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) six 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 AYAs' GS results. RESULTS: Most AYAs reported equally sharing DM with their parents (55%) or leading DM (36%) about GS research. Compared to their cancer care DM role, 56% of AYAs reported the same level of involvement in GS research DM while 32% were more involved and 13% were less involved (p=0.011). 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.

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.

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.

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.

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.

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.

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.

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.

Views of Adolescents and Young Adults with Cancer and Their Oncologists Toward Patients' Participation in Genomic Research.

Purpose: With increased use of genomic testing in cancer research and clinical care, it is important to understand the perspectives and decision-making preferences of adolescents and young adults (AYAs) with cancer and their treating oncologists. Methods: We conducted an interview substudy of the BASIC3 Study, which enrolled newly diagnosed cancer patients <18 years of age with assent. Of 32 young adults (YAs) with cancer who reached the age of majority (AOM; 18 years) while on study, 12 were successfully approached and all consented to study continuation at AOM. Of those, seven completed an interview. Patients' oncologists, who enrolled and participated in return of clinical genomic results, were also interviewed (n = 12). Interviews were transcribed, deidentified, and analyzed using thematic analysis. Results: YAs cited the possibility of helping others and advancing science as major reasons for their assent to initial study enrollment and their willingness to consent at AOM. YAs thought obtaining informed consent from research participants for study continuation at AOM was a good idea in case they changed their minds or wanted to make their own decisions, and to keep them aware of study activities. There was diversity in what YAs understood and learned from genomic testing: some recalled specific findings, while some remembered minimal information about their results. Oncologists varied in their assessment of adolescents' engagement with the study and understanding of their results. Conclusion: Given the different ways AYAs engage with genomic information, careful assessment of AYAs' diverse communication and decision-making preferences is needed to tailor interactions accordingly.

Proton Whole-Lung Irradiation: Initial Report of Outcomes.

PURPOSE: Whole-lung irradiation is typically used in pediatric patients to decrease the risk of future lung metastases, but radiation dose to normal tissue is associated with long-term risks. Proton whole-lung irradiation (PWLI) provides an opportunity to decrease radiation dose to normal tissue and potentially decrease late toxicity. METHODS AND MATERIALS: This retrospective study included patients treated with spot-scanning PWLI at a single institution. Toxicity and oncologic outcomes were reviewed. Intensity modulated radiation therapy (IMRT) plans were created prospectively or retrospectively for dosimetric comparisons. Simple paired t tests were performed to assess differences between IMRT and PWLI dosimetric parameters. RESULTS: Twelve patients treated with PWLI were included in this study. Median age was 15 years (range, 3-34). Most (75%) had Ewing sarcoma. Most (92%) received 15 Gy in 10 fractions PWLI, and 3 (25%) received a focal pulmonary boost. Median follow-up was 16.5 months (range, 0-40.4 months). At last follow-up, 1 patient died of disease, while 11 were still alive (7 without disease, 4 with ongoing disease). During and immediately after treatment, 5 patients developed fatigue, 2 patients developed cough, and 1 patient developed nausea. Each treatment-related adverse event was Common Terminology Criteria for Adverse Events (version 5.0) grade 1 and resolved within 3 weeks of treatment completion. No patients have experienced clinical or radiographic pneumonitis or evidence of clinically apparent cardiac toxicity. Compared with IMRT plans, PWLI decreased mean dose to the heart, coronary artery, cardiac valve, left ventricle, aorta, breast, esophagus, kidney, liver, pancreas, thyroid, stomach, and spleen (all P < .001), without sacrificing target coverage. CONCLUSIONS: PWLI is feasible to deliver, decreases dose to normal tissue compared with IMRT, and appears to be well-tolerated. PWLI provides potential for decreased late toxicity and merits further investigation.

Cellular variant of kaposiform lymphangiomatosis: a report of three cases, expanding the morphologic and molecular genetic spectrum of this rare entity.

Kaposiform lymphangiomatosis (KLA) is a very rare form of generalized lymphatic anomaly, consisting of a diffuse proliferation of abnormal, dilated lymphatics, and small fascicles of hemosiderin-laden spindled lymphatic endothelial cells. KLA occurs in children and young adults and may present with multicentric disease, pleural and pericardial effusions, and life-threatening coagulopathy. Genetically, KLA most often harbors somatic activating mutations in NRAS. We recently encountered 3 cases of KLA with cellular features, resembling kaposiform hemangioendothelioma (KHE), and studied their clinicopathologic, radiologic, and molecular genetic features. The patients (1 male, 2 females; aged 2 years, 2 months, 4 years) presented with multicentric disease involving skin, soft tissue, bone, and spleen and thrombocytopenia/coagulopathy. Advanced imaging studies confirmed multicentric disease. Biopsies (skin, soft tissue, bone, and spleen) demonstrated both conventional KLA and much more cellular foci, consisting of sheets, nodules, glomeruloid structures, and sieve-like arrays of lymphatic endothelial cells (positive for CD31 and D2-40). Cellular areas superficially resembled KHE but displayed more epithelioid cytology and lacked surrounding hyaline fibrosis and minute platelet aggregates. Molecular genetic studies demonstrated NRAS c.181C > A p.Q61K (Gln61Lys) in 2 specimens from one patient and HRAS p.A59_Q61delinsGGSIL in another. Two patients were treated with sirolimus; all are currently alive with stable disease. We conclude that cellular morphology in KLA, a previously undescribed feature, does not appear to be associated with clinical features, site of disease, mutation type, response to sirolimus, or outcome. Although cellular KLA may mimic KHE, there are sufficient clinical, morphologic, and genetic differences such that these are likely unrelated diseases.

