Genomic sequencing research in pediatric cancer care: Decision making, attitudes, and perceived utility among adolescents and young adults and their parents.

PURPOSE: Professional guidelines recommend engaging adolescents and young adults (AYAs) in medical decision making (DM), including whether to undergo genomic sequencing (GS). We explored DM around GS and attitudes after return of GS results among a diverse group of AYAs with cancer and their parents. METHODS: We surveyed AYAs with cancer (n = 75) and their parents (n = 52) 6 months after receiving GS results through the Texas KidsCanSeq study. We analyzed AYAs' DM role in GS research enrollment and their satisfaction with that role. We compared AYAs' and parents' self-reported understanding of, attitudes toward, and perceived utility of the AYA's GS results. RESULTS: Most AYAs reported equally sharing DM with their parents (55%) or leading DM (36%) about GS research. Compared with their cancer care DM role, 56% of AYAs reported the same level of involvement in GS research DM, whereas 32% were more involved, and 13% were less involved (P = .011). AYAs were satisfied (99%) with their DM role regarding GS study participation. AYAs and parents had similar self-reported understanding of, attitudes toward, and perceived utility of the GS results. CONCLUSION: Our results support engaging AYAs in DM about GS research and provide insights into AYAs' DM preferences and positive attitudes toward GS.

Adolescent and Young Adult (AYA) Oncology, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on considerations for the comprehensive care of AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.

Treatment outcomes of extraskeletal Ewing sarcoma.

PURPOSE: Extraskeletal Ewing sarcoma (EES), is a rare soft tissue sarcoma. Treatment for EES commonly involves chemotherapy and surgical resection (ST) or less commonly combined chemotherapy, surgery, and radiotherapy (ST + RT). The purpose of the current study was to evaluate our institutional experience treating EES. METHODS: We reviewed 36 (18 males:18 females) patients (mean age 30 years) with a nonretroperitoneal/visceral EES treated with either ST (n = 24, 67%) or ST + RT (n = 12, 33%). All patients were treated with chemotherapy, most commonly vincristine, doxorubicin, cyclophosphamide/ifosfamide and etoposide (VDC/IE, n = 23, 66%) Radiotherapy was mostly delivered preoperatively (n = 9). The mean follow-up was 8 years. RESULTS: The 10-year disease specific survival for patients was 78%, with no difference in the survival between patients in the ST versus the ST + RT groups (83% vs. 71%, p = 0.86). There was no difference in the 10-year local recurrence (91% vs. 100%, p = 0.29) or metastatic free survival (87% vs. 75%, p = 0.45) between the ST and ST + RT groups. CONCLUSION: The results of the current study highlight the ability to achieve excellent local control with chemotherapy and surgery for EES. We recommend for multidisciplinary management of patients with EES, including chemotherapy and surgery, with use of radiotherapy if there is concern for a potentially close margin of resection.

An update on rhabdomyosarcoma risk stratification and the rationale for current and future Children's Oncology Group clinical trials.

Children and adolescents with rhabdomyosarcoma (RMS) comprise a heterogeneous population with variable overall survival rates ranging between approximately 6% and 100% depending on defined risk factors. Although the risk stratification of patients has been refined across five decades of collaborative group studies, molecular prognostic biomarkers beyond FOXO1 fusion status have yet to be incorporated prospectively in upfront risk-based therapy assignments. This review describes the evolution of risk-based therapy and the current risk stratification, defines a new risk stratification incorporating novel biomarkers, and provides the rationale for the current and upcoming Children's Oncology Group RMS studies.

The Best Pharmaceuticals for Children Act and Pediatric Research Equity Act reach the age of majority-An oncology perspective.

The scarcity of adequate pediatric drug labeling information has long been problematic in the pediatric population, which may place children at risk for adverse drug effects. The ontogeny of infants, children, and adolescents over the course of the first two decades of life pose complex pharmacokinetic, dosing, administration, effectiveness, and toxicity-related questions that require specific investigation. Here, we review the history that led to the passage of the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA), and provide commentary on issues relevant to pediatric oncology now and in the future.

Primary Renal Ewing Sarcoma in Children and Young Adults.

