The impact of hiring a full-time fertility navigator on fertility-related care and fertility preservation at a pediatric institution.

Fertility navigators (FNs) are important in communicating infertility risk and fertility preservation (FP) options to patients receiving gonadotoxic therapies. This retrospective study examined electronic medical records of patients with fertility consults at a large pediatric institution (2017-2019), before and after hiring a full-time FN. Of 738 patient encounters, 173 consults were performed pre-navigator and 565 post-navigator. Fertility consults for long-term follow-up cancer survivors increased most substantially: pre-navigator (n = 7) and post-navigator (n = 387). Across diagnoses, females had a larger increase in consults compared to males (χ2 [3, N = 738] = 8.17, p < .05). Findings highlight FNs' impact on counseling rates, particularly in survivorship.

Targeted Therapy in a Young Adult With a Novel Epithelioid Tumor Driven by a PRRC2B-ALK Fusion.

This case report describes an 18-year-old woman with an unusual epithelioid tumor of the omentum with a novel PRRC2B-ALK fusion. Although the atypical pathologic features raised significant diagnostic challenges, expression of CD30 on tumor cells and detection of an ALK rearrangement provided critical information for selecting targeted therapy in a patient not suitable for surgical resection. Despite an initially promising therapeutic response, the patient died. The efficacy of treatment was confirmed by the lack of viable tumor cells at autopsy. This case highlights the role of timely targeted therapy in patients with rare tumors and novel actionable molecular targets.

Parent-Adolescent Concordance Regarding Fertility Perspectives and Sperm Banking Attempts in Adolescent Males With Cancer.

OBJECTIVE: Approximately half of male childhood cancer survivors experience impaired fertility, yet fertility preservation (FP) remains underutilized. Although parent recommendation influences adolescents' decision-making, parents may be uncertain and/or underrate their sons' parenthood goals. This study assessed parent-adolescent and family-level concordance regarding adolescent fertility perspectives (i.e., values, goals) and associations with FP attempts. METHODS: A prospective pilot study examined the impact of a family-centered values clarification tool (FAST) on banking attempts among adolescent males newly diagnosed with cancer at risk for infertility. The FAST assessed adolescent and parent perceptions of adolescents' fertility values and goals (i.e., perceived threat of infertility, perceived benefits/barriers to banking). Parent-adolescent concordance and family-level concordance on fertility perspectives were examined, along with associations with banking attempts and salient demographic factors. RESULTS: Ninety-eight participants (32 adolescents aged 12-20, 37 mothers, 29 fathers) from 32 families completed the FAST before treatment initiation. Parent-adolescent dyads were concordant on approximately one-half of responses. Banking attempts were associated with higher family-level concordance regarding perceived benefits, r(32) = .40, p = .02. Older adolescent age was associated with higher family-level concordance regarding perceived threat, r(31) = .37, p = .04, and benefits, r(32) = .40, p = .03. Fathers' education was associated with higher family-level concordance regarding barriers, r(21) = .53, p = .01. CONCLUSIONS: When parents were concordant with their son's fertility values and goals, particularly perceived benefits, adolescents were more likely to attempt FP. Clinicians should facilitate sharing of fertility perspectives within families before cancer treatment, especially with younger adolescents. Psychosocial support for families facing FP decisions is recommended at diagnosis and across the care continuum.

Impact of a novel family-centered values clarification tool on adolescent sperm banking attempts at the time of a new cancer diagnosis.

PURPOSE: Over half of males experience fertility impairment after childhood cancer therapy, which often causes psychosocial distress. Yet, fertility preservation (FP) remains underutilized. The goals of this study were to determine the feasibility and impact of implementing a family-centered FP values clarification tool on sperm banking attempts among adolescent males newly diagnosed with cancer, and identify key determinants of banking attempts. METHODS: A prospective pilot study was conducted among families of males (12-25 years old), prior to cancer therapy. Thirty-nine of 41 families agreed to participate (95%); 98 participants (32 adolescents, 37 mothers, 29 fathers) completed the Family-centered Adolescent Sperm banking values clarification Tool (FAST). Analyses assessed the impact of the FAST on banking attempts and examined associations between demographic/medical characteristics, FAST subscales (perceived threat, benefits, barriers), and banking attempts. RESULTS: Twenty-three (59%) adolescents attempted to bank, compared to 8 adolescents (33%) during baseline assessment (p=.04). Significant associations were identified between banking attempts and adolescents' report of perceived threat (rpb=.45, p=.01) and benefits (rpb=.57, p=.01). Only mothers' proxy reports of adolescent perceived threat (rpb=.42, p=.01) and benefits (rpb=.47, p=.003) were associated with banking attempts, while fathers' self-reported perceived benefits (rpb=.43, p=.03), self-reported barriers (rpb=.49, p=.01), and proxy reports of adolescent perceived threat (rpb=.38, p=.04) and benefits (rpb=.59, p=.02) were associated with banking attempts. CONCLUSION: Adolescent sperm banking attempt rates significantly increased after implementation of a family-centered FP values clarification tool prior to cancer treatment. Findings underscore the importance of targeting both adolescents and their parents, particularly fathers, in FP efforts.

