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Background MYCN-amplified RB1 wild-type (MYCNARB1+/+) retinoblastoma is a rare but clinically important subtype of retinoblastoma due to its aggressive character and relative resistance to typical therapeutic approaches. Because biopsy is not indicated in retinoblastoma, specific MRI features might be valuable to identify children with this genetic subtype. Purpose To define the MRI phenotype of MYCNARB1+/+ retinoblastoma and evaluate the ability of qualitative MRI features to help identify this specific genetic subtype. Materials and Methods In this retrospective, multicenter, case-control study, MRI scans in children with MYCNARB1+/+ retinoblastoma and age-matched children with RB1-/- subtype retinoblastoma were included (case-control ratio, 1:4; scans acquired from June 2001 to February 2021; scans collected from May 2018 to October 2021). Patients with histopathologically confirmed unilateral retinoblastoma, genetic testing (RB1/MYCN status), and MRI scans were included. Associations between radiologist-scored imaging features and diagnosis were assessed with the Fisher exact test or Fisher-Freeman-Halton test, and Bonferroni-corrected P values were calculated. Results A total of 110 patients from 10 retinoblastoma referral centers were included: 22 children with MYCNARB1+/+ retinoblastoma and 88 control children with RB1-/- retinoblastoma. Children in the MYCNARB1+/+ group had a median age of 7.0 months (IQR, 5.0-9.0 months) (13 boys), while children in the RB1-/- group had a median age of 9.0 months (IQR, 4.6-13.4 months) (46 boys). MYCNARB1+/+ retinoblastomas were typically peripherally located (in 10 of 17 children; specificity, 97%; P < .001) and exhibited plaque or pleomorphic shape (in 20 of 22 children; specificity, 51%; P = .011) with irregular margins (in 16 of 22 children; specificity, 70%; P = .008) and extensive retina folding with vitreous enclosure (specificity, 94%; P < .001). MYCNARB1+/+ retinoblastomas showed peritumoral hemorrhage (in 17 of 21 children; specificity, 88%; P < .001), subretinal hemorrhage with a fluid-fluid level (in eight of 22 children; specificity, 95%; P = .005), and strong anterior chamber enhancement (in 13 of 21 children; specificity, 80%; P = .008). Conclusion MYCNARB1+/+ retinoblastomas show distinct MRI features that could enable early identification of these tumors. This may improve patient selection for tailored treatment in the future. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Rollins in this issue.

This figure demonstrates the relationship between prior treatment with chimeric or humanized 14.18 K322A antibody and A) the area under the concentration curve for the antibody (AUC); B elimination half-life of the antibody (T1/2 Beta); and C) the highest observed concentration of the antibody (Cmax). Although the data in panels A and B suggest that prior exposure to ch14.18 or hu14.18K322A tends to increase the AUC and the elimination half-life, there is no significant difference between prior treatment groups using the Kruskal-Wallis non-parametric test. The data in panel C do not suggest an association between prior exposure and the peak serum concentration of the hu14.18K322A antibody.

Box and whisker plot showing absolute NK cells per mm3 in samples. NK cells were identified by flow cytometry as CD14 negative, CD56 positive, CD3 negative and percentage of total WBC was computed from flow cytometry results. Absolute WBC count was obtained using a Sysmex{trade mark, serif} KX-21 blood cell analyzer, and final absolute NK count was obtained by multiplying percent NK by absolute WBC. Sample identifiers and associated N are: DONOR (N=10) blood sample drawn at or before time of first NK cell donation; CS1_PRE (N=13), Patient blood drawn prior to first treatment course; CS1_14 (N=9); Patient on day +14 of first treatment course; CS1_21 (N=14), Patient on day +21 of first treatment course; CS2_NK_07 (N=11), Patient on day +7 following NK cell administration in second treatment course; CS2_NK_14 (N=11), Patient on day +14 following NK cell administration in second treatment course; CS3_14 (N=7), Patient on day +14 of third treatment course; CS3_21 (N=9), Patient on day +21 of third treatment course; CS4_NK_07 (N=9), Patient on day +7 following NK cell administration in fourth treatment course; CS4_NK_14 (N=10), Patient on day +14 following NK cell administration in fourth treatment course; CS5_14 (N=3), Patient on day +14 of fifth treatment course; CS5_21 (N=8), Patient on day +21 of fifth treatment course; CS6_PRE (N=1), Patient blood drawn prior to initiation of 6th treatment course; CS6_NK_07 (N=7), Patient on day +7 following NK cell administration in sixth treatment course; CS6_NK_14 (N=7), Patient on day +14 following NK cell administration in sixth treatment course. Central Point (ï�¯) - median; Box - Inner quartiles (25th percentile to 75th percentile) of data; Whiskers - non-outlier min and max data; Outliers (ï,¡) - data points outside of median {plus minus} inner quartile range; Extreme Outliers (*) - data points outside of median {plus minus} 1.5 X inner quartile range.

Human anti-human antibody (HAHA) level and peak hu14.18K322A serum level by course and prior antibody therapy.

Purpose: Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells.Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m2/dose, days 2–5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Rα) levels, and human antihuman antibodies (HAHA) were obtained.Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239–568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Rα levels, indicating immune activation.Conclusions: Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma. Clin Cancer Res; 23(21); 6441–9. ©2017 AACR.