The Ewing sarcoma family of tumors (ESFT) are high-grade small round blue cell malignancies traditionally presenting in children and adolescents. The most common site of primary disease is bone, though extraskeletal primary sites are well-recognized. We present 6 cases of primary ESFT of the kidney and 1 case of the adrenal gland. Patients were 11 to 18 years of age at diagnosis. Metastases at diagnosis were present in most cases (n=6). All patients underwent surgery, and most received radiation (n=5). Five patients relapsed after initial remission. Comprehensive review of the primary renal ESFT literature was used to analyze various factors, including age, sex, disease metrics, metastases at diagnoses, and overall survival in a total of 362 cases. Notably, while the general ESFT population has reported rates of metastasis at diagnosis of 20% to 25%, this rate in the renal ESFT population was 53% with a rate of 59% in adolescent and young-adult patients (11 to 24 y). Nodal disease at diagnosis was present in 24% of renal ESFT cases compared with 3.2% in patients with primary skeletal ESFT. While this malignant process may share histologic and molecular features with its bone and soft tissue counterparts, primary renal ESFT presentations seem to be more aggressive and have worse outcomes.

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group.

Patients who are diagnosed with osteosarcoma (OS) today receive the same therapy that patients have received over the last 4 decades. Extensive efforts to identify more effective or less toxic regimens have proved disappointing. As we enter a postgenomic era in which we now recognize OS not as a cancer of mutations but as one defined by p53 loss, chromosomal complexity, copy number alteration, and profound heterogeneity, emerging threads of discovery leave many hopeful that an improving understanding of biology will drive discoveries that improve clinical care. Under the organization of the Bone Tumor Biology Committee of the Children's Oncology Group, a team of clinicians and scientists sought to define the state of the science and to identify questions that, if answered, have the greatest potential to drive fundamental clinical advances. Having discussed these questions in a series of meetings, each led by invited experts, we distilled these conversations into a series of seven Provocative Questions. These include questions about the molecular events that trigger oncogenesis, the genomic and epigenomic drivers of disease, the biology of lung metastasis, research models that best predict clinical outcomes, and processes for translating findings into clinical trials. Here, we briefly present each Provocative Question, review the current scientific evidence, note the immediate opportunities, and speculate on the impact that answered questions might have on the field. We do so with an intent to provide a framework around which investigators can build programs and collaborations to tackle the hardest problems and to establish research priorities for those developing policies and providing funding.

Generation of patient-derived tumor xenografts from percutaneous tumor biopsies in children with bone sarcomas.

One of the limitations of performing percutaneous biopsies in patients with bone sarcomas is the small amount of tumor that can be obtained for research purposes. Here, we describe our experience developing patient-derived tumor xenografts (PDXs) using percutaneous tumor biopsies in children with bone sarcomas. We generated 14 bone sarcoma PDXs from percutaneous tumor biopsies. We also developed eight bone sarcoma PDXs from surgical resection of primary bone tumors and pulmonary metastases. A multidisciplinary team approach was critical to establish an accurate diagnosis and to provide adequate tumor samples for PDX generation.

Local therapy to distant metastatic sites in stage IV rhabdomyosarcoma.

PURPOSE: To determine the impact of surgery and/or radiation therapy on distant metastatic sites (DMS) in children with stage IV rhabdomyosarcoma (RMS). METHODS: A retrospective chart review was conducted on all patients with stage IV RMS at Texas Children's Hospital from 1992 to 2012. Data analyzed included age, gender, primary site, histologic subtype, number and sites of metastases, treatment including local therapy to DMS, and Oberlin score. RESULTS: The 5-year progression-free survival (PFS) and overall survival (OS) rates were 20% and 25%. The 5-year PFS in patients receiving local therapy to all DMS (n = 16) and to less than all DMS (n = 19) was 31.3% versus 0% (P = 0.002), whereas the 5-year OS was 37.3% versus 0% (P < 0.001), respectively. The 5-year PFS in patients with isolated lung metastasis versus other types of metastasis was 29% versus 7% (P = n.s.), whereas the 5-year OS was 43% versus 10% (P = 0.01). The 5-year pulmonary local control was improved by the use of whole lung irradiation (WLI; 56% vs. 10%, P = 0.03). CONCLUSIONS: Local treatment to all metastatic sites was associated with improved PFS and OS at 5 years. The use of WLI improved pulmonary control in patients with lung metastasis. We recommend an aggressive approach including local therapy to DMS in children with stage IV RMS.

miR-130b directly targets ARHGAP1 to drive activation of a metastatic CDC42-PAK1-AP1 positive feedback loop in Ewing sarcoma.

