[11C]-methionine positron emission tomography in the evaluation of pediatric low-grade gliomas.

Background: [11C]-Methionine positron emission tomography (PET; [11C]-MET-PET) is principally used for the evaluation of brain tumors in adults. Although amino acid PET tracers are more commonly used in the evaluation of pediatric brain tumors, data on [11C]-MET-PET imaging of pediatric low-grade gliomas (pLGG) is scarce. This study aimed to investigate the roles of [11C]-MET-PET in the evaluation of pLGGs. Methods: Eighteen patients with newly diagnosed pLGG and 26 previously treated pLGG patients underwent [11C]-MET-PET met the inclusion and exclusion criteria. Tumor-to-brain uptake ratio (TBR) and metabolic tumor volumes were assessed for diagnostic performances (newly diagnosed, 15; previously treated 26), change with therapy (newly diagnosed, 9; previously treated 7), and variability among different histology (n = 12) and molecular markers (n = 7) of pLGGs. Results: The sensitivity of [11C]-MET-PET for diagnosing pLGG, newly diagnosed, and previously treated combined was 93% for both TBRmax and TBRpeak, 76% for TBRmean, and 95% for qualitative evaluation. TBRmax showed a statistically significant reduction after treatment, while other PET parameters showed a tendency to decrease. Median TBRmax, TBRpeak, and TBRmean values were slightly higher in the BRAFV600E mutated tumors compared to the BRAF fused tumors. Median TBRmax, and TBRpeak in diffuse astrocytomas were higher compared to pilocytic astrocytomas, but median TBRmean, was slightly higher in pilocytic astrocytomas. However, formal statistical analysis was not done due to the small sample size. Conclusions: Our study shows that [11C]-MET-PET reliably characterizes new and previously treated pLGGs. Our study also shows that quantitative parameters tend to decrease with treatment, and differences may exist between various pLGG types.

Nuclear Medicine Imaging Tools in Fever of Unknown Origin: Time for a Revisit and Appropriate Use Criteria.

Fever of unknown origin (FUO) is a clinical conundrum for patients and clinicians alike, and imaging studies are often performed as part of the diagnostic workup of these patients. Recently, the Society of Nuclear Medicine and Molecular Imaging convened and approved a guideline on the use of nuclear medicine tools for FUO. The guidelines support the use of 2-18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in adults and children with FUO. 18F-FDG PET/CT allows detection and localization of foci of hypermetabolic lesions with high sensitivity because of the 18F-FDG uptake in glycolytically active cells that may represent inflammation, infection, or neoplasia. Clinicians should consider and insurers should cover 18F-FDG PET/CT when evaluating patients with FUO, particularly when other clinical clues and preliminary studies are unrevealing.

Regional lymph node evaluation in pediatric conventional melanoma subtype: a single-center 10-year review.

PURPOSE: To assess the prognostic and therapeutic significance of sentinel lymph node biopsy (SLNB) and completion lymph node dissection (CLND) in pediatric conventional melanoma (CM), while evaluating potential predictive factors for outcomes. METHODS: We conducted a retrospective analysis of medical records spanning 2009-2020, focusing on patients aged 18 or younger with localized cutaneous conventional melanoma. RESULTS: Among the 33 patients, SLNB detected metastasis in 57.6% of cases, with 52.6% undergoing CLND. Positive SLN patients had higher relapse risk (HR 5.92; 95% CI 1.27-27.7; P = 0.024) but similar overall survival (HR 3.19; 95% CI 0.31-33.1, P = 0.33). No significant differences in disease-free survival (DFS) and OS were found between patients who underwent CLND and those who did not (HR 1.91; 95% CI 0.49-7.43, P = 0.35, and HR 0.52; 95% CI 0.03-8.32, P = 0.64, respectively). Univariate analysis showed age at diagnosis (P = 0.02) correlated with higher recurrence risk, with a 21% hazard increase per additional year of age. CONCLUSIONS: Positive SLN status and age at diagnosis were associated with worse DFS in CM patients. Our study did not find any prognostic or therapeutic value in CLND for pediatric melanoma. Further multicenter trials are needed to confirm our single-institution experience. LEVEL OF EVIDENCE: Level IV.

PET/CT and PET/MR in Soft Tissue Sarcoma: An Update.

