimulates the growth of bifidobacteria and may promote anti-inflammatory activity. The aim of this study was to determine if supplementation of a postICR diet with FOS in a mouse model would be effective in stimulating the growth of bifidobacteria and reducing systemic and local inflammation. Methods: ICR was performed in IL10-/- mice (129S1/SvlmJ) with colitis. Following surgery, nonICR control and ICR mice were fed a chow diet ± 10% FOS for 28 days. Serum, colon, and terminal ileum (TI) were analyzed for cytokine expression by MesoScale discovery platform. DNA extracted from stool was analyzed using 16s rRNA sequencing and qPCR. Expression of occludin and ZO1 was assessed using qPCR. Short-chain fatty acid (SCFA) concentrations were assessed using gas chromatography. Results: ICR led to increased systemic inflammation (P < 0.05) and a significant decline in fecal microbial diversity (P < 0.05). Mice on the FOS diet had a greater reduction in microbial diversity and also had worsened inflammation as evidenced by increased serum IL-6 (P < 0.05) and colonic IFNγ and TNFα (P < 0.05). Expression of occludin and ZO1 were significantly reduced in FOS-supplemented mice. There was a correlation between loss of diversity and the bifidogenic effectiveness of FOS (r = -0.61, P < 0.05). Conclusions: FOS-supplementation of a postICR diet resulted in a decrease in fecal bacterial diversity, reduction in barrier function, and increased gut inflammation.

Ileocolic resection is associated with increased susceptibility to injury in a murine model of colitis.

Ileocolic resection (ICR) is the most common intestinal resection performed for Crohn's disease, with recurrences commonly occurring at the site of the anastomosis. This study used an animal model of ICR in wild-type mice to examine immunologic changes that developed around the surgical anastomosis and how these changes impacted gut responses to minor acute injury. ICR was performed in adult 129S1/SvlmJ mice and results compared with mice receiving sham or no surgery. Dextran sodium sulfate was given either on post-operative day 9 or day 24 to evaluate immune responses in the intestine both immediately following surgery and after a period of healing. Fecal occult blood measurements and animal weights were taken daily. Cytokine levels were measured in ileal and colonic tissue. Bacterial load in the neo-terminal ileum was measured using qPCR. Immune cell populations in the intestinal tissue, mesenteric lymph nodes, and spleen were assessed using flow cytometry. Cytokine secretion in response to microbial products was measured in isolated mesenteric lymph nodes and spleen cells. ICR resulted in an initial elevation of inflammatory markers in the terminal ileum and colon followed by enhanced levels of bacterial growth in the neo-terminal ileum. Intestinal surgical resection resulted in the recruitment of innate immune cells into the colon that exhibited a non-responsiveness to microbial stimuli. DSS colitis phenotype was more severe in the ileocolic resection groups and this was associated with local and systemic immunosuppression as evidenced by a reduced cytokine responses to microbial stimuli. This study reveals the development of an immune non-responsiveness to microbial products following ileocolic resection that is associated with enhanced levels of bacterial growth in the neo-terminal ileum. These surgical-induced altered immune-microbial interactions in the intestine may contribute to disease recurrence at the surgical anastomosis site following ileocolic resections in patients with Crohn's disease.

A safety and pharmacokinetic dosing study of glucagon-like peptide 2 in infants with intestinal failure.

BACKGROUND & AIMS: Glucagon-like peptide 2 (GLP-2) analogues are approved for adults with intestinal failure (IF), but no studies have included infants. This study examined the pharmacokinetics (PK), safety, and nutritional effects of GLP-2 in infants with IF. METHODS: With parental consent (Health Canada Protocol:150,979), parenteral nutrition (PN)-dependent infants were treated with 5-20-µg/kg/day GLP-2 for 3days (phase 1), and if tolerated continued for 42days (phase 2). Nutritional therapy was by primary caregivers, and follow-up was to one year. RESULTS: Six patients were enrolled, age 5.4±3.2months, bowel length: 27±12% of predicted, PN dependent (67±18% of calories). GLP-2 did not affect vital signs, nor were there significant adverse events during the trial. Dosing 5µg/kg/day gave GLP-2 levels of 52-57pmol/L, with no change in half-life or endogenous GLP-2 levels. Enteral feeds, weight, Z scores, stooling frequency, and citrulline levels improved numerically. The trial was discontinued early because of a drop in potency. CONCLUSIONS: GLP-2 was well tolerated in infants, and pK was similar to children with no changes in endogenous GLP-2 release. The findings suggest that GLP-2 ligands may be safely used in infants and may have beneficial effects on nutritional status. Further study is required. LEVEL OF EVIDENCE: 2b Prospective Interventional Study.