Bilateral Wilms tumor with anaplasia: A report from the Children's Oncology Group Study AREN0534.

INTRODUCTION: The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials. METHODS: Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed. RESULTS: Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7 years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p = .79; HR = 0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18 months. CONCLUSION: Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed.

Corrigendum: Landscape of pediatric cancer treatment refusal and abandonment in the US: a qualitative study.

[This corrects the article DOI: 10.3389/fped.2022.1049661.].

Treatment and outcomes of clear cell sarcoma of the kidney: A report from the Children's Oncology Group studies AREN0321 and AREN03B2.

BACKGROUND: On the fifth National Wilms Tumor Study, treatment for clear cell sarcoma of the kidney (CCSK) included combined vincristine, doxorubicin, cyclophosphamide, and etoposide (regimen I) plus radiation therapy (RT), yielding 5-year event-free survival (EFS) rates of 100%, 88%, 73%, and 29% for patients who had with stage I, II, III, and IV disease, respectively. In the Children's Oncology Group study AREN0321 of risk-adapted therapy, RT was omitted for stage I disease if lymph nodes were sampled, and carboplatin was added for stage IV disease (regimen UH-1). Patients who had stage II/III disease received regimen I with RT. METHODS: Four-year EFS was analyzed for patients enrolled on AREN0321 and on those enrolled on AREN03B2 who received AREN0321 stage-appropriate chemotherapy. RESULTS: Eighty-two patients with CCSK enrolled on AREN0321, 50 enrolled on AREN03B2 only. The 4-year EFS rate was 82.7% (95% confidence interval [CI], 74.8%-91.4%) for AREN0321 and 89.6% (95% CI, 81.3%-98.7%) for AREN03B2 only (p = .28). When combining studies, the 4-year EFS rates for patients who had stage I (n = 10), II (n = 47), III (n = 65), and IV (n = 10) disease were 90% (95% CI, 73.2%-100.0%), 93.4% (95% CI, 86.4%-100.0%), 82.8% (95% CI, 74.1%-92.6%), and 58.3% (95% CI, 34%-100.0%), respectively. There were no local recurrences among seven patients with stage I disease who were treated without RT. One stage I recurrence occurred in the brain, which was the most common site of relapse overall. Among patients with local stage III tumors, neither initial procedure type, margin status, nor lymph node involvement were prognostic. CONCLUSIONS: Patients with stage I CCSK had excellent outcomes without local recurrences when treated without RT. Patients with stage IV disease appeared to benefit from a carboplatin-containing regimen, although their outcomes remained unsatisfactory. Further research is needed to improve outcomes for patients with advanced-stage disease (ClinicalTrials.gov identifiers NCT00335556 and NCT00898365).

Race and Ethnic Group Enrollment and Outcomes for Wilms Tumor: Analysis of the Current Era Children's Oncology Group Study, AREN03B2.

BACKGROUND: To review race and ethnic group enrollment and outcomes for Wilms tumor (WT) across all 4 risk-assigned therapeutic trials from the current era Children's Oncology Group Renal Tumor Biology and Risk Stratification Protocol, AREN03B2. STUDY DESIGN: For patients with WT enrolled in AREN03B2 (2006 to 2019), disease and biologic features, therapeutic study-specific enrollment, and event-free (EFS) and overall (OS) 4-year survival were compared between institutionally reported race and ethnic groups. RESULTS: Among 5,146 patients with WT, no statistically significant differences were detected between race and ethnic groups regarding subsequent risk-assigned therapeutic study enrollment, disease stage, histology, biologic factors, or overall EFS or OS, except the following variables: Black children were older and had larger tumors at enrollment, whereas Hispanic children had lower rates of diffuse anaplasia WT and loss of heterozygosity at 1p. The only significant difference in EFS or OS between race and ethnic groups was observed among the few children treated for diffuse anaplasia WT with regimen UH-1 and -2 on high-risk protocol, AREN0321. On this therapeutic arm only, Black children showed worse EFS (hazard ratio = 3.18) and OS (hazard ratio = 3.42). However, this finding was not replicated for patients treated with regimen UH-1 and -2 under AREN03B2 but not on AREN0321. CONCLUSIONS: Race and ethnic group enrollment appeared constant across AREN03B2 risk-assigned therapeutic trials. EFS and OS on these therapeutic trials when analyzed together were comparable regarding race and ethnicity. Black children may have experienced worse stage-specific survival when treated with regimen UH-1 and -2 on AREN0321, but this survival gap was not confirmed when analyzing additional high-risk AREN03B2 patients.