Soft tissue sarcomas account for 6%-8% of pediatric cancers. The rhabdomyosarcoma family is the most frequent soft tissue sarcoma in this age group accounting for 3% of pediatric cancers. Rhabdomyosarcomas are high-grade tumors with a high propensity to metastasize. The risk-adapted, multimodal therapeutic approach for rhabdomyosarcomas incorporates a combination of surgery, radiotherapy, and multi-agent cytotoxic chemotherapy. Soft tissue sarcomas other than rhabdomyosarcoma account for 3%-4% of pediatric cancers. The nonrhabdomyosarcoma soft tissue sarcomas include both low-grade and high-grade tumors. While surgery is the mainstay of therapy in most non-rhabdomyosarcoma soft tissue sarcomas, many cases require a multimodal therapeutic approach including radiotherapy and chemotherapy. In North America, most pediatric patients with soft tissue sarcomas are treated in Children's Oncology Group clinical trials. In this article, we will primarily focus on the staging, risk stratification, imaging recommendations, and interpretations in accordance with the Children's Oncology Group trials. We will review the results and recommendations of International Soft Tissue Sarcoma Database Consortium and European trials in relevant sections where they provide complementary guidelines.

INternational Soft Tissue saRcoma ConsorTium (INSTRuCT) consensus statement: Imaging recommendations for the management of rhabdomyosarcoma.

Rhabdomyosarcoma is the most common soft-tissue neoplasm in the pediatric population. The survival of children with rhabdomyosarcoma has only marginally improved over the past 25 years and remains poor for those with metastatic disease. A significant challenge to advances in treatment of rhabdomyosarcoma is the relative rarity of this disease, necessitating years to complete clinical trials. Progress can be accelerated by international cooperation and sharing national experiences. This necessitates agreement on a common language to describe patient cohorts and consensus standards to guide diagnosis, treatment, and response assessment. These goals formed the premise for creating the INternational Soft Tissue saRcoma ConsorTium (INSTRuCT) in 2017. Multidisciplinary members of this consortium have since developed international consensus statements on the diagnosis, treatment, and management of pediatric soft-tissue sarcomas. Herein, members of the INSTRuCT Diagnostic Imaging Working Group present international consensus recommendations for imaging of patients with rhabdomyosarcoma at diagnosis, at staging, and during and after completion of therapy. The intent is to promote a standardized imaging approach to pediatric patients with this malignancy to create more-reliable comparisons of results of clinical trials internationally, thereby accelerating progress in managing rhabdomyosarcoma and improving survival.

Assessing the role of positron emission tomography and bone scintigraphy in imaging of pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Given the rarity of PPB, the role of positron emission tomography (PET) and bone scintigraphy (bone scans) in diagnostic evaluation and surveillance has not been documented to date. Available PET and bone scan data are presented in this study. PROCEDURES: Patients with PPB enrolled in the International PPB/DICER1 Registry and available PET imaging and/or bone scan reports were retrospectively abstracted. RESULTS: On retrospective analysis, 133 patients with type II and III (advanced) PPB were identified with available report(s) (PET scan only = 34, bone scan only = 83, and both bone scan and PET = 16). All advanced primary PPB (n = 11) and recurrent (n = 8) tumors prior to treatment presented with 18 F-fluorodeoxyglucose (FDG)-avid lesions, with median maximum standardized uptake values of 7.4 and 6.7, respectively. False positive FDG uptake in the thorax was noted during surveillance (specificity: 59%). Bone metastases were FDG-avid prior to treatment. Central nervous system metastases were not discernable on PET imaging. Sensitivity and specificity of bone scans for metastatic bone disease were 89% and 92%, respectively. Bone scans had a negative predictive value of 99%, although positive predictive value was 53%. Four patients with distant bone metastases had concordant true positive bone scan and PET. CONCLUSION: Primary, recurrent, and/or extracranial metastatic PPB presents with an FDG-avid lesion on PET imaging. Additional prospective studies are needed to fully assess the utility of nuclear medicine imaging in surveillance for patients with advanced PPB.