The left panel plots the calculated area under the concentration vs time curve (AUC) of hu14.18K322A and the right panel plots the highest observed serum concentration of hu14.18K322A (Cmax) against the pre-treatment concentration of HAHA antibodies, reported in units of optical density. There is no clear association between the concentration of HAHA at the start of treatment and the AUC of hu14.18K322A and the peak concentration of hu14.18K322A using the Spearman test.

Plot of ADCC assay reports comparing 6 lots of hu14.18K322A in comparison to dinutuximab (unituxin). M21 cells, expressing the GD2 cell surface epitope, served as the target cells. Engineered Jurkat cells, with a cell-surface FcyRIIIa (V158) receptor, served as the effector cells. Crosslinking of the two cells by either hu14.18K322A or dinutuximab led to gene transcription through NFAT (nuclear factor of activated T-cells) with subsequent NFAT response element (RE) driving expression of a firefly luciferase reporter protein. The luciferase reporter substrate was converted to a luminescent product and quantified as relative luminescence units (RLU) on a plate reader.

Tables of antibody infusion times and Curie Scores

Purpose:We sought to evaluate whether combining a humanized antidisialoganglioside mAb (hu14.18K322A) with induction chemotherapy improves early responses and outcomes in children with newly diagnosed high-risk neuroblastoma.Patients and Methods:We conducted a prospective nonrandomized, single-arm, two-stage, phase II clinical trial. Six courses of induction chemotherapy were coadministered with hu14.18K322A and followed with granulocyte–macrophage colony-stimulating factor (GM-CSF) and low-dose IL2. Consolidation was performed with a busulfan/melphalan preparative regimen. An additional course of hu14.18K322A was administered with parent-derived natural killer cells, when available, during consolidation. Hu14.18K322A, GM-CSF, IL2, and isotretinoin were then administered. Secondary outcomes included reduced tumor volume and semiquantitative 123I-metaiodobenzylguanidine scoring [i.e., Curie scores (CS)] at the end of induction.Results:Forty-two patients received hu14.18K322A and induction chemotherapy. This regimen was well tolerated, with continuous-infusion narcotics adjusted to patient tolerance. Partial responses (PR) or better after the first two chemoimmunotherapy courses occurred in 32 patients [76.2%; 95% confidence interval (CI), 60.6–88.0]. This was accompanied by primary tumor volume reductions (median, –76%; range, –100% to 5%). Of 35 patients with stage IV disease who completed induction, 31 had end-of-induction CSs of 2 or less. No patients experienced progression during induction. Two-year event-free survival (EFS) was 85.7% (95% CI, 70.9–93.3).Conclusions:Adding hu14.18K322A to induction chemotherapy produced early PR or better in most patients, reduced tumor volumes, improved CSs at the end of induction, and yielded an encouraging 2-year EFS. These results, if validated in a larger study, may change the standard of care for children with high-risk neuroblastoma.

Individual pharmacokinetic parameters in 3 subpopulations (no prior 14.18 mAb, prior dinutuximab mAb, prior hu14.18K322A mAb).

ADCC EC50 values of hu14.18K322A and dinutuximab.

Donor characteristics, dose and chimerism of NK cells infused.

Supplementary Table 1, Figures 1-3 from Targeting the p53 Pathway in Retinoblastoma with Subconjunctival Nutlin-3a

The three most common pediatric solid tumors of the abdomen are neuroblastoma, Wilms tumor, and hepatoblastoma. These embryonal tumors most commonly present in the first decade of life. Each tumor ...

Retinoblastoma is the most common intraocular childhood cancer and is typically diagnosed in young children. With increasing number of survivors and improved medical outcomes, long-term psychosocial impacts need to be explored. Thus, the current study sought to assess functioning in school-aged survivors of retinoblastoma.Sixty-nine survivors of retinoblastoma underwent a one-time evaluation of psychosocial functioning. Survivors (MOn the whole, both survivors and caregivers indicated QoL and behavioral and emotional health within the typical range of functioning. Survivors reported better physical QoL compared to both parent report and a national healthy comparison sample, whereas caregivers reported that survivors experienced lower social, school, and physical QoL than a healthy comparison. Regarding behavioral and emotional health, survivors indicated more anxiety than a nationally representative sample. Parents of female survivors endorsed lower adaptive scores than parents of male survivors.Results indicated that survivors of retinoblastoma reported QoL and behavioral and emotional health within normal limits, although parents appear to perceive greater impairment across several assessed domains. Understanding both survivor and parent reports remains important for this population. Future research should explore psychosocial functioning of these survivors as they transition to adolescence and early adulthood, given the increased independence and behavioral and emotional concerns during these developmental periods.