Treatment of children with favorable histology Wilms tumor with extrapulmonary metastases: A report from the COG studies AREN0533 and AREN03B2 and NWTSG study NWTS-5.

BACKGROUND: Patients with stage IV favorable histology Wilms tumor (FHWT) with extrapulmonary metastases (EPM) constitute a small subset of patients with FHWT. Because of their rarity and heterogeneity, optimal FHWT treatment is not well understood. Children's Oncology Group protocol AREN0533 assigned patients with FHWT and EPM to intensified chemotherapy, regimen M, after initial DD-4A chemotherapy. To improve understanding of prognostic factors and best therapies, experiences of patients with EPM on AREN0533, as well as on protocols AREN03B2 and NWTS-5, were reviewed. METHODS: Combined outcomes for patients with EPM from NWTS-5, AREN0533, and AREN03B2 were determined. Those treated on AREN0533 were compared with those treated on NWTS-5. Prognostic factors were explored in the pooled cohort. RESULTS: Forty-seven patients with FHWT with EPM enrolled on AREN0533, 37 enrolled on NWTS-5, and 64 were followed only on AREN03B2. The pooled cohort of all 148 patients demonstrated a 4-year event-free survival (EFS) of 77.3% (95% CI, 70.8-84.4) and 4-year overall survival of 88.9% (95% CI, 83.9-94.2). Four-year EFS of patients with EPM treated on AREN0533 was 76.0% (95% CI, 64.6-89.4) vs 64.9% (95% CI, 51.7-82.2) on NWTS-5; hazard ratio, 0.64, p = .26; no difference in overall survival was observed. Increasing linear age and slow incomplete lung response were associated with worse EFS in a pooled cohort. CONCLUSIONS: Outcomes for patients with EPM are among the lowest for children with FHWT. Further trials with standardized surgical and radiation treatment to metastatic sites, and prospectively collected biologic and treatment details are needed. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov identifiers: NCT00379340, NCT00898365, and NCT00002611.

Overcoming refusal of treatment in pediatric cancer without legal involvement: A descriptive case series from interviews with pediatric oncologists.

To describe strategies that pediatric oncologists utilize to persuade families to initiate or continue chemotherapy after refusing treatment, we examined transcripts from interviews of oncologists with relevant experience. We identified three cases in which the pediatric oncologists' approaches led to voluntary acceptance of recommended treatment without legal intervention. Strategies used include direct communication with alternative medicine providers, time-limited trial of alternative therapy, and praying with the family. While we cannot conclude whether these approaches could be generalized to other cases, they offer ideas for pediatric oncologists to consider when facing the decision to seek judicial involvement or discontinue persuasive efforts.

Outcomes and Histological Variations of Neuroblastoma and Ganglioneuroblastoma with Paraneoplastic Syndromes.

BACKGROUND: Neuroblastomas are the most common extracranial solid malignancy in children with variable manifestations and complications depending on the presence of paraneoplastic syndromes. MATERIALS AND METHODS: We performed a single institution retrospective cohort study of all patients less than 18 years old diagnosed with neuroblastoma or ganglioneuroblastoma between January 2002 and July 2022. Patients were identified through the pathology and cancer registry and cross-referenced with pediatric records. Patient demographics, clinical presentation, treatment, and outcomes were collected. A univariate descriptive analysis of the collected data was conducted. RESULTS: In our study period, 130 children were diagnosed with neuroblastoma, and 15 were diagnosed with ganglioneuroblastoma. There were 12 children with a paraneoplastic syndrome identified, 8 with NBL and 4 with ganglioneuroblastoma (GNBL). The average age at diagnosis was 22 months. All but 1 underwent resection prior to treatment of paraneoplastic syndrome, and 4 children required neoadjuvant therapy. Neurological complications were the most common with 10 children (83%). The average time from symptom onset to diagnosis was 0.7 months. Eight children had complete resolution of their symptoms after treatment and resection, 2 children recently started treatment within a year, 1 had partial resolution, and 1 died during treatment. The presence of tumor-infiltrating lymphocytes occurred in 4 children with neurologic paraneoplastic syndromes. Six children had neuropil rich tumors. CONCLUSION: The histological profile of paraneoplastic syndromes of neuroblastoma and ganglioneuroblastoma and their treatment across a single institution can be highly variable. The presence of tumor-infiltrating lymphocytes and neuropil may have an impact on paraneoplastic pathology.