Outcomes After Preoperative Chemoradiation With or Without Pazopanib in Non-Rhabdomyosarcoma Soft Tissue Sarcoma: A Report From Children's Oncology Group and NRG Oncology.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.ARST1321 was a phase II study designed to compare the near complete pathologic response rate after preoperative chemoradiation with/without pazopanib in children and adults with intermediate-/high-risk chemotherapy-sensitive body wall/extremity non-Rhabdomyosarcoma Soft Tissue Sarcoma (ClinicalTrials.gov identifier: NCT02180867). Enrollment was stopped early following a predetermined interim analysis that found the rate of near complete pathologic response to be significantly greater with the addition of pazopanib. As a planned secondary aim of the study, the outcome data for this cohort were analyzed. Eight-five eligible patients were randomly assigned to receive (regimen A) or not receive (regimen B) pazopanib in combination with ifosfamide and doxorubicin + preoperative radiotherapy followed by primary resection at week 13 and then further chemotherapy at week 25. As of December 31, 2021, at a median survivor follow-up of 3.3 years (range, 0.1-5.8 years), the 3-year event-free survival for all patients in the intent-to-treat analysis was 52.5% (95% CI, 34.8 to 70.2) for regimen A and 50.6% (95% CI, 32 to 69.2) for regimen B (P = .8677, log-rank test); the 3-year overall survival was 75.7% (95% CI, 59.7 to 91.7) for regimen A and 65.4% (95% CI, 48.1 to 82.7) for regimen B (P = .1919, log-rank test). Although the rate of near complete pathologic response was significantly greater with the addition of pazopanib, outcomes were not statistically significantly different between the two regimens.

Impact of diagnostic and end-of-induction Curie scores with tandem high-dose chemotherapy and autologous transplants for metastatic high-risk neuroblastoma: A report from the Children's Oncology Group.

BACKGROUND: Diagnostic mIBG (meta-iodobenzylguanidine) scans are an integral component of response assessment in children with high-risk neuroblastoma. The role of end-of-induction (EOI) Curie scores (CS) was previously described in patients undergoing a single course of high-dose chemotherapy (HDC) and autologous hematopoietic cell transplant (AHCT) as consolidation therapy. OBJECTIVE: We now examine the prognostic significance of CS in patients randomized to tandem HDC and AHCT on the Children's Oncology Group (COG) trial ANBL0532. STUDY DESIGN: A retrospective analysis of mIBG scans obtained from patients enrolled in COG ANBL0532 was performed. Evaluable patients had mIBG-avid, International Neuroblastoma Staging System (INSS) stage 4 disease, did not progress during induction therapy, consented to consolidation randomization, and received either single or tandem HDC (n = 80). Optimal CS cut points maximized the outcome difference (≤CS vs. >CS cut-off) according to the Youden index. RESULTS: For recipients of tandem HDC, the optimal cut point at diagnosis was CS = 12, with superior event-free survival (EFS) from study enrollment for patients with CS ≤ 12 (3-year EFS 74.2% ± 7.9%) versus CS > 12 (59.2% ± 7.1%) (p = .002). At EOI, the optimal cut point was CS = 0, with superior EOI EFS for patients with CS = 0 (72.9% ± 6.4%) versus CS > 0 (46.5% ± 9.1%) (p = .002). CONCLUSION: In the setting of tandem transplantation for children with high-risk neuroblastoma, CS at diagnosis and EOI may identify a more favorable patient group. Patients treated with tandem HDC who exhibited a CS ≤ 12 at diagnosis or CS = 0 at EOI had superior EFS compared to those with CS above these cut points.

18F-FDG PET/CT in the Management of Osteosarcoma.

Osteosarcoma is the most common type of primary malignant bone tumor. 18F-FDG PET/CT is useful for staging, detecting recurrence, monitoring response to neoadjuvant chemotherapy, and predicting prognosis. Here, we review the clinical aspects of osteosarcoma management and assess the role of 18F-FDG PET/CT, in particular with regard to pediatric and young adult patients.

KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children's Oncology Group.