Ewing Sarcoma (ES) is a highly aggressive bone tumor with peak incidence in the adolescent population. It has a high propensity to metastasize, which is associated with dismal survival rates of approximately 25%. To further understand mechanisms of metastasis we investigated microRNA regulatory networks in ES. Our studies focused on miR-130b due to our analysis that enhanced expression of this microRNA has clinical relevance in multiple sarcomas, including ES. Our studies provide insights into a novel positive feedback network involving the direct regulation of miR-130b and activation of downstream signaling events contributing toward sarcoma metastasis. Specifically, we demonstrated miR-130b induces proliferation, invasion, and migration in vitro and increased metastatic potential in vivo. Using microarray analysis of ES cells with differential miR-130b expression we identified alterations in downstream signaling cascades including activation of the CDC42 pathway. We identified ARHGAP1, which is a negative regulator of CDC42, as a novel, direct target of miR-130b. In turn, downstream activation of PAK1 activated the JNK and AP-1 cascades and downstream transcriptional targets including IL-8, MMP1 and CCND1. Furthermore, chromatin immunoprecipitation of endogenous AP-1 in ES cells demonstrated direct binding to an upstream consensus binding site within the miR-130b promoter. Finally, small molecule inhibition of PAK1 blocked miR-130b activation of JNK and downstream AP-1 target genes, including primary miR-130b transcripts, and miR-130b oncogenic properties, thus identifying PAK1 as a novel therapeutic target for ES. Taken together, our findings identify and characterize a novel, targetable miR-130b regulatory network that promotes ES metastasis.

Coamplification of Myc/Pvt1 and homozygous deletion of Nlrp1 locus are frequent genetics changes in mouse osteosarcoma.

Osteosarcomas (OSs) are characterized by high levels of genomic instability (GI). To gain insights into the GI and its contribution toward understanding the genetic basis of OS, we characterized 19 primary and 13 metastatic mouse tumors in a genetically engineered novel mouse model of OS by a combination of genomic techniques. Through the bone-specific deletion of the wild-type Trp53 locus or activation of a metastatic-promoting missense R172Hp53 allele, C57BL/6 mice developed either localized or metastatic OS. Subsequent tumors were isolated and primary cultures created from primary bone and/or distal metastatic lesions, for example, lung and liver. These tumors exhibited high levels of GI with complex chromosomal rearrangements, amplifications, and deletions comparable to human OS. The combined genomic approaches identified frequent amplification of chromosome 15D1 and loss of 11B4 by CGH and/or SKY. Both 15D1 and 11B4 have homology with frequently altered chromosomal bands 8q24 and 17p13 in human OS, respectively. Subsequent array CGH, FISH, and qRT-PCR analysis identified coamplification and overexpression of Myc/Pvt1 transcripts from the 15D1 amplicon and loss and decreased expression of the Nlrp1b from 11B4. The Nlrp1 gene is the key mediator of apoptosis and interacts strongly with caspase 2.

An unusual case of metastatic trophoblastic neoplasm presenting with diffuse cystic lung disease and pulmonary artery pseudoaneurysms in a teenager.

Diffuse cystic lung diseases (DCLDs) are a diverse group of lung disorders characterized by the presence of multiple air filled cysts within the lung tissue. These cysts are thin walled and surrounded by normal lung tissue. In adults, DCLD can be associated with various conditions such as lymphangioleiomyomatosis (LAM), Langerhans cell histiocytosis, cancers, and more. In children, DCLD is often linked to lung developmental abnormalities, with bronchopulmonary dysplasia being a common cause. Patients with pulmonary cysts are typically asymptomatic, but some may experience mild symptoms or pneumothorax. While DCLD in children is rarely due to malignancy, metastatic lung disease can be a cause. It is important for clinicians to be aware of the possibility of metastatic lung disease when encountering DCLD.

