Background: The International Neuroblastoma Risk Group (INRG) classifier utilizes a staging system based on pretreatment imaging criteria in which image-defined risk factors (IDRFs) are used to evaluate the extent of locoregional disease. Children's Oncology Group (COG) study ANBL0531 prospectively examined institutional determination of IDRF status and compared that to a standardized central review. Methods: Between 9/2009-6/2011, patients with intermediate-risk neuroblastoma were enrolled on ANBL0531 and had IDRF assessment at treating institutions. Paired COG pediatric surgeons and radiologists performed blinded central review of diagnostic imaging for the presence or absence of IDRFs. Second blinded review was performed in cases of discordance. Comparison of local and central review was performed using the Kappa coefficient to determine concordance in IDRF assessment. Results: 211 patients enrolled in ANBL0531 underwent IDRF assessment; 3 patients were excluded due to poor image quality. Central reviewer pairs agreed on the presence or absence of any IDRF in 170/208 (81.7%; K = 0.48) cases. Thirteen (6.3%) cases could not be adjudicated after second blinded review. Radiologists were more likely to identify IRDFs as present than surgeons (p < 0.001). Local and central reviewers agreed on the presence or absence of any IDRF in only108/208 (51.9%; K = 0.06) cases. Conclusions: Among experienced pediatric surgeons and radiologists participating in central review, concordance was moderate, with agreement in 81.7% of cases. On comparison of local and central assessment of IDRFs, concordance was poor. These data indicate that greater standardization, education, technology, and training are needed to improve the assessment of IDRFs in children with neuroblastoma. Level of Evidence: Treatment Study, Level III. (c) 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

PURPOSE:National Wilms Tumor Study-5 (NWTS-5) and AREN0321 evaluated the outcomes of children with rhabdoid tumor of the kidney (RTK) and malignant rhabdoid tumor of soft tissues (MRT). PATIENTS AND METHODS:Eligible patients with RTK were enrolled prospectively on NWTS-5 (1995-2002) and treated with carboplatin and etoposide alternating with cyclophosphamide (Regimen RTK). Patients with RTK or MRT were enrolled on AREN0321 (2005-2012) and received vincristine, doxorubicin, and cyclophosphamide alternating with carboplatin, cyclophosphamide, and etoposide (Regimens UH-1 or dose-reduced Revised UH-1). We report event-free survival (EFS) and overall survival (OS) from each study. RESULTS:Thirty patients received Regimen RTK on NWTS-5; on AREN0321, 20 received UH-1 and 19 received Revised UH-1. Patient and disease characteristics were statistically similar between studies. Patients on AREN0321 had significantly improved EFS and OS compared to those on NWTS-5 (4-year EFS = 23.1% vs. 16.7%; p = 0.020; 4-year OS = 30.6% vs. 20.0%; p = 0.014), mostly driven by patients with Stage I/II disease (p = 0.05). Median time to an event was 3.6 months on NWTS-5 compared to 7.2 months on AREN0321. There were no differences in EFS or OS by revised versus original Regimen UH-1 on AREN0321, or by renal versus extra-renal primary disease when the studies were pooled. CONCLUSIONS:The more intensive treatment regimen used on AREN0321 improved EFS and OS overall, a result driven by patients with Stage I/II disease. Despite this improvement, outcomes for patients with rhabdoid tumor remain unsatisfactory and there is a need for novel therapeutic strategies.

Diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) represents a unique category of nephroblastomatosis. Treatment has ranged from observation to multiple regimens of chemotherapy. Wilms tumors (WTs) develop in 100% of untreated patients and between 32 and 52% of treated patients. Renal preservation rates have not been previously reported. An aim of the Children’s Oncology Group (COG) study AREN0534 was to prospectively evaluate the efficacy of chemotherapy in preserving renal units and preventing WT development in children with DHPLN. Patients were enrolled through the COG protocol AREN03B2 with central radiological review. DHPLN was defined as the cortical surface of the kidney being composed of hyperplastic rests, with the entire nephrogenic zone involved, and with a thick rind capping all of one or both kidneys. Treatment was with vincristine and dactinomycin (regimen EE4A), with cross-sectional imaging at weeks 6 and 12. If the patient’s disease was stable or decreasing, treatment was continued for 19 weeks. Renal preservation, WT development rates at 1 year, and overall survival (OS) are reported. Nine patients were enrolled (five females and four males), with a median age at enrollment of 10.22 months (range 2.92–29.11). One patient who was enrolled was deemed unevaluable because they did not meet the radiological criteria for DHPLN, resulting in eight evaluable patients. These eight patients had DHPLN confirmed via radiological criteria (all bilateral). Initial chemotherapy was EE4A for all eight patients, with seven of eight patients starting chemotherapy without tissue diagnosis.One patient who had an upfront partial nephrectomy was found to have DHPLN in the specimen and was subsequently treated with EE4A. All patients remained alive, with a median follow-up of 6.6 years (range 4.5–9.1). No patients were anephric; 14 of 16 kidneys were functioning (87.5%). Six of eight patients (75%) did not have WT on therapy, but two of these patients relapsed within 6 months of stopping therapy; both had favorable histology WT. One patient who was diagnosed with WT on therapy relapsed at 12 months (one of eight [12.5%]) and developed anaplastic histology. Chemotherapy for patients with DHPLN was effective in preserving kidney function. Five-year OS is excellent, however the ideal type and duration of chemotherapy to prevent WT development remains elusive.

A patient developed the severe amnesic syndrome 8 years after temporal lobe surgery for epilepsy. He underwent left temporal lobectomy (6 cm, 43.5 g; hippocampal sclerosis) aged 19, and remained seizure free for 8 years until a convulsion followed a head injury. He became severely amnesic after a fourth convulsion 16 months later. He was right-handed, pre-operative IQ was average, verbal memory poor and non-verbal memory normal. Post-operatively, these were unchanged. After the first post-operative seizure he began professional training. After onset of amnesia IQ was unchanged, anterograde memory severely impaired and retrograde amnesia dense for at least 16 months. He died 2 years later. Magnetic resonance imaging before amnesia showed absence of anterior left temporal lobe, atrophy of left fornix and mamillary body, and normal right temporal lobe. Four months after onset of amnesia, right hippocampal volume had reduced by 36%. Autopsy showed: previous left temporal lobectomy with absence of left amygdala and hippocampus, atrophy of fornix and mamillary body; neuronal loss in the right hippocampus, severe in CA1 and CA4; intact right amygdala and parahippocampal gyrus; recent diffuse damage associated with cause of death. A convulsion can cause severe hippocampal damage in adult life. Hippocampal zones CA1 and/or CA4 are critical for maintaining memory and the amygdala and parahippocampal gyrus cortex alone cannot support acquisition of new memories.

PURPOSE:AREN0321 evaluated the activity of vincristine and irinotecan (VI) in patients with newly diagnosed diffuse anaplastic Wilms tumor (DAWT) and whether a regimen containing carboplatin (regimen UH1) in addition to regimen I agents used in the National Wilms Tumor Study 5 (NWTS-5; vincristine, doxorubicin, cyclophosphamide, and etoposide plus radiotherapy) would improve patient outcomes.PATIENTS AND METHODS:Patients with stage II to IV DAWT without measurable disease received regimen UH1. Patients with stage IV measurable disease were eligible to receive VI (vincristine, 1.5 mg/m2 per day intravenously on days 1 and 8; irinotecan, 20 mg/m2 per day intravenously on days 1-5 and 8-12 of a 21-day cycle) in an upfront window; those with complete (CR) or partial response (PR) had VI incorporated into regimen UH1 (regimen UH2). The study was designed to detect improvement in outcomes of patients with stage II to IV DAWT compared with historical controls treated with regimen I.RESULTS:Sixty-six eligible patients were enrolled. Of 14 patients with stage IV measurable disease who received VI, 11 (79%) achieved CR (n = 1) or PR (n = 10) after 2 cycles. Doses of doxorubicin, cyclophosphamide, and etoposide were reduced midstudy because of nonhematologic toxicity. Four patients (6%) died as a result of toxicity. Four-year event-free survival, relapse-free survival, and overall survival rates were 67.7% (95% CI, 55.9% to 79.4%), 72.9% (95% CI, 61.5% to 84.4%), and 73.7% (95% CI, 62.7% to 84.8%), respectively, compared with 57.5% (95% CI, 47.6% to 67.4%; P = .26), 57.5% (95% CI, 47.6% to 67.4%; P = .048), and 59.2% (95% CI, 49.4% to 69.0%; P = .08), respectively, in NWTS-5.CONCLUSION:VI produced a high response rate in patients with metastatic DAWT. AREN0321 treatment seemed to improve outcomes for patients with stage II to IV DAWT compared with NWTS-5, but with increased toxicity. The UH2 regimen warrants further investigation with modifications to reduce toxicity.