BACKGROUND: In the Children's Oncology Group ANBL1221 phase 2 trial for patients with first relapse/first declaration of refractory high-risk neuroblastoma, irinotecan and temozolomide (I/T) combined with either temsirolimus (TEMS) or immunotherapy (the anti-GD2 antibody dinutuximab (DIN) and granulocyte macrophage colony stimulating factory (GM-CSF)) was administered. The response rate among patients treated with I/T/DIN/GM-CSF in the initial cohort (n=17) was 53%; additional patients were enrolled to permit further evaluation of this chemoimmunotherapy regimen. Potential associations between immune-related biomarkers and clinical outcomes including response and survival were evaluated. METHODS: Patients were evaluated for specific immunogenotypes that influence natural killer (NK) cell activity, including killer immunoglobulin-like receptors (KIRs) and their ligands, Fc gamma receptors, and NCR3. Total white cells and leucocyte subsets were assessed via complete blood counts, and flow cytometry of peripheral blood mononuclear cells was performed to assess the potential association between immune cell subpopulations and surface marker expression and clinical outcomes. Appropriate statistical tests of association were performed. The Bonferroni correction for multiple comparisons was performed where indicated. RESULTS: Of the immunogenotypes assessed, the presence or absence of certain KIR and their ligands was associated with clinical outcomes in patients treated with chemoimmunotherapy rather than I/T/TEMS. While median values of CD161, CD56, and KIR differed in responders and non-responders, statistical significance was not maintained in logistic regression models. White cell and neutrophil counts were associated with differences in survival outcomes, however, increases in risk of event in patients assigned to chemoimmunotherapy were not clinically significant. CONCLUSIONS: These findings are consistent with those of prior studies showing that KIR/KIR-ligand genotypes are associated with clinical outcomes following anti-GD2 immunotherapy in children with neuroblastoma. The current study confirms the importance of KIR/KIR-ligand genotype in the context of I/T/DIN/GM-CSF chemoimmunotherapy administered to patients with relapsed or refractory disease in a clinical trial. These results are important because this regimen is now widely used for treatment of patients at time of first relapse/first declaration of refractory disease. Efforts to assess the role of NK cells and genes that influence their function in response to immunotherapy are ongoing. TRIAL REGISTRATION NUMBER: NCT01767194.

A retrospective investigation of the relationship between neuroblastoma response to anti-GD2 monoclonal antibodies and exposure to opioids for pain management.

OBJECTIVE: Recent increased awareness and research studies reflect possible associations between opioid exposure and cancer outcomes. Children with neuroblastoma (NB) often require opioid treatment for pain. However, associations between tumor response to chemotherapy and opioid exposure have not been investigated in clinical settings. METHODS: This is a single-institution retrospective review of patients with NB treated between 2013 and 2016. We evaluated opioid consumption quantified in morphine equivalent doses (mg/kg) based on nurse- or patient-controlled analgesia during antibody infusions. We also analyzed their associations with change in primary tumor volume and total tumor burden. RESULTS: Of 42 patients given opioids for pain related to anti-disialoganglioside monoclonal antibodies (anti-GD2 mAb), data completion was achieved for 36, and details of statistical analyses were entered. Median total weight-based morphine equivalent (over 8 days) was 4.71 mg/kg (interquartile range 3.49-7.96). We found a statistically insignificant weak negative relationship between total weight-based morphine equivalents and tumor volume ratio (correlation coefficient -.0103, p-value .9525) and a statistically insignificant weak positive relationship between total weight-based morphine equivalent and Curie score ratio (correlation coefficient .1096, p-value .5247). CONCLUSION: Our study found no statistically significant correlation between opioid consumption and natural killer (NK) cell-mediated killing of NB cells as measured by effects on tumor volume/tumor load.

Imaging of pediatric spine and spinal cord tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee/ASPNR White Paper.

Childhood spinal tumors are rare. Tumors can involve the spinal cord, the meninges, bony spine, and the paraspinal tissue. Optimized imaging should be utilized to evaluate tumors arising from specific spinal compartments. This paper provides consensus-based recommendations for optimized imaging of tumors arising from specific spinal compartments at diagnosis, follow-up during and after therapy, and response assessment.

Fetal Dose from PET and CT in Pregnant Patients.

When pregnancy is discovered during or after a diagnostic examination, the physician or the patient may request an estimate of the radiation dose received by the fetus as per guidelines and standard operating procedures. This study provided the imaging community with dose estimates to the fetus from PET/CT with protocols that are adapted to University of Michigan low-dose protocols for patients known to be pregnant. Methods: There were 9 patients analyzed with data for the first, second, and third trimesters, the availability of which is quite rare. These images were used to calculate the size-specific dose estimate (SSDE) from the CT scan portion and the SUV and 18F-FDG uptake dose from the PET scan portion using the MIRD formulation. The fetal dose estimates were tested for correlation with each of the following independent measures: gestational age, fetal volume, average water-equivalent diameter of the patient along the length of the fetus, SSDE, SUV, and percentage of dose from 18F-FDG. Stepwise multiple linear regression analysis was performed to assess the partial correlation of each variable. To our knowledge, this was the first study to determine fetal doses from CT and PET images. Results: Fetal self-doses from 18F for the first, second, and third trimesters were 2.18 mGy (single data point), 0.74-1.82 mGy, and 0.017-0.0017 mGy, respectively. The combined SSDE and fetal self-dose ranged from 1.2 to 8.2 mGy. These types of images from pregnant patients are rare. Conclusion: Our data indicate that the fetal radiation exposure from 18F-FDG PET and CT performed, when medically necessary, on pregnant women with cancer is low. All efforts should be made to minimize fetal radiation exposure by modifying the protocol.