OBJECTIVES We aimed to clinically characterize the health, neurocognitive, and physical function outcomes of curative treatment of Wilms tumor. METHODS Survivors of Wilms tumor (n = 280) participating in the St. Jude Lifetime Cohort, a retrospective study with prospective follow-up of individuals treated for childhood cancer at St. Jude Children’s Research Hospital, were clinically evaluated and compared to age and sex-matched controls (n = 625). Health conditions were graded per a modified version of the National Cancer Institute’s Common Terminology Criteria for Adverse Events. Standardized neurocognitive testing was graded by using age-adjusted z-scores. Impaired physical function was defined by age- and sex-matched z-scores >1.5 SD below controls. Modified Poisson regression was used to compare the prevalence of conditions and multivariable logistic regression to examine treatment associations. RESULTS Median age at evaluation was similar between survivors and controls (30.5 years [9.0–58.0] and 31.0 [12.0–70.0]). Therapies included nephrectomy (100%), vincristine (99.3%), dactinomycin (97.9%), doxorubicin (66.8%), and abdominal (59.3%) and/or chest radiation (25.0%). By age 40 years, survivors averaged 12.7 (95% confidence interval [CI] 11.7–13.8) grade 1–4 and 7.5 (CI: 6.7–8.2) grade 2 to 4 health conditions, compared to 4.2 (CI: 3.9–4.6) and 2.3 (CI: 2.1–2.5), respectively, among controls. Grade 2 to 4 endocrine (53.9%), cardiovascular (26.4%), pulmonary (18.2%), neurologic (8.6%), neoplastic (7.9%), and kidney (7.2%) conditions were most prevalent. Survivors exhibited neurocognitive and physical performance impairments. CONCLUSIONS Wilms tumor survivors experience a threefold higher burden of chronic health conditions compared to controls and late neurocognitive and physical function deficits. Individualized clinical management, counseling, and surveillance may improve long-term health maintenance.

Objectives The preschool years (ages 4–6) are essential for the development of social–emotional skills, such as problem solving, emotion regulation, and conflict resolution. For children with cancer treated during this period, especially those with brain tumors, there are questions regarding the consequences of missed normative social experiences. The objective of this pilot study was to explore the social–emotional functioning of young children with brain tumors, as compared to those with non-CNS solid tumors, who have recently completed treatment. Methods Children with brain (n = 23) or solid tumors (n = 20) 4–6 years of age (5.42 ± 0.73 years; 60.5% male, 65.1% white) who were 8.21 (SD = 2.42) months post-treatment completed objective measures (Challenging Situations Task, NEPSY-II) of social functioning while a caregiver completed questionnaires (e.g., BASC-3, NIH Toolbox Emotion Measures). Results A large portion of the sample (brain tumor: 65.2%, solid tumor: 44.4%) fell in the clinical range on parent-report measures of peer interaction. There were no statistically significant differences between patient groups across measures, but effect sizes suggest youth with brain tumors potentially experienced more difficulties on some indices. All children were more likely to choose prosocial responses when presented with a challenging social situation where they were physically provoked (e.g., hit) versus socially provoked (e.g., left out). Conclusions Preschool-aged children with cancer may experience weaknesses in social functioning shortly after treatment, with youth with brain tumors potentially demonstrating greater concerns. Emphasizing social interaction is critical to ensure young children have the opportunity to develop critical social–emotional skills.

To determine the safety and toxicity profile of intravitreal carboplatin as salvage treatment for retinoblastoma with vitreous disease.Single institution, interventional prospective clinical trial PARTICIPANTS: Patients with progressive or recurrent vitreous seeds following completion of primary treatment for intraocular retinoblastoma.Eligible eyes received an intravitreal injection of carboplatin every 14-21 days with simultaneous focal therapy (laser, thermotherapy, brachytherapy) provided at the discretion of the ocular oncologist. Evaluation with exam under anesthesia (EUA), ultrasound biomicroscopy and electroretinography were performed prior to each injection to assess for tumor response and drug-related toxicity. A serious adverse event resulted in dose recalculation and ultimately early closure of the study.Regression pattern of vitreous disease and incidence of dose-limiting toxicities.Four patients were enrolled at an initial dose of 0.3 mg. Complete regression of vitreous seeds was noted in all patients following 5, 2, 2 and 1 injections (respectively). Two patients developed recurrent vitreous disease at 3 months and 25 months after complete regression, and ultimately required enucleation. A serious adverse event occurred in one patient who developed acute vision loss with extinguished electroretinography response 72 hours after the second injection; ultimately this eye developed cataract and required enucleation. Following temporary suspension and dose modification, three patients were enrolled at an injection dose of 3 μg and treated with a total of 5, 2 and 1 injections respectively. Complete regression of vitreous disease was not achieved in any patient though ERG amplitudes remained stable. Following removal from protocol, all three patients had a complete response to intravitreal melphalan. Concern for dose escalation and further toxicity in the setting of an effective and safe alternative (melphalan) led to termination of the study.Intravitreal carboplatin may be effective in treating progressive vitreous seeding at higher doses, but permanent retinal toxicity was observed. Other alternative agents should be considered.

Background Talazoparib combined with irinotecan and temozolomide demonstrated efficacy in a murine Ewing sarcoma model. Based on these data, we conducted a phase I trial of talazoparib and irinotecan with/without temozolomide in paediatric patients with recurrent/refractory solid malignancies. Patients and methods Cohorts of 3–6 patients with recurrent/refractory solid malignancies received escalating doses of oral talazoparib and intravenous irinotecan (arm A) and oral talazoparib, oral temozolomide and intravenous irinotecan (arm B) in a 3 + 3 design. Talazoparib was administered on days 1–6, and intravenous irinotecan and oral temozolomide were administered on days 2–6, of a 21-day course. Serum for talazoparib and irinotecan pharmacokinetics was obtained during course 1. UGT1A1 polymorphism and Schlafen family member 11 (SLFN11) immunohistochemical staining were performed. Results Forty-one patients (20 males; median age, 14.6 years; 24 with recurrent disease) were evaluable for dose escalation. Twenty-nine and 12 patients were treated on arm A and arm B, respectively, for a total of 208 courses. The most common diagnosis was Ewing sarcoma (53%). The most common ≥grade III haematologic toxicities in arms A and B included neutropenia (78% and 31%, respectively) and thrombocytopenia (42% and 31%, respectively). In arms A and B, febrile neutropenia (24% and 14%, respectively) and diarrhoea (21% and 7%, respectively) were the most common ≥grade III non-hematologic toxicities. Six patients (Ewing sarcoma [5 patients] and synovial sarcoma [1 patient]) had a response (1 with a complete response, 5 with a partial response). The objective response rates were 10.3% (arm A) and 25% (arm B). Pharmacokinetic testing demonstrated no evidence of drug-drug interaction between talazoparib and irinotecan. UGT1A1 was not related to response. SLFN11 positivity was associated with best response to therapy. Conclusions The combination of talazoparib and irinotecan with/without temozolomide is feasible and active in Ewing sarcoma, and further investigation is warranted.