Factors Associated With Long-term Survival in Children With Bronchial and Lung Carcinoid Tumors.

BACKGROUND AND AIMS: Bronchial carcinoids are rare in children and the treatment is based on tumor behavior in adults. The purpose of this study was to determine factors and management strategies associated with long-term survival in the pediatric population using a national cohort. METHODS: Patients aged ≤20 years with bronchial carcinoid tumors were identified in the 2004-2020 National Cancer Database using ICD-O-3 codes. Tumor characteristics and management were compared among typical (TC) and atypical (AC) histological subtypes using Chi-square and Fisher's exact tests. Kaplan-Meier and univariate Cox proportional hazards analyses were used to assess survival. RESULTS: Of 273 patients, 251 (92%) had TCs, and 22(8%) had ACs. The median (IQR) age was 18 (16,19) years. Most patients underwent lobectomy or bilobectomy (67%), followed by sublobar resection (17%), no resection or bronchoscopic excision or ablation (8%), and pneumonectomy (7.7%). Margins were negative in 96%. Lymph node (LN) assessment was performed in 216 patients (84%) with a median (IQR) of 7(3,13) LNs, and 50 (23%) had ≥1 positive LN. There was no difference in age, resection, margin status, LN assessment, or positivity between TC and AC (all p > 00.05). Detection of nodal metastasis did not increase beyond the resection of 1-3 LNs (p = 0.72). Ten-year survival was worse for AC than TC (79% (41, 100) vs 98% (95, 100), HR = 6.9 (95% CI: 1.2-38.3, p = 0.03). Ten-year survival among those with and without LN assessment was 97% (94, 100) vs 91% (81, 100), HR = 4.0, 95% CI: 0.8-19.9, p = 0.09). There were no deaths in those with negative LN while 10-year survival was 89% (72, 100) in those with ≥1 positive LN. CONCLUSION: Among children with bronchial carcinoids, survival is excellent with TC or negative LN. Atypical histology and positive LN have poor survival and should prompt close monitoring. These risk factors may be missed in the absence of surgical resection and lymph node sampling. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Retrospective Study.

Ovarian non-gestational placental site trophoblastic tumor with lung metastasis: further evidence for a distinct category of trophoblastic neoplasm.

We previously described a series of cases which characterize a distinct group of primary ovarian placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) as a non-gestational set consistent with germ cell type/origin. Here we report a new case of ovarian non-gestational PSTT. The patient was a 13 year-old young female admitted for a spontaneous pneumothorax of the left lung. The pathology of lung wedge excision specimen demonstrated metastatic PSTT and ovarian biopsy showed atypical intermediate trophoblastic proliferation which was found to be PSTT in the subsequent salpingo-oophorectomy specimen. In the ovary, the tumor was composed of singly dispersed or small clusters of predominantly mononuclear cells and rare multinucleated cells extensively infiltrating the ovarian parenchyma, tubal mucosa, and paraovarian/paratubal soft tissue. A minor component of mature cystic teratoma (less than 5% of total tumor volume) was present. Immunohistochemically, the neoplastic cells of main tumor were diffusely immunoreactive for hPL, Gata3 and AE1/AE3, and had only rare hCG-positive or p63-positive cells. The morphology and immunohistochemical results support a PSTT. Molecular genotyping revealed an identical genotype pattern between the normal lung tissue and the metastatic PSTT, indicating its non-gestational nature of germ cell type/origin. This case represents the first case of such tumor with distant (lung) metastasis. This case also provides further evidence to support our recommendation that primary ovarian non-gestational intermediate trophoblastic tumors of germ cell type/origin, including PSTT and ETT, should be formally recognized in classification systems.

Leuprolide Protects Ovarian Reserve in Adolescents Undergoing Gonadotoxic Therapy.