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.

Identified Enrollment Challenges of Adolescent and Young Adult Patients on the Nonchemotherapy Arm of Children's Oncology Group Study ARST1321.

ARST1321, a trial of patients with advanced soft tissue sarcoma, was the first National Clinical Trials Network study codeveloped by pediatric and adult consortia with two treatment cohorts. We report on the findings of a survey to identify barriers to enrolling adolescent and young adult patients (15-39 years) onto the nonchemotherapy arm. The survey response rate was 31% with a 70% completion rate. Common identified reasons for low accrual in order of decreasing frequency included insufficient funding, lack of study awareness or interest, competing trials, toxicity concerns, philosophical differences in the therapy backbone, and regulatory and infrastructure barriers. Clinical Trials.gov ID: NCT02180867.

Women Oncologists' Perceptions and Factors Associated With Decisions to Pursue Academic vs Nonacademic Careers in Oncology.

Importance: Women outnumber men in US medical school enrollment, but they represent less than 40% of academic oncology faculty. Objective: To identify the key factors associated with female oncologists' decision to pursue academic or nonacademic oncology practice and to characterize their perceptions about their current career. Design, Setting, and Participants: This cross-sectional survey study was distributed through email and social media to female physicians in academic and nonacademic oncology practice in the United States. The survey was open for 3 months, from August 1 to October 31, 2020. Main Outcomes and Measures: No single primary study outcome was established because of the cross-sectional nature of the survey. Data were collected anonymously and analyzed using t tests for continuous variables and χ2 tests for categorical variables. Results: Among the 667 female respondents, 422 (63.2%) identified as academic oncologists and 245 (36.8%) identified as nonacademic oncologists. Approximately 25% of respondents reported that their spouse or partner (156 [23.5%]) and/or family (176 [26.4%]) extremely or moderately affected their decision to pursue academic practice. Academic oncologists perceived the biggest sacrifice of pursuing academics to be time with loved ones (181 [42.9%]). Nonacademic oncologists perceived the biggest sacrifice of pursuing academics to be pressure for academic promotion (102 [41.6%]). Respondents had different perceptions of how their gender affected their ability to obtain a chosen job, with 116 academic oncologists (27.6%) and 101 nonacademic oncologists (41.2%) reporting a positive or somewhat positive impact (P = .001). More than half of the women surveyed (54.6% academic oncologists [230]; 50.6% nonacademic oncologists [123]; P = .61) believed they were less likely to be promoted compared with male colleagues. Academic and nonacademic oncologists reported rarely or never having a sense of belonging in their work environment (33 [7.9%] and 5 [2.0%]; P < .001). Most respondents reported that they would choose the same career path again (301 academic oncologists [71.3%]; 168 nonacademic oncologists [68.6%]); however, 92 academic oncologists (21.9%) reported they were likely to pursue a career outside of academic oncology in the next 5 years. Conclusions and Relevance: This survey study found that a spouse or partner and/or family were factors in the career choice of both academic and nonacademic oncologists and that female gender was largely perceived to adversely affect job promotion. Given that more than 20% of female academic oncologists were considering leaving academia, gender inequality is at high risk of continuing if the culture is not addressed.

Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children's Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force.

Rhabdomyosarcoma is the most common soft tissue sarcoma diagnosed in children and adolescents. Patients that are diagnosed with advanced or relapsed disease have exceptionally poor outcomes. The Children's Oncology Group (COG) convened a rhabdomyosarcoma new agent task force in 2020 to systematically evaluate novel agents for inclusion in phase 2 or phase 3 clinical trials for patients diagnosed with rhabdomyosarcoma, following a similar effort for Ewing sarcoma. The task force was comprised of clinicians and basic scientists who collectively identified new agents for evaluation and prioritization in clinical trial testing. Here, we report the work of the task force including the framework upon which the decisions were rendered and review the top classes of agents that were discussed. Representative agents include poly-ADP-ribose polymerase (PARP) inhibitors in combination with cytotoxic agents, mitogen-activated protein kinase (MEK) inhibitors in combination with type 1 insulin-like growth factor receptor (IGFR1) inhibitors, histone deacetylase (HDAC) inhibitors, and novel cytotoxic agents.

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.

Availability of Fertility Preservation Information on the Websites of U.S. News and World Report Top-Ranked Pediatric Cancer Programs.

Purpose: To evaluate the availability of fertility preservation (FP) services and educational resources on the websites of top-ranked U.S. pediatric cancer programs. Methods: Cross-sectional survey of information and resources related to FP on websites from top-ranked pediatric cancer programs according to the 2018-2019 U.S.-News & World Report (USNWR) ranking. Factors that predicted the website availability of FP information or a fertility team were analyzed, as was availability in Spanish and for specific groups by sex and puberty status. As a surrogate marker of comprehensive oncological services, the availability of resources for psychological support was compared to FP. Results: A fertility team was referenced on the website of 36% of programs, but only 32% provided FP educational resources for patients. Among them, 100%, 93.8%, 93.8%, and 68.8% provided specific information for postpubertal females, prepubertal females, postpubertal males, and prepubertal males, respectively. The majority (93.8%) did not provide information in Spanish. The ranking on USNWR (p < 0.05) and patient volume (p < 0.05) positively correlated with the availability of FP information and fertility team on the program's website. Information regarding psychological support was provided more often than information regarding FP (96% vs. 32%, p < 0.05). Conclusion: The majority of the top-ranked pediatric cancer programs in the United States do not list FP resources or a fertility team on their website. The lack of resources is particularly concerning for the Spanish-speaking population, as well as for prepubertal males. This may be potentially hindering access to FP and contributing to health care disparities.