Emerging Trends in Radionuclide Imaging of Infection and Inflammation in Pediatrics: Focus on FDG PET/CT and Immune Reactivity.

The most common indication for 18F-FDG PET/CT is tumor imaging, which may be performed for initial diagnosis, staging, therapeutic response monitoring, surveillance, or suspected recurrence. In the routine practice of pediatric nuclear medicine, most infectious, inflammatory, and autoimmune processes that are detected on 18F-FDG PET/CT imaging - except for imaging in fever or inflammation of unknown origin - are coincidental and not the main indication for image acquisition. However, interpreting these "coincidental" findings is of utmost importance to avoid erroneously attributing these findings to a neoplastic process. We review the recent literature on fever of unknown origin as well as inflammation of unknown origin in pediatrics and then focus on the 18F FDG PET/CT imaging findings seen in two specific entities with increased immune reactivity: hemophagocytic lymphohistiocytosis syndrome and the immune-related adverse events associated with checkpoint inhibitors. We will subsequently close with two sections highlighting related topics and relevant references for further reading.

Imaging of pediatric adrenal tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Adrenal tumors other than neuroblastoma are uncommon in children. The most frequently encountered are adrenocortical carcinoma and pheochromocytoma. This paper offers consensus recommendations for imaging of pediatric patients with a known or suspected primary adrenal malignancy other than neuroblastoma at diagnosis and during follow-up.

Imaging of pediatric neuroblastoma: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Neuroblastoma is the most common extracranial solid neoplasm in children. This manuscript provides consensus-based imaging recommendations for pediatric neuroblastoma patients at diagnosis and during follow-up.

Outcomes Following GD2-Directed Postconsolidation Therapy for Neuroblastoma After Cessation of Random Assignment on ANBL0032: A Report From the Children's Oncology Group.

PURPOSE: Postconsolidation immunotherapy including dinutuximab, granulocyte-macrophage colony-stimulating factor, and interleukin-2 improved outcomes for patients with high-risk neuroblastoma enrolled on the randomized portion of Children's Oncology Group study ANBL0032. After random assignment ended, all patients were assigned to immunotherapy. Survival and toxicities were assessed. PATIENTS AND METHODS: Patients with a pre-autologous stem cell transplant (ASCT) response (excluding bone marrow) of partial response or better were eligible. Demographics, stage, tumor biology, pre-ASCT response, and adverse events were summarized using descriptive statistics. Event-free survival (EFS) and overall survival (OS) from time of enrollment (up to day +200 from last ASCT) were evaluated. RESULTS: From 2009 to 2015, 1,183 patients were treated. Five-year EFS and OS for the entire cohort were 61.1 ± 1.9% and 71.9 ± 1.7%, respectively. For patients ≥ 18 months old at diagnosis with International Neuroblastoma Staging System stage 4 disease (n = 662) 5-year EFS and OS were 57.0 ± 2.4% and 70.9 ± 2.2%, respectively. EFS was superior for patients with complete response/very good partial response pre-ASCT compared with those with PR (5-year EFS: 64.2 ± 2.2% v 55.4 ± 3.2%, P = .0133); however, OS was not significantly different. Allergic reactions, capillary leak, fever, and hypotension were more frequent during interleukin-2-containing cycles than granulocyte-macrophage colony-stimulating factor-containing cycles (P < .0001). EFS was superior in patients with higher peak dinutuximab levels during cycle 1 (P = .034) and those with a high affinity FCGR3A genotype (P = .0418). Human antichimeric antibody status did not correlate with survival. CONCLUSION: Analysis of a cohort assigned to immunotherapy after cessation of random assignment on ANBL0032 confirmed previously described survival and toxicity outcomes. EFS was highest among patients with end-induction complete response/very good partial response. Among patients with available data, higher dinutuximab levels and FCGR3A genotype were associated with superior EFS. These may be predictive biomarkers for dinutuximab therapy.