Purpose: Treatment sequelae compromising reproductive health are highly prevalent in childhood cancer survivors, and a main determinant of health and quality of life. Follicular reserve determines ovarian function life span; thus, its preservation is important in the care of female survivors. Anti-Müllerian hormone (AMH) is a biomarker to measure functional ovarian reserve. We aimed to evaluate the effect of leuprolide during gonadotoxic therapy on pubertal females' post-treatment functional ovarian reserve using AMH levels. Methods: We conducted a single-center retrospective study including all pubertal females who had undergone gonadotoxic treatments between January 2010 and April 2020, and had an AMH level after completion of therapy. We used multivariable linear regressions to compare AMH-level beta coefficients in patients stratified by gonadotoxic risk, adjusting for leuprolide use. Results: Fifty-two females meeting study eligibility were included, of which 35 received leuprolide. The use of leuprolide was associated with higher post-treatment AMH levels in the lower gonadotoxic risk group (beta 2.74, 95% CI 0.97-4.51; p = 0.004). This association was lost in the higher gonadotoxic risk groups. Conclusions: Leuprolide may have a protective effect on the functional ovarian reserve. However, this is limited by increasing treatment gonadotoxicity. Larger, prospective studies are needed to elucidate the potential benefits of gonadotropin-releasing hormone agonist on preservation of ovarian reserve among children receiving gonadotoxic therapies, as cancer survivors.

Vincristine-Induced Acrocyanosis and Erythema Pernio.

INTRODUCTION: Acrocyanosis and erythema pernio are 2 dermatologic manifestations of vasospastic changes. Primary care providers should consider that these conditions can occur as primary or idiopathic conditions and as secondary conditions related to another disease or medication. Herein we describe a case of acrocyanosis and erythema pernio attributed to vincristine therapy. CASE DESCRIPTION: A 22-year-old man was evaluated for discomfort and red lesions involving the toes of both feet for several weeks. He had completed chemotherapy 1 month earlier for Ewing sarcoma in the right femur. Local control for the primary tumor included wide local excision and reconstruction with a vascularized fibular allograft from the right fibula. On examination, his right foot was dark blue and cool. Toes on both feet had nonpainful erythematous papules. After the case was discussed with the patient's oncology team, the diagnosis was medication-induced acrocyanosis of the right foot and bilateral erythema pernio. Treatment consisted of supportive care to keep the feet warm and promote circulation to the feet. At 2-week follow-up, the patient's symptoms and the appearance of his feet had markedly improved. DISCUSSION: Primary care clinicians should be able to recognize dermatologic manifestations of vasospastic changes, including acrocyanosis and erythema pernio, and rule out possible secondary causes, such as pharmacologic agents. This patient's history of therapy for Ewing sarcoma prompted consideration of medication-induced vasospastic changes most likely related to the adverse vasospastic effects of vincristine. Symptoms should improve with cessation of the offending medication.

Alveolar rhabdomyosarcoma has superior response rates to vinorelbine compared to embryonal rhabdomyosarcoma in patients with relapsed/refractory disease: A meta-analysis.

BACKGROUND: Patients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide. AIMS: The goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination. MATERIALS & METHODS: Five Phase 2 trials that enrolled RMS patients were included in the meta-analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose oral cyclophosphamide, and one study evaluated vinorelbine and intravenous cyclophosphamide in combination with temsirolimus or bevacizumab. All RMS patients had relapsed or refractory disease and had received at least one prior therapy. Response was reported according to RECIST1.1 and was defined as a complete or partial response. Response data was obtained from published results or from trial principal investigator. RMS NOS patients were grouped with ERMS patients for this analysis. Summary estimates comparing differences between ARMS and ERMS response rates were generated using a random-effects model to account for heterogeneity among the studies. RESULTS: One hundred fifty-six enrolled patients evaluable for response were included in the meta-analysis, 85 ARMS, 64 ERMS and 7 RMS-NOS. The combined effect generated from the random-effects model demonstrated a 41% increase (p = 0.001, 95% CI; 0.21-0.60) in response to vinorelbine as a single agent or in combination in patients with ARMS compared to patients with ERMS. There was no significant difference in the rate of progressive disease between patients with ARMS compared to ERMS (p = 0.1, 95%CI; -0.26-0.02). DISCUSSION: Vinorelbine is an active agent for the treatment of relapsed or refractory RMS and a meta-analysis of Phase 2 studies shows that radiographic responses in patients with ARMS were significantly higher than ERMS or RMS-NOS. CONCLUSION: These data support further investigation of vinorelbine in newly diagnosed patients with RMS particularly those with alveolar histology.