Because of the increasing use of nephron-sparing surgery (NSS) in bilateral Wilms tumor, we sought to review the early postoperative complications associated with NSS.A retrospective review of patients who underwent NSS at our institution from 2000 to 2017 was performed. For comparison, a cohort of patients who underwent radical nephrectomy (RN) was also reviewed. Early (30-day) postoperative complications and oncologic outcomes were assessed.Fifty-five patients underwent either bilateral (46) NSS or unilateral (9) NSS owing to prior resection or congenital solitary kidney. Fifty-four patients who underwent unilateral RN were also evaluated. Twenty NSS patients (36.4%) experienced 21 postoperative complications, including prolonged urine leak (9), infection (8), transient renal insufficiency (1), and intussusception (3). Seven RN patients (13.0%) experienced surgical complications, including infection (4) and intussusception (3). Average intraoperative blood loss was significantly greater in NSS as compared to RN (483.51 ± 337.92 mL and 278.15 mL ± 390.25, respectively, p0.001), as was the incidence of positive tumor resection margins (20 [36.4%] and 12 [22.2%], respectively, (p = 0.037).In our experience, prolonged urine leak, intraoperative blood loss, and positive margins were more frequent in patients undergoing NSS as compared to RN. However, the complications were successfully managed, suggesting that an aggressive approach to NSS in patients with bilateral Wilms tumor is safe and appropriate.Level III TYPE OF STUDY: Treatment study.

Purpose: We sought to evaluate whether combining a humanized antidisialoganglioside mAb (hu14.18K322A) with induction chemotherapy improves early responses and outcomes in children with newly diagnosed high-risk neuroblastoma. Patients and Methods: We conducted a prospective nonrandomized, single-arm, two-stage, phase II clinical trial. Six courses of induction chemotherapy were coadministered with hu14.18K322A and followed with granulocyte–macrophage colony-stimulating factor (GM-CSF) and low-dose IL2. Consolidation was performed with a busulfan/melphalan preparative regimen. An additional course of hu14.18K322A was administered with parent-derived natural killer cells, when available, during consolidation. Hu14.18K322A, GM-CSF, IL2, and isotretinoin were then administered. Secondary outcomes included reduced tumor volume and semiquantitative 123I-metaiodobenzylguanidine scoring [i.e., Curie scores (CS)] at the end of induction. Results: Forty-two patients received hu14.18K322A and induction chemotherapy. This regimen was well tolerated, with continuous-infusion narcotics adjusted to patient tolerance. Partial responses (PR) or better after the first two chemoimmunotherapy courses occurred in 32 patients [76.2%; 95% confidence interval (CI), 60.6–88.0]. This was accompanied by primary tumor volume reductions (median, –76%; range, –100% to 5%). Of 35 patients with stage IV disease who completed induction, 31 had end-of-induction CSs of 2 or less. No patients experienced progression during induction. Two-year event-free survival (EFS) was 85.7% (95% CI, 70.9–93.3). Conclusions: Adding hu14.18K322A to induction chemotherapy produced early PR or better in most patients, reduced tumor volumes, improved CSs at the end of induction, and yielded an encouraging 2-year EFS. These results, if validated in a larger study, may change the standard of care for children with high-risk neuroblastoma.

An American Society of Anesthesiology-Physical Status (ASA-PS) score is assigned topatients prior to undergoing anesthesia as a means of quantifying the impact of a patient's comorbidities. While this is the most common use, ASA-PS scores are also usedinclinical research and to determinefinancial reimbursement for anesthesia services.

Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. Children with germline mutations in RB1 have a high likelihood of developing retinoblastoma and other malignancies later in life. Genetically engineered mouse models of retinoblastoma share some similarities with human retinoblastoma but there are differences in their cellular differentiation. To develop a laboratory model of human retinoblastoma formation, we make induced pluripotent stem cells (iPSCs) from 15 participants with germline RB1 mutations. Each of the stem cell lines is validated, characterized and then differentiated into retina using a 3-dimensional organoid culture system. After 45 days in culture, the retinal organoids are dissociated and injected into the vitreous of eyes of immunocompromised mice to support retinoblastoma tumor growth. Retinoblastomas formed from retinal organoids made from patient-derived iPSCs have molecular, cellular and genomic features indistinguishable from human retinoblastomas. This model of human cancer based on patient-derived iPSCs with germline cancer predisposing mutations provides valuable insights into the cellular origins of this debilitating childhood disease as well as the mechanism of tumorigenesis following RB1 gene inactivation., Retinoblastoma is a heritable pediatric cancer driven by mutations in RB1. Here, the authors demonstrate the first patient derived model of retinoblastoma using iPSCs from patients with germline mutations in RB1.