BackgroundA primary objective of Children's Oncology Group study AREN0534 (Treatment for Patients With Multicentric or Bilaterally Predisposed, Unilateral Wilms Tumor) was to facilitate partial nephrectomy in 25% of children with bilaterally predisposed unilateral tumors (Wilms tumor/aniridia/genitourinary anomalies/range of developmental delays [WAGR] syndrome; and multifocal and overgrowth syndromes). The purpose of this prospective study was to achieve excellent event‐free survival (EFS) and overall survival (OS) while preserving renal tissue through preoperative chemotherapy, completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histologic response.MethodsThe treating institution identified whether a predisposition syndrome existed. Patients underwent a central review of imaging studies through the biology and classification study AREN03B2 and then were eligible to enroll on AREN0534. Patients were treated with induction chemotherapy determined by localized or metastatic disease on imaging (and histology if a biopsy had been undertaken). Surgery was based on radiographic response at 6 or 12 weeks. Further chemotherapy was determined by histology. Patients who had stage III or IV disease with favorable histology received radiotherapy as well as those who had stage I through IV anaplasia.ResultsIn total, 34 patients were evaluable, including 13 males and 21 females with a mean age at diagnosis of 2.79 years (range, 0.49‐8.78 years). The median follow‐up was 4.49 years (range, 1.67‐8.01 years). The underlying diagnosis included Beckwith‐Wiedemann syndrome in 9 patients, hemihypertrophy in 9 patients, multicentric tumors in 10 patients, WAGR syndrome in 2 patients, a solitary kidney in 2 patients, Denys‐Drash syndrome in 1 patient, and Simpson‐Golabi‐Behmel syndrome in 1 patient. The 4‐year EFS and OS rates were 94% (95% CI, 85.2%‐100%) and 100%, respectively. Two patients relapsed (1 tumor bed, 1 abdomen), and none had disease progression during induction. According to Response Evaluation Criteria in Solid Tumor 1.1 criteria, radiographic responses included a complete response in 2 patients, a partial response in 21 patients, stable disease in 11 patients, and progressive disease in 0 patients. Posttherapy histologic classification was low‐risk in 13 patients (including the 2 complete responders), intermediate‐risk in 15 patients, and high‐risk in 6 patients (1 focal anaplasia and 5 blastemal subtype). Prenephrectomy chemotherapy facilitated renal preservation in 22 of 34 patients (65%).ConclusionsA standardized approach of preoperative chemotherapy, surgical resection within 12 weeks, and histology‐based postoperative chemotherapy results in excellent EFS, OS, and preservation of renal parenchyma.

OBJECTIVE. Distinguishing nephrogenic rests from small Wilms tumors can be challenging. This retrospective study was performed to determine if imaging characteristics can be used to distinguish nephrogenic rests from Wilms tumors. MATERIALS AND METHODS. All cases of pathologically confirmed nephrogenic rests and Wilms tumors smaller than 5 cm in maximum dimension on imaging in patients younger than 5 years old were identified from the Children's Oncology Group AREN03B2 study (July 2006-August 2016). Exclusion criteria were chemotherapy before pathologic evaluation or more than 30 days between imaging and surgery; in addition, patients with nephrogenic rests occurring within or juxtaposed to a Wilms tumor and patients with diffuse hyperplastic perilobar nephroblastomatosis were excluded. Two radiologists who were blinded to pathology results assessed all lesions. The two-sample t test was used for continuous variables, and the Fisher exact test was used for categoric variables. ROC analysis was performed to determine the optimal size cutoff for distinguishing between nephrogenic rests and Wilms tumors. RESULTS. Thirty-one pathologically confirmed rests (20 perilobar, 11 intralobar) and 26 Wilms tumors smaller than 5 cm met the eligibility criteria for study inclusion. The median diameter of the nephrogenic rests was 1.3 cm (range, 0.7-3.4 cm) and the median diameter of the Wilms tumor was 3.2 cm (range, 1.8-4.9 cm) (p < 0.001). Imaging findings supportive of Wilms tumors were spherical (p < 0.001) and exophytic (p < 0.001) lesions. Perilobar rests (17/20) were more likely to be homogeneous than intralobar rests (3/11) or Wilms tumor (3/26) (p < 0.001). ROC analysis showed that the optimal size cutoff for distinguishing between nephrogenic rests and Wilms tumors was 1.75 cm. CONCLUSION. In children younger than 5 years old, the diagnosis of a Wilms tumor should be favored over a nephrogenic rest when a renal mass is spherical, exophytic, or larger than 1.75 cm. Homogeneity favors the diagnosis of perilobar nephrogenic rests, whereas intralobar rests and Wilms tumors are more likely to be inhomogeneous.