Ocular hemorrhage secondary to thioguanine-associated veno-occlusive disease in a child with acute lymphoblastic leukemia in delayed intensification.

Hepatic VOD is a potentially fatal complication during stem cell transplantation and is rarely seen in the non-transplant setting. We report the case of a five-year-old boy who presented with visual complaints during delayed intensification phase of treatment for ALL. He was found to have bilateral retinal hemorrhages associated with profound thrombocytopenia due to chemotherapy. VOD was diagnosed based on EBMT criteria and was managed with supportive care. Despite resolution of VOD, his vision progressively deteriorated and resulted in blindness. This case highlights the significance of close monitoring of ALL patients in delayed intensification when they are at risk for developing VOD, the importance of refractory thrombocytopenia as a diagnostic feature and the potential for VOD to manifest with intraocular bleeding.

First-in-Human Intravenous Seprehvir in Young Cancer Patients: A Phase 1 Clinical Trial.

Seprehvir (HSV1716) is an oncolytic herpes simplex virus-1 (HSV-1) previously demonstrated to be well tolerated in pediatric patients when administered intratumorally. To determine the safety of administering Seprehvir systemically, we conducted the first-in-human phase I trial of intravenous injection in young patients with relapsed or refractory extra-cranial solid cancers. We delivered a single dose of 5 × 104 infectious units (iu)/kg (maximum dose of 2 × 106) or 2.5 × 105 iu/kg (maximum dose of 1 × 107 iu) of Seprehvir via the peripheral vein, monitored adverse events, and measured tumor responses by imaging. We monitored HSV-1 serology as well as viremia and shedding by PCR and culture. We administered a single dose of Seprehvir to seven patients and multiple doses to two patients. We did not observe any dose-limiting toxicities. All five HSV-1 seronegative patients seroconverted by day 28. Four of nine patients had detectable HSV-1 genomes in peripheral blood appearing on day +4 consistent with de novo virus replication. Two patients had stable disease in response to Seprehvir. Intravenous Seprehvir is well tolerated without viral shedding in children and young adults with late-stage cancer. Viremia consistent with virus replication holds promise for future Seprehvir studies at higher doses and/or in combination with other anti-neoplastic therapies.

Perceptions of participating in family-centered fertility research among adolescent and young adult males newly diagnosed with cancer: A qualitative study.

BACKGROUND: Over half of male childhood cancer survivors experience infertility after treatment, which is known to cause distress and impact future quality of life. Sperm banking rates remain low, and little is known about how adolescent and young adult (AYA) males and their families make fertility preservation (FP) decisions. This study examined AYA and parent perceptions of participating in a research study focused on testing a new FP decision tool at the time of cancer diagnosis. METHODS: Forty-four participants (19 mothers, 11 fathers, 14 male AYAs 12-25 years old) from 20 families completed brief assessments at diagnosis and approximately one month later, including a qualitative interview exploring the impact of study participation. Verbatim transcripts were coded through thematic content analysis using the constant comparison method. RESULTS: Two major themes emerged: (1) a positive effect of participating in the study and (2) a neutral effect (no positive/negative effect of participation). Subthemes that emerged for participants who noted a positive effect included (a) participation prompted deeper thinking, (b) participation influenced family conversations, and (c) participation resulted in altruism/helping others. No participant reported a negative effect. CONCLUSIONS: This study demonstrates that participation in family-centered research focused on FP among AYA males, before treatment begins, is perceived as beneficial or neutral at the time of a new cancer diagnosis. These findings provide support for future family-centered FP interventions for this population.

Conducting reproductive research during a new childhood cancer diagnosis: ethical considerations and impact on participants.