Background Indocyanine green (ICG), a water-soluble tricarbocyanine fluorophore, is being increasingly used for tumor localization based on its passive intra-tumoral accumulation due to enhanced permeability and retention in tumor tissue. Therefore, we hypothesized that ICG can provide contrast to facilitate accurate, real-time recognition of renal tumors at the time of nephron-sparing surgery in children. Methods This retrospective study examined the feasibility of ICG in guiding nephron-sparing surgery for pediatric renal tumors. Results We reviewed the medical records of 8 pediatric patients with renal tumors in 12 kidneys. Intraoperative localization of tumor with near infrared guidance was successful in all 12 kidneys. However, we consistently found an inverse pattern of near infrared signal in which the normal kidney demonstrated increased fluorescent signal relative to the kidney tumor. Conclusions Fluorescence-guided renal tumor delineation is unique because it has an inverse pattern of near infrared signal in which the normal kidney demonstrates increased signal relative to the adjacent tumor. Nevertheless fluorescence-guided distinguishing of renal tumor from surrounding normal kidney is feasible.

PURPOSE To describe the trajectory of cognitive and adaptive functioning in pediatric patients with retinoblastoma from diagnosis through age 10. This is an extension of a previous report that discussed findings from diagnosis through age 5. PATIENTS AND METHODS Ninety-eight participants with retinoblastoma completed psychological assessments as part of their enrollment on an institutional treatment protocol, with 73 completing an additional assessment at age 10. Trajectories of adaptive and cognitive functioning were determined, with data analyzed by treatment strata, and patients with 13q- analyzed separately. RESULTS Longitudinal trajectories identified a significant change point in trends at age 5, with functioning declining from diagnosis through age 5 and then increasing from age 5 to age 10. This pattern was observed for all strata for adaptive functioning, but only for enucleation-only patients (strata C low) for cognitive functioning. Cognitive trajectories were also influenced by laterality and enucleation status. At age 10, overall functioning was generally within the average range, although estimated intelligence quotient was significantly below the normative mean for enucleation-only (C low) patients. Patients with 13q- demonstrated very low functioning, but few analyses were significant because of small sample size. CONCLUSION The results generally indicate that previously demonstrated declines in functioning from diagnosis through age 5 improve by age 10. However, these early declines, as well as the continuous difficulties observed in patients treated with enucleation only, suggest the need for early intervention services for young patients with retinoblastoma. Continuous monitoring of the psychological functioning of patients with retinoblastoma, increased awareness of risk factors such as unilateral disease, enucleation, race, and surgery-only treatment plans, and referral to Early Intervention for all patients are indicated.

The three most common pediatric solid tumors of the abdomen are neuroblastoma, Wilms tumor, and hepatoblastoma. These embryonal tumors most commonly present in the first decade of life. Each tumor has unique imaging findings, including locoregional presentation and patterns of distant spread. Neuroblastoma, Wilms tumor, and hepatoblastoma have unique staging systems that rely heavily on imaging and influence surgical and oncologic management. The staging systems include image-defined risk factors for neuroblastoma, the Children's Oncology Group staging system for Wilms tumor, and the pretreatment extent of tumor system (PRETEXT) for hepatoblastoma. It is important for radiologists to be aware of these staging systems to optimize image acquisition and interpretation. This article provides a practical and clinically oriented approach to the role of imaging in the staging of these common embryonal tumors of childhood. The selection among imaging modalities, key findings for determining tumor stage, and the role of imaging in posttreatment response evaluation and surveillance are discussed. Recent updates to the relevant staging systems are highlighted with attention to imaging findings of particular prognostic importance. The information presented will help radiologists tailor the imaging approach to the individual patient and guide optimal oncologic management.

Standardized guidelines for assessing tumor response to therapy are essential for designing and conducting clinical trials. The Response Evaluation Criteria In Solid Tumors (RECIST) provide radiological standards for assessment of solid tumors. However, no such guidelines exist for the evaluation of intraocular cancer, and ocular oncology clinical trials have largely relied on indirect measures of therapeutic response-such as progression-free survival-to evaluate the efficacy of treatment agents. Herein, we propose specific criteria for evaluating treatment response of retinoblastoma, the most common pediatric intraocular cancer, and emphasize a multimodal imaging approach for comprehensive assessment of retinoblastoma tumors in clinical trials.

BACKGROUND Evaluate the efficacy of two courses of vincristine and topotecan (VT) neoadjuvant intravenous chemotherapy in reducing retinoblastoma tumor volumes. METHODS Twenty-seven patients with previously untreated, bilateral advanced retinoblastoma who were enrolled on a prospective treatment protocol (NCT00186888). Patients underwent high-resolution ophthalmic imaging at diagnosis and were reimaged following treatment with two cycles of VT. Tumor height and diameter were measured before and after treatment, and tumor volumes were calculated. Statistical methods for dependent samples were used. RESULTS Imaging was completed for 75 tumors in 23 patients (43 eyes). After two cycles of VT, median decrease in tumor height was 47% and median decrease in tumor diameter was 22%. Median decrease in estimated tumor volume was 74%. Sixty-one of 75 tumors demonstrated >50% reduction in tumor volume. Distance from the optic nerve (=0 vs >0), age ( 4 months), macular location (within vs outside), and time (pre- and posttreatment) were found significantly associated with log-transformed tumor volume adjusting for the repeated effect of patient eye using generalized estimating equations to estimate the parameters of a generalized linear model (P