ACRIN Principal Investigator InterSPORE Principal Investigator Nola M. Hylton, PhD Laura J. Esserman, MD, MBA University of California, San Francisco UCSF Mt. Zion MRSC, Box 1290 Carol Franc Buck Breast Ctr. One Irving St., Room AC-109 2356 Sutter St., 6 Floor San Francisco, CA 94143-1290 San Francisco, CA 94115 Phone: (415) 476-8856 Phone: (415) 885-7691 Fax: (415) 475-8809 Fax: (415) 353-9571 nola.hylton@radiology.ucsf.edu laura.esserman@ucsfmedctr.org

Wilms tumor is the most common pediatric renal tumor, accounting for approximately 7% of all childhood cancers. Imaging plays an important role in the detection, staging, post-therapy evaluation and surveillance of Wilms tumor. Wilms tumor can be detected during surveillance of a known cancer predisposition or after a child presents with symptoms. In this manuscript we describe an evidence-based approach to the initial evaluation of Wilms tumor using current guidelines from the Children’s Oncology Group (COG). We illustrate the COG staging system for pediatric renal tumors and highlight key imaging findings that are critical for surgical management. We also discuss the controversies regarding detection and significance of <5-mm pulmonary nodules at initial staging. And finally, we present some thoughts regarding surveillance of Wilms tumor, where overall survival has now approached 90%.

The classic radiographic features of interstitial disease in the adult are peribronchial cuffing, a reticulonodular pattern of the lung, Kerley "B" lines, subpleural edema or pleural effusions, hypo-inflation due to restrictive lung disease, and lastly, the honeycomb pattern of end-stage interstitial fibrosis. Occasionally, interstitial distension becomes so massive that large solid areas are noted on the radiograph, indistinguishable from the alveolar consolidation. However, a honeycomb pattern is specific for end stage interstitial fibrosis. Interstitial pneumonitis has the same radiographic features as interstitial fibrosis. The activity of the pneumonitis cannot solely be judged on the radiographic pattern. Pulmonary scintigraphy, specifically Gallium Scanning, may be the only way to differentiate active interstitial pneumonitis from interstitial fibrosis since the uptake of Gallium correlates with the degree of inflammation. A variety of the primary pulmonary disorders may produce respiratory distress in the newborn infant.

Background The National Wilms Tumor Study (NWTS) approach to treating stage III favorable-histology Wilms tumor (FHWT) is Regimen DD4A (vincristine, dactinomycin, and doxorubicin) and radiation therapy. Further risk stratification is required to improve outcomes and reduce late effects. We evaluated clinical and biologic variables for patients with stage III FHWT without combined loss of heterozygosity (LOH) at chromosomes 1p and 16q treated in the Children's Oncology Group protocol AREN0532. Methods From October 2006 to August 2013, 588 prospectively treated, centrally reviewed patients with stage III FHWT were treated with Regimen DD4A and radiation therapy. Tumor LOH at 1p and 16q was determined by microsatellite analysis. Ineligible patients (n = 5) and those with combined LOH 1p/16q (n = 40) were excluded. Results A total of 535 patients with stage III disease were studied. Median follow-up was 5.2 years (range, 0.2 to 9.5). Four-year event-free survival (EFS) and overall survival estimates were 88% (95% CI, 85% to 91%) and 97% (95% CI, 95% to 99%), respectively. A total of 58 of 66 relapses occurred in the first 2 years, predominantly pulmonary (n = 36). Eighteen patients died, 14 secondary to disease. A better EFS was associated with negative lymph node status ( P < .01) and absence of LOH 1p or 16q ( P < .01), but not with gross residual disease or peritoneal implants. In contrast, the 4-year EFS was only 74% in patients with combined positive lymph node status and LOH 1p or 16q. A total of 123 patients (23%) had delayed nephrectomy. Submitted delayed nephrectomy histology showed anaplasia (n = 8; excluded from survival analysis); low risk/completely necrotic (n = 7; zero relapses), intermediate risk (n = 63; six relapses), and high-risk/blastemal type (n=7; five relapses). Conclusion Most patients with stage III FHWT had good EFS/overall survival with DD4A and radiation therapy. Combined lymph node and LOH status was highly predictive of EFS and should be considered as a potential prognostic marker for future trials.