PURPOSE: Research among adults shows benefits and low perceived burden of engaging in behavioral research. However, questions remain regarding the ethics of conducting behavioral research in pediatric populations during sensitive situations, including during a new life-threatening diagnosis or at end-of-life. We examined reactions to participating in a behavioral reproductive research study among male adolescents newly diagnosed with cancer and their parents, as a step towards optimizing fertility preservation utilization in a population where future infertility is common. METHODS: Pediatric literature regarding the ethics of behavioral research was reviewed. In our pilot, forty-four participants (19 mothers, 11 fathers, 14 male adolescents newly diagnosed with cancer) from 20 families completed demographic questionnaires and a fertility preservation decision tool developed by the study team. Qualitative interviews exploring the impact of study participation were subsequently conducted. Verbatim transcripts were coded for thematic content using the constant comparison method. RESULTS: Literature review showed positive reactions to research participation among youth/caregivers. In our pilot study, 89% (n = 17) of mothers, 64% (n = 7) of fathers, and 71% (n = 10) of adolescents reported at least one benefit of participating. Eleven percent (n = 2) of mothers, 36% (n = 4) of fathers, and 29% (n = 4) of adolescents said they were not affected; none of the participants reported a negative effect. CONCLUSION: Consistent with prior literature, our study suggests behavioral reproductive research prior to cancer treatment can offer direct benefits to participants and society, without increasing burden. These findings will inform future interventions to improve long-term psychosocial and reproductive outcomes for youth with cancer.

Fertility perspectives and priorities among male adolescents and young adults in cancer survivorship.

Infertility is a common and distressing late effect of cancer treatment among male survivors. Investigators examined desire for parenthood, prioritization of fertility compared to other life goals, and reports of fertility-related discussions among a cohort of male adolescent and young adult survivors. Eighty percent desired a biological child, yet only 31% ranked having a child among their "top 3" life goals. Only 40% reported fertility-related discussions with their health care providers in survivorship. Given the importance of biological children among this cohort, future guidelines should encourage a more proactive approach to providing fertility counseling and offering testing, to mitigate distress and prevent unplanned pregnancies.

Rhabdomyosarcoma of the Breast in Adolescent and Young Adult (AYA) Women.

Soft tissue sarcoma constitutes 8% of all tumors in adolescent and young adults (AYA), with rhabdomyosarcoma (RMS) accounting for 5.2% to 6.5% of the soft tissue sarcoma total within this group. AYAs have a higher propensity for metastasis and inferior outcomes. Metastases to the breast have been reported in ∼3% to 6% of RMS cases. A review of our hospital's tumor registry identified cases of RMS diagnosed between January 1, 2004 and December 31, 2013. A total of 46 patients with RMS were identified, having a mean age of 12.5 years (range, 1 to 49 y). There were 26 males (57%) and 20 females (43%). Eighteen patients (39%) were AYAs, including 10 women. Four patients (8.7%) were identified with breast involvement, all of whom were AYA females. Treatment modalities included chemotherapy, surgical resection, and radiation. One patient is a long-term survivor. Although RMS is uncommon in AYAs, breast involvement occurs almost exclusively in AYA women and is associated with alveolar histology, metastatic disease, and poor outcomes. In total, 4/10 of all AYA females had breast involvement. Routine examination or imaging of the breasts in AYAs with RMS is not currently standard practice at diagnosis or follow-up, but this analysis suggests it should be considered in female AYA patients.

Hypoxic Proliferation of Osteosarcoma Cells Depends on Arginase II.

BACKGROUND/AIMS: Despite significant advancements in the diagnosis and treatment of osteosarcoma, the overall survival has remained relatively unchanged for over two decades. Hypoxic conditions have been demonstrated in solid tumors and are associated with increased cell proliferation and angiogenesis. L-arginine metabolism by arginase produces L-ornithine, the precursor for polyamine and proline synthesis required for cellular proliferation. We hypothesized that hypoxia would increase cellular proliferation via arginase induction in human osteosarcoma cell lines. METHODS: We utilized a variety of approaches to examine the role of arginase II in hypoxic (1% O2, 5% CO2) cellular proliferation. RESULTS: Arginase II mRNA and protein levels were significantly increased in osteosarcoma cells exposed to hypoxia for 48 hours. There were twice as many viable cells following 48 hours of hypoxia than following 48 hours of normoxia (21% O2, 5% CO2). The addition of difluoromethylornithine (DFMO), a putative arginase inhibitor, prevented hypoxia-induced proliferation. Transfection of small interfering RNAs (siRNA) targeting arginase II resulted in knockdown of arginase II protein levels and prevented hypoxia-induced cellular proliferation. CONCLUSIONS: These data support our hypothesis that hypoxia increases proliferation of osteosarcoma cells in an arginase II-dependent manner. We speculate that arginase II may represent a therapeutic target in osteosarcoma.

εGγAγδß0-thalassemia: a rare but clinically significant cause of hemolytic anemia in infants.

Normal hemoglobin is made of a tetramer of 2 α-globin and 2 ß-globin polypeptide chains. Deletions in the ß-globin gene cluster can range from a few hundred base pairs to loss of the entire cluster resulting in rare, but clinically significant, thalassemias. One such entity is εGγAγδß0-thalassemia, a condition that presents within the first few weeks of life as a Coombs-negative hemolytic anemia and is not identified on routine newborn screening or hemoglobin electrophoresis.