BACKGROUND: The impact of specific treatment modalities on long-term renal function and blood pressure among adult survivors of Wilms tumor (WT) has not been well-documented. METHODS: Among 40 WT survivors and 35 non-cancer controls, we estimated the glomerular filtration rate (eGFR) using the Chronic Kidney Disease-Epidemiology (CKD-EPI) equations with and without cystatin C, obtained 24-hour ambulatory blood pressure readings, and, among survivors only, measured (99m)Tc diethylenetriamine pentaacetic acid (DTPA) plasma clearance. Survivors were treated with unilateral nephrectomy and non-nephrotoxic chemotherapy. Twenty received whole abdomen radiation therapy (WART) [median –16.5 Gray (Gy)], and 20 received no radiation therapy. Pairwise comparisons between survivors treated with and without WART, and each group to controls were performed using two-sample t-tests. RESULTS: Twenty-six (65%) WT survivors were female and 33 (83%) were non-Hispanic white. GFR estimated with creatinine or creatinine + cystatin C was decreased among irradiated survivors compared to controls. No irradiated or unirradiated participant had an eGFR (creatinine + cystatin C) < 60 ml/min/1.73m(2). The prevalence of hypertension was significantly increased among unirradiated (25%) and irradiated survivors (35%) compared to controls (0%). Of the 24-hour ambulatory blood pressure monitoring parameters evaluated, only mean sleep period diastolic blood pressure load of those who received WART was significantly different from that of controls. CONCLUSIONS: Chronic kidney disease was infrequent in long-term survivors of unilateral non-syndromic WT, whether treated with WART or no radiation. The prevalence of hypertension was increased in both groups compared to controls, emphasizing the need for ongoing monitoring of renal and cardiovascular health.

Background Extracranial pure malignant rhabdoid tumors (MRT) are aggressive tumors that carry a poor prognosis. Bladder MRTs are very rare and only 8 cases have been reported previously. Observation We present a case of a child with bladder MRT. Despite the aggressive nature of the bladder tumor, it was successfully treated with bladder-sparing surgery, adjuvant radiotherapy, and chemotherapy. Conclusions Our case, and review of 8 previously reported cases, suggests that bladder MRT seems to behave less aggressively when compared with other extracranial MRTs, and bladder preserving surgery should be considered when feasible.

Aims Several morphologically overlapping (myo)fibroblastic neoplasms harbour USP6 fusions, including aneurysmal bone cysts, nodular fasciitis, myositis ossificans, cranial fasciitis, fibro-osseous pseudotumour of the digits, and cellular fibroma of the tendon sheath. USP6-induced neoplasms are almost universally benign and cured by local excision. We aim to highlight the diagnostic value of USP6 fusion detection in a series of aggressive-appearing paediatric myofibroblastic tumours. Methods and results Three deep-seated, radiographically aggressive, and rapidly growing childhood myofibroblastic neoplasms were morphologically and molecularly characterised by USP6 break-apart fluorescence in-situ hybridisation (FISH), transcriptome sequencing, and targeted capture analysis. Each tumour occurred in the lower-extremity deep soft tissue of a child presenting with pain, limping, or a mass. In all three patients, imaging studies showed a solid mass that infiltrated into surrounding skeletal muscle or involved/eroded underlying bone. The biopsied tumours consisted of variably cellular myofibroblastic proliferations with variable mitotic activity that lacked overt malignant cytological features. FISH showed that all tumours had USP6 rearrangements. On the basis of these results, all three patients were treated with conservative excision with positive margins. The excised tumours had foci resembling nodular fasciitis, fibromatosis, and pseudosarcomatous proliferation. Next-generation sequencing revealed COL1A1-USP6 fusions in two tumours and a COL3A1-USP6 fusion in the third tumour. One tumour had a subclonal somatic APC in-frame deletion. No recurrence was observed during follow-up (8-40 months). Conclusion We present a series of benign, but aggressive-appearing, USP6-rearranged myofibroblastic tumours. These deep-seated tumours had concerning clinical and radiographic presentations and did not fit into one distinct histological category. These cases highlight the diagnostic value of USP6 fusion detection to identify benign nondescript tumours of this group, especially those with aggressive features, to avoid overtreatment.

Purpose Vitreous seeding remains the primary reason for treatment failure in eyes with retinoblastoma (Rb). Systemic and intra-arterial chemotherapy, each with its own inherent set of complications, have improved salvage rates for eyes with advanced disease, but the location and biology of vitreous seeds present a fundamental challenge in developing treatments with minimal toxicity and risk. The aim of this study was to target the platelet-derived growth factor (PDGF)- PDGF-receptor β (PDGFRβ) signaling pathway and investigate its role in the growth of Rb seeds, apoptotic activity, and invasive potential. Methods We performed ex vivo analyses on vitreous samples from Rb patients that underwent enucleation and from patient-derived xenografts. These samples were evaluated by quantitative PCR, immunohistochemistry, and ELISA. The effects of disruption of the PDGF-PDGFRβ signaling pathway, both by pharmacologic and genomic knockdown approaches, were evaluated in vitro by cell proliferation and apoptotic assays, quantitative PCR analyses, Western blotting, flow cytometry, and imaging flow cytometry. A three-dimensional cell culture system was generated for in-depth study of Rb seeds. Results Our results demonstrated that PDGFRβ signaling is active in the vitreous of Rb patients and patient-derived xenografts, sustaining growth and survival in an AKT-, MDM2-, and NF-κB-dependent manner. The novel three-dimensional cell culture system mimics Rb seeds, as the in vitro generated spheroids have similar morphologic features to Rb seeds and mimicked their natural physiology. Conclusions Targeting the PDGFRβ pathway in vitro reduces Rb cell growth, survival, and invasiveness and could augment current therapies. This represents a novel signaling pathway for potential targeted therapy to further improve ocular survival in advanced Rb.