Tolerability of ifosfamide-containing regimen in patients with high-risk renal and INI-1-deficient tumors.

BACKGROUND: Outcomes for children with high-risk renal (HRR) and INI-1-deficient (INI-) tumors are unacceptably poor. Concerns about excessive toxicity-as many are infants and/or undergo nephrectomy-have resulted in decreased chemotherapy dosing and omission of the nephrotoxic drug ifosfamide in collaborative group studies. As cause of death for children with these cancers remains overwhelmingly more from progressive disease rather than treatment toxicity, we examined the tolerability of an intensive ifosfamide-containing regimen. PROCEDURE: Retrospective review of children with HRR/INI- tumors treated at a single institution with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, carboplatin, etoposide (VDC-ICE) from 2006-2016. The primary outcome was regimen tolerability, including kidney injury and grade 3-5 nonhematologic toxicities. RESULTS: Fourteen patients with a median age of 1.7 years (range: 0.1-10.5) treated with VDC-ICE were identified. Diagnosis included malignant rhabdoid tumor (n = 9) (primary renal [n = 2]); diffuse anaplastic Wilms tumor (n = 3); clear cell sarcoma of the kidney (n = 1); and anaplastic chordoma (n = 1). All children with primary renal tumors (43%) underwent complete (n = 5) or partial nephrectomy (n = 1) before chemotherapy. Nine (64%) completed all intended cycles of chemotherapy; n = 5 (36%) did not due to disease progression. Unplanned hospitalizations occurred in 13 (93%) patients, most commonly for febrile neutropenia. No patient experienced severe organ toxicity, diminished renal function, treatment discontinuation due to toxicities, or treatment-related death. CONCLUSIONS: In children with HRR/INI- tumors, VDC-ICE chemotherapy was well-tolerated without excessive toxicities, even amongst young patients with solitary kidneys. Concerns about toxicity should not preclude an intensive ifosfamide-containing regimen from use in future trials in this population.

Pediatric renal tumor epidemiology: Global perspectives, progress, and challenges.

Pediatric renal tumors account for 3%-11% of childhood cancers, the most common of which is Wilms tumor or nephroblastoma. Epidemiology plays a key role in cancer prevention and control by describing the distribution of cancer and discovering risk factors for cancer. Large pediatric research consortium trials have led to a clearer understanding of pediatric renal tumors, identification of risk factors, and development of more risk-adapted therapies. These therapies have improved event-free and overall survival for children. However, several challenges remain and not all children have benefited from the improved outcomes. In this article, we review the global epidemiology of pediatric renal tumors, including key consortium and global studies. We identify current knowledge gaps and challenges facing both high and low middle-incomes countries.

The role of ethicists in pediatric hematology/oncology: Current status and future needs.

As pediatric hematology/oncology (PHO) becomes more complex and sub-subspecialized, dedicated PHO ethicists have emerged as sub-subspecialists focused on addressing ethical issues encountered in clinical and research practices. PHO physicians and other clinicians with advanced training in bioethics contribute to the field through ethics research, education, and ethics consultation services. Furthermore, there exists a newer generation of PHO trainees interested in bioethics. This review details the experiences of current PHO ethicists, providing a blueprint for future educational, research and service activities to strengthen the trajectory of the burgeoning sub-subspecialty of PHO ethics. Creating an American Society of Pediatric Hematology/Oncology (ASPHO) ethics Special Interest Group, enhancing clinical ethics education for pediatric hematologists/oncologists (PHOs), developing multi-institutional research collaborations, and increasing attention to ethical issues germane to nonmalignant hematology will serve the interests of the entire field of PHO, enhancing the care of PHO patients and careers of PHOs.

Pediatric renal tumor epidemiology: Global perspectives, progress, and challenges.

Pediatric renal tumors account for 3%-11% of childhood cancers, the most common of which is Wilms tumor or nephroblastoma. Epidemiology plays a key role in cancer prevention and control by describing the distribution of cancer and discovering risk factors for cancer. Large pediatric research consortium trials have led to a clearer understanding of pediatric renal tumors, identification of risk factors, and development of more risk-adapted therapies. These therapies have improved event-free and overall survival for children. However, several challenges remain and not all children have benefited from the improved outcomes. In this article, we review the global epidemiology of pediatric renal tumors, including key consortium and global studies. We identify current knowledge gaps and challenges facing both high and low middle-incomes countries.