10000 Background: The Children’s Oncology Group (COG) Renal Tumor (RT) Biology and Risk Stratification Protocol incorporates real-time central review to direct risk stratification and enrollment on COG therapeutic studies. We assessed the feasibility of the real-time central review process and its impact on the accuracy of risk stratification. Methods: 3,000 patients were enrolled on AREN03B2 between 2/2006 and 1/2012, with submissions from 214 COG institutions. Eligible diagnoses included any RT and extra-renal Wilms tumor or non-CNS rhabdoid tumor. Enrollment on AREN03B2 was required to enroll on a RT treatment study. Submission of pathology slides, radiology images, operative reports, and tumor and blood for analysis was required within 7 days of surgery to meet enrollment deadlines stipulated by the therapeutic studies. Central pathology review for histology and stage, radiology review for presence of bilateral lesions and pulmonary metastases, and surgical review for operative stage were completed electronically by a panel of expert reviewers. An initial risk assignment (IRA) was made by the study chairs based on the multidisciplinary central reviews. Results: 2,913/3,000 met all eligibility and submission requirements. The median time from enrollment to IRA was 8 days. 1,205 discrepancies between central and institutional review potentially impacting IRAs were observed; including differences in initial histology in 253 unilateral and 69 bilateral tumors, pathologic staging of 294 tumors, diagnostic imaging of 92 bilateral cases and 112 cases of pulmonary metastases, and the surgical review of 244 cases of rupture and 141 instances of node sampling. Conclusions: Real time central review is feasible in a large multi-center study. Discrepancies between local and central risk stratification were identified in a substantial number of participants. Communication of these findings in real time supported increased accuracy of enrollment on appropriate clinical trials and strengthened the comprehensive annotation of a rich RT biorepository. Expansion of this process to other pediatric tumor registry protocols should be strongly considered.

10032 Background: Patients with metastatic diffuse anaplastic histology Wilms tumor (DAWT) had an unacceptably low 4-year event-free survival (EFS) and overall survival of 33% on the National Wilms Tumor Study-5. Preclinical and clinical data showed promising antitumor activity of the camptothecins in Wilms tumor. Methods: AREN0321 evaluated the activity of vincristine (Vinc) and irinotecan (Irino) in a phase 2 window in newly-diagnosed patients with Stage IV DAWT. Patients received Vinc (1.5 mg/m2/day) intravenously (IV) on days 1 and 8, and Irino (20 mg/m2/day) IV on days 1-5 and 8-12 of a 21-day cycle. In the absence of progressive disease (PD), a second cycle was administered. Tumor responses after 2 cycles of therapy were centrally reviewed and assessed using the RECIST criteria. Patients with partial response (PR) had Vinc/Irino incorporated into a chemotherapy regimen consisting of Vinc, doxorubicin, cyclophosphamide, carboplatin, and etoposide, plus local and whole lung radiation therapy. Patients with stable disease or PD did not receive additional cycles of Vinc/Irino. A 2-stage design was used with the aim to accrue 10 patients in the first stage and continue accrual if an adequate number of responses was observed. The window study closed after other strata of AREN0321 reached their accrual targets. Results: Twenty-four patients with stage IV DAWT were enrolled from June 2006 to December 2012. Five patients did not have measurable disease and were ineligible for window therapy. Nineteen had measurable disease, 14 of whom elected to participate in the window. Of these 14 patients, 11 (79%) had PR and 3 had PD. Two of the 3 non-responders also did not achieve complete response to the other agents in the chemotherapy regimen. The most common grade 3-4 toxicities during the window were diarrhea (n=3), hypoxia (n=2), elevation of aspartate aminotransferase (n=2), hypoalbuminemia (n=2), and hyperglycemia (n=2). Conclusions: The Vinc/Irino combination was well tolerated and produced a high response rate in patients with metastatic DAWT. Its incorporation into Wilms tumor treatment regimens deserves further evaluation. Clinical trial information: NCT00335556.