Purpose: Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells. Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m2/dose, days 2–5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Rα) levels, and human antihuman antibodies (HAHA) were obtained. Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239–568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Rα levels, indicating immune activation. Conclusions: Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma. Clin Cancer Res; 23(21); 6441–9. ©2017 AACR.

10038 Background: We aimed to characterize late health, neurocognitive, and physical performance outcomes among survivors of Wilms tumor. Methods: Wilms tumor survivors (n = 280), ≥ 5 years from diagnosis, participating in SJLIFE were clinically assessed along with a community control sample (n = 625). Health outcomes were graded per a modified Common Terminology Criteria for Adverse Events (grade 1 [mild] to grade 4 [life threatening]). Standardized neurocognitive testing was graded using age-adjusted z-scores. Aerobic function (six-minute walk), mobility (timed up and go) and flexibility (sit and reach) were assessed. Associations between treatment exposures and prevalent conditions were examined by multivariable logistic regression, adjusted for current age, sex and race. Results: Survivors (59% female, 73% white), median age 3 years (range 0-15) at diagnosis and 31 years (9-58) at evaluation, were comprehensively evaluated on the St. Jude campus. Two-thirds (67%) were treated with doxorubicin (median dose 175 mg/m2 range 52-490), 167 (60%) received abdominal radiation (median dose 12 Gy range 8.8-61.2) and 25% received chest radiation (12 Gy range 9-44). By age 40 years, survivors averaged 12.7 (95% confidence interval [CI] 11.7-13.8) grade 1-4 and 7.5 (CI 6.7-8.2) grade 2-4 conditions, compared to 4.2 (CI 3.9-4.6) and 2.3 (CI 2.1-2.5), respectively, among controls. The most prevalent medical conditions (grade ≥ 2) are reported in the table. Abnormal glucose metabolism was associated with abdominal radiation (relative risk [RR] 5.1 CI 1.4-19.0); restrictive pulmonary defects with chest radiation (RR 24.0 CI 3.2-180); and cardiomyopathy (RR 15.6 CI 1.9-128), pulmonary diffusion (RR 4.5 CI 1.3-15.1), and chronic kidney disease (RR 4.5 CI 1.3-16.1) with doxorubicin exposure. Survivors had a three-fold higher risk (standardized incidence ratio 3.5, CI 2.2-6.6) for subsequent neoplasms. Impairments (grade ≥ 2) in executive function (20% vs. 12%), attention (17% vs. 9%), memory (21% vs. 10%), and processing speed (20% vs. 8%) were more frequent in survivors than controls (p < 0.05). Impairments in aerobic function (13.6%), mobility (13.6%), and flexibility (11.1%) were higher than expected (p < 0.01). Significant associations were not identified between treatment exposures and neurocognitive or physical performance outcomes. Conclusions: Systematic clinical assessment identified a significant burden of chronic health conditions and previously unrecognized neurocognitive and physical performance limitations in survivors of Wilms tumor.[Table: see text]

Retinoblastoma is an ocular tumor that occurs in young children, in either heritable or sporadic manner. The relative rarity of retinoblastoma, and the need for expensive equipment, anesthesia, and pediatric ophthalmologic expertise, are barriers for effective treatment in developing countries. Also, with an average age-adjusted incidence of two to five cases per million children, patient number limits development of local expertise in countries with small populations. Lebanon is a small country with a population of approximately 4.5 million. In 2012, a comprehensive retinoblastoma program was formalized at the Children's Cancer Institute (CCI) at the American University of Beirut Medical Center, and resources were allocated for efficient interdisciplinary coordination to attract patients from neighboring countries such as Syria and Iraq, where such specialized therapy is also lacking. Through this program, care was coordinated across hospitals and borders such that patients would receive scheduled chemotherapy at their institution, and monthly retinal examinations and focal laser therapy at the CCI in Lebanon. Our results show the feasibility of successful collaboration across borders, with excellent patient and physician adherence to treatment plans. This was accompanied by an increase in patient referrals, which enables continued expertise development. However, the majority of patients presented with advanced intraocular disease, necessitating enucleation in 90% of eyes in unilateral cases, and more than 50% of eyes in bilateral cases. Future efforts need to focus on expanding the program that reaches to additional hospitals in both countries, and promoting early diagnosis, for further improvement of globe salvage rates.