Thrombotic Microangiopathy Due to Progressive Disseminated Histoplasmosis in a Child With Down Syndrome and Acute Lymphoblastic Leukemia.

Histoplasmosis, a common mycosis in the south-central United States, may be life threatening in immunocompromised patients. We describe a 4-year-old female with Down syndrome and acute lymphoblastic leukemia who developed hemolytic anemia, thrombocytopenia, and renal failure, consistent with thrombotic microangiopathy. Bone marrow biopsy revealed non-necrotizing granulomas with GMS staining demonstrating budding yeast. Serum Histoplasma antigen testing was positive, providing further evidence for the diagnosis of progressive disseminated histoplasmosis. Treatment with amphotericin B, plasma exchange, and ventilator, vasopressor, and renal replacement support led to a full recovery. Providers should have a low threshold for histoplasmosis testing in ill immunocompromised patients, who are at greater risk for infection-related morbidity.

Oncologic Fidelity of Minimally Invasive Surgery to Resect Neoadjuvant-Treated Wilms Tumors.

BACKGROUND: The Children's Oncology Group recommends upfront resection of Wilms tumor (WT), however, unique scenarios warrant neoadjuvant chemotherapy and delayed resection. We hypothesized that in the context of neoadjuvant chemotherapy, minimally invasive surgery (MIS) to resect WT achieves equivalent oncologic fidelity and better maintains therapy schedules. METHODS: A retrospective analysis of WT treated between 2010-2021 at a free-standing children's hospital was performed. Patient and disease specific characteristics were collected, and pre-resection tumor volumes (TV) were calculated. Impact of MIS or open resection on oncologic fidelity and time to resume chemotherapy was analyzed. RESULTS: For the study period, 62 patients were treated for 65 WT, and 14 patients (22.6%) received neoadjuvant chemotherapy to treat 17 WT (26.2%): 7 Stage I (all predisposition syndromes), 2 stage III, 7 stage IV, and 1 stage V (bilateral). MIS was utilized to resect 6 WT from 5 patients. For partial nephrectomy, pre-resection TV was 0.38 ml if MIS and 10.38 ml if open (P = .025). For radical nephrectomy, pre-resection TV was 31.58 ml if MIS and 175.00 ml if open (P = .101). No significant differences between surgical approach were detected regarding pathologic variables or survival. Epidural use was significantly greater with open procedures (P = .001). Length of stay was 2.00 days after MIS compared to 6.00 for open resection (P = .004). Time to resume chemotherapy was 7.00 days after MIS versus 27.00 for open (P = .004). CONCLUSION: After neoadjuvant chemotherapy for WT, MIS partial and radical nephrectomies achieved equivalent oncologic fidelity, reduced epidural use and post-operative stays, and better maintained adjuvant therapy timelines when compared to open resections.

Waitlist mortality and post-liver transplant outcomes of pediatric patients with hepatocellular carcinoma and hepatoblastoma in the United States.

BACKGROUND: Liver transplantation (LT) is offered in cases of advanced disease for both pediatric patients with hepatoblastoma (HBL) and those with hepatocellular carcinoma (HCC). Current United States organ allocation priorities differ between the two groups. METHODS: We retrospectively examined the waitlist and posttransplant outcomes of pediatric LT candidates with HBL and HCC using the United Network for Organ Sharing registry (February 2002 to September 2020). RESULTS: Six hundred sixty-eight children with HBL and 95 children with HCC listed for first LT were identified. Patients with HBL were younger (p < .001), had lower laboratory Model for End-stage Liver Disease (MELD)/Pediatric End-stage Liver Disease (PELD) scores (p < .001), and had lesser proportion with encephalopathy (p = .01). Patients with HCC had an increased risk of waitlist mortality in univariable (unadjusted subdistribution hazard ratio [sHR] = 4.37, 95% confidence interval [CI], 2.01-9.51, p < .001) and multivariable competing risk regression (adjusted sHR = 3.08, 95% CI 1.13-8.37, p = .03) accounting for age and laboratory MELD/PELD score. Five hundred ninety-five children underwent LT for HBL and 76 for HCC. Patients transplanted for HBL had a significantly higher proportion with status 1B exception (71.3% vs. 7.9%, p < .001). No difference was observed in patient (unadjusted log-rank test, p = .52; adjusted hazard ratio [HR] = 0.77, 95% CI, 0.40-1.48, p = .43) or graft survival (unadjusted log-rank test, p = .93; adjusted HR = 0.74, 95% CI 0.42-1.33, p = .32) between HCC and HBL recipients. CONCLUSION: Waitlist mortality for pediatric LT candidates with HCC is significantly higher than for HBL, while posttransplant patient and graft survival are similar. This highlights an opportunity to improve equitable prioritization for children with HCC who may have reduced access to size-appropriate deceased donor organs and less effective bridge-to-transplant therapies.