One-third of gastrointestinal stromal tumors (GISTs) that lack KIT or PDGFRA mutations show succinate dehydrogenase (SDH) mutations or promoter hypermethylation. Most SDH-deficient GISTs occur in the pediatric, adolescent, or young adult setting and have unique features including predilection for the stomach, multinodular plexiform architecture, epithelioid cytology, prominence of lymphovascular invasion, and predilection for nodal metastasis. Dedifferentiation in GIST is a rare histologic change which may occur de novo or secondary to imatinib therapy and is characterized by abrupt transition of well-differentiated (WD) GIST to a subclonal anaplastic process that shows loss of immunohistochemical marks (CD117, DOG1). We describe the case of a previously healthy 18-year-old man who presented with a large gastric wall mass that contained 2 distinct morphologic populations. The first was WD and characterized by sweeping fascicles of bland spindled cells. This population abruptly transitioned to dedifferentiated (DD) foci composed of large sheets of discohesive cells that displayed a spectrum of rhabdoid and epithelioid morphologies with marked pleomorphism and mitotic activity. Immunohistochemically, the tumor showed variable staining in the 2 components with diffuse DOG-1 and CD117 positivity in the WD component and complete absence in the DD foci. SDH-B staining was lost in both components. Whole exome and transcriptome analysis was performed on tissue from both components and both showed an SDHB mutation (c.286G>A) as well as unique mutational burden and copy number profiles. Herein, we describe the first case of a DD SDH-deficient GIST with morphologic, immunophenotypic, and molecular characterization.

Dear Editor,Retinoblastoma and Hermansky-Pudlak syndrome (HPS) are two rare ophthalmic disorders which arise from sporadic or germline mutations in specific genes. Retinoblastoma occurs in 1 in 15,...

In the United States and other developed nations, more patients with retinoblastoma will die from non-ocular second malignant neoplasms than from their primary intraocular tumor. There is an increased lifetime risk of the development of second malignant neoplasms in survivors of heritable retinoblastoma compared with their nonheritable counterparts. Radiation increases the risk of second malignant neoplasms and should be avoided when possible. All patients at risk must be educated to remain vigilant for future signs or symptoms of malignancies and counseled to avoid exposure to other mutagens. The prognosis for patients with second malignant neoplasms is guarded and underscores the importance of counseling patients with the heritable form of the disease.

Background A total of 5–10% of patients with retinoblastoma (RB) harbor deletion of the long arm (q) chromosome 13 (13q-). The treatment-related toxicities in this population have not been described. Methods Sixty-eight RB patients on a single institutional protocol (RET5) from 2005 to 2010 were reviewed. Genetic screening identified 11 patients (seven female) with 13q-. Patients with early (Reese-Ellsworth [R-E] group I–III) disease (6/23 with 13q-) received eight courses of vincristine/carboplatin (VC). Patients with advanced (R-E group IV-V) bilateral disease (2/27 with 13q-) received two courses of vincristine/topotecan (VT) followed by nine courses of alternating VT/VC. Patients undergoing upfront enucleation received histopathology-based chemotherapy: intermediate risk (2/8 with 13q-) or high risk (1/10 with 13q-). Dose reductions were mandated for >7 day delay in two consecutive courses following hematologic toxicity. Grades 3 and 4 hematologic, infectious, and gastrointestinal toxicities were compared between RET5 patients with and without 13q-. Results Demographics were similar between groups. When present, prolonged neutropenia (median 7 days, range 0–14 days) delayed chemotherapy and resulted in more frequent dose reductions among 13q- patients (5/11) than non-13q- patients (4/57) (P < 0.01). GI toxicity was similar between groups (5/11 13q- vs. 13/57 non-13q-; P = 0.14), but halted chemotherapy in one 13q- patient. Infectious complications and disease outcomes were similar between groups. At follow-up, all patients are alive (median 6.1 years, range 7.6 months–9.5 years). Conclusions 13q- RB patients had a higher incidence of neutropenia requiring chemotherapy dose reductions, but did not have increased treatment failure.

Objectives Wilms tumor is the most common renal cancer in children. Approximately 5% of children with Wilms tumor present with disease in both kidneys. The treatment challenge is to achieve a high cure rate while maintaining long-term renal function. We retrospectively reviewed our institutional experience with nephron sparing surgery (NSS) in patients with synchronous bilateral Wilms tumor (BWT) operated on between 2001 and 2014. Methods Imaging studies, surgical approach, adjuvant therapy, and pathology reports were reviewed. Outcomes evaluated included surgical complications, tumor recurrence, patient survival, and renal function, as assessed by estimated glomerular filtration rate. Results A total of 42 patients with BWT were identified: 39 (92.9%) patients underwent bilateral NSS; only 3 patients (7.1%) underwent unilateral nephrectomy with contralateral NSS. Postoperative complications included prolonged urine leak (10), infection (6), intussusception (2), and transient renal insufficiency (1). Three patients required early (within 4 months) repeat of NSS for residual tumor. In the long-term, 7 (16.7%) patients had local tumor recurrence (managed with repeat NSS in 6 and completion nephrectomy in 1) and 3 had an episode of intestinal obstruction requiring surgical intervention. Overall survival was 85.7% (mean follow-up, 4.1 years). Of the 6 patients who died, 5 had diffuse anaplastic histology. All of the patients had an estimated glomerular filtration rate more than 60 mL/min/1.73 m at the last follow-up; no patient developed end-stage renal disease. Conclusions In patients with synchronous, BWT, bilateral NSS is safe and almost always feasible, thereby preserving maximal renal parenchyma. With this approach, survival was excellent, as was maintenance of the renal function.