Landscape of pediatric cancer treatment refusal and abandonment in the US: A qualitative study.

Objective: To describe United States (US) pediatric oncologists' experiences with treatment refusal or abandonment, exploring types and frequency of decision-making conflicts, and their impact. Study design: We conducted exploratory qualitative interviews of pediatric oncologists (n = 30) with experience caring for a pediatric patient who refused or abandoned curative treatment. Interviewees were recruited using convenience and nominated expert sampling, soliciting experiences from diverse geographic locations and institution sizes across the US. We analyzed transcripts using applied thematic analysis to identify and refine meaningful domains. Results: Many oncologists reported multiple experiences with refusal and abandonment. Most anticipated case frequency would increase due to misinformation, particularly on the internet. Interviewees described cases of treatment refusal and abandonment, but also a wider variety of cases than previously described in existing publications, including cases involving: non-adherence; negotiations for different treatments; negotiations for complementary and alternative medicine; delayed treatment initiation; and refusal of a component of recommended therapy. Cases often involved multiple stages or types of conflicts. Recurring patient/family behaviors emerged: clear opposition to treatment from the outset; hesitancy about treatment despite initiating therapy; and psychosocial circumstances becoming an obstacle to treatment completion. Oncologists revealed substantial professional and personal repercussions of these cases. Conclusion: Oncologist interviews highlight a broad range of conflicts, yielding a taxonomy of treatment refusal, non-adherence and abandonment (TRNA) that accounts for the heterogeneity of situations described. Cases' complexity and interrelatedness points to a functional model of TRNA that includes families' behaviors. This preliminary taxonomy and model warrant further research and examination to refine the model and generate strategies to prevent and mitigate TRNA.

Second Report of PDE10A-BRAF Fusion in Pediatric Spindle Cell Sarcoma With Infantile Fibrosarcoma-Like Morphology Suggesting PDE10A-BRAF Fusion Is a Recurrent Event.

Infantile/congenital fibrosarcoma (IFS) is the most common soft tissue tumor in children less than one year of age. The most common anatomic site of IFS is in the extremities or trunk, and rarely in the abdomen or retroperitoneum. Approximately 70-90% of cases are characterized by a distinct t(12;15)(p13;q25) translocation resulting in an ETV6-NTRK3 gene fusion. As such, TRK inhibitors are considered frontline therapy in TRK-fusion positive IFS. The ETV6-NTRK3 fusion is also detected in congenital mesoblastic nephroma (CMN) and less frequently in myeloid leukemias, secretory breast carcinoma, and mammary-type secretory carcinoma of the skin and salivary glands. Infrequently, cases of tumors with IFS-like morphology without the characteristic ETV6-NTRK3 gene fusion have been identified. Herein, an ETV6-NTRK3 fusion negative spindle cell sarcoma with IFS-like morphology subjected to genomic profiling revealed a PDE10A-BRAF fusion, a fusion event that has been detected previously in an isolated case of undifferentiated infantile sarcoma.

Ethical Challenges in Pediatric Oncology Care and Clinical Trials.

The care of pediatric cancer patients is a vast departure from cancer care of adults. While the available treatment modalities-chemotherapy, radiation, and surgery-are the same, the diseases, care-delivery, and outcomes differ greatly. And just as 'children are not just little adults,' pediatric bioethics occupies a distinct place within the broader field of bioethics. In this chapter, we will begin with an introduction to fundamental principles and frameworks for understanding ethical issues in pediatrics, highlighting the triadic nature of medical decision-making between a physician, the child-patient, and the child's parent as the surrogate decision-maker. We will then delve into further details of how these principles and frameworks shape the care of children with cancer, examining specific ethical challenges commonly encountered by pediatric oncologists. We will traverse this landscape by examining issues involving (a) informed consent; (b) research involving children; (c) end of life; (d) genetic and genomic testing; and (e) professionalism. We also examine ethical challenges in clinical research, in children and more broadly. While not an exhaustive exploration of the myriad ethical issues one might encounter in pediatric cancer medicine and clinical trials, this chapter provides readers with a foundation for further reading.