Length of stay and treatment-related complications are similar in pediatric and AYA patients with bone sarcoma in United States children's hospitals.

BACKGROUND: Adolescent and young adult (AYA) cancer patients have been shown to have unique clinical characteristics and inferior outcomes compared to younger patients. More than 2,500 new bone sarcomas are diagnosed yearly in the US, many of whom are AYAs treated at pediatric hospitals. Pediatric providers must understand the impact of increasing age on complications, costs, and outcomes. The study set-out to determine if AYA patients with bone sarcomas have increased healthcare utilization and treatment-related complications as compared to younger patients. PROCEDURE: Data were obtained from the Pediatric Health Information System for bone sarcoma admissions at 41 US children's hospitals from 2006 to 2010. Patient demographics and morbidities were compared in patients 0-14 and 15-28 years using two sample t-tests, Wilcoxon two sample tests, or chi-squared tests. RESULTS: We identified 835 pediatric and 562 AYA patients with bone sarcomas. Mean length of stay (LOS) was comparable between age groups (4.6 and 4.8 days, P = 0.46), although AYA patients had greater mean pharmaceutical charges ($18,124 vs. $13,637, P < 0.0001). Common treatment-related complications were similar between groups, with the exceptions that febrile neutropenia admissions were more likely in younger patients, and thrombosis, renal failure, and pain were more common in AYA patients. CONCLUSIONS: In US children's hospitals, AYA patients with sarcomas do not have prolonged LOS or an increased risk of the most common treatment-related complications as compared to younger patients. Chronic pain appears to be a greater burden in AYA patients, and may account for their higher inpatient pharmaceutical costs.

Malnutrition identification and management variability: An administrative database study of children with solid tumors.

BACKGROUND: Malnutrition during cancer treatment increases treatment-related morbidity and mortality. Our study better characterizes variability in malnutrition identification and treatment by examining nutrition-related diagnoses and support for children with central nervous system (CNS) and non-CNS solid tumors during therapy. We examined diagnosis of malnutrition, use of tube feeding or parenteral nutrition (PN), and appetite stimulants. METHODS: We retrospectively reviewed 0 to 21-year-old patients in the Pediatric Health Information System from 2015 to 2019. Patients were classified as having (1) billed malnutrition diagnosis, (2) malnutrition diagnosis or using PN and enteral nutrition ("functional malnutrition"), and (3) any previous criteria or prescribed appetite stimulants ("possible malnutrition"), as well as associated risk factors. RESULTS: Among 13,375 unique patients, CNS tumors were most common (24.4%). Overall, 26.5% of patients had malnutrition diagnoses, 45.4% met functional malnutrition criteria, and 56.0% had possible malnutrition. Patients with adrenal tumors had highest billed, functional, and possible malnutrition (36.6%, 64.1%, and 69.4%, respectively) followed by CNS tumors (29.1%, 52.4%, and 64.1%). Patients with adrenal tumors had highest rates of PN use (47.4%) and those with CNS tumors had the highest tube feeding use (26.8%). Hospital admissions with malnutrition had a longer hospital length of stay (LOS) (6 vs 3 days, P < 0.0001), more emergency department admissions (24.4% vs 21.8%, P < 0.0001), and more opioid use (58.6% vs 41.4%, P < 0.0001). CONCLUSIONS: Variability in malnutrition diagnoses hinders clinical care and nutrition research in pediatric oncology. Improving disease-specific recognition and treatment of malnutrition can target nutrition support, ensure appropriate reimbursement, and potentially improve outcomes for children with solid tumors.

Clinical outcomes and efficacy of stereotactic body radiation therapy in children, adolescents, and young adults with metastatic solid tumors.

OBJECTIVE: The objective of this study is to report disease outcomes and toxicity with the use of stereotactic body radiation therapy (SBRT) in the treatment of pediatric metastatic disease. METHODS: All pediatric and adolescent young adult (AYA) patients' who received SBRT were included between the years 2000 and 2020. Study endpoints included local control (LC), progression-free survival (PFS), overall survival (OS), cumulative incidence (CI) of death or local failure and toxicity. The end points with respect to survival and LC were calculated using the Kaplan-Meier estimate. The cumulative incidence of local failure was calculated using death as a competing risk. RESULTS: 16 patients with 36 lesions irradiated met inclusion criteria and formed the study cohort. The median OS and PFS for the entire cohort were 17 months and 15.7 months, respectively. The 1 year OS for the entire cohort was 75%. The 6- and 12 month local control was 85 and 78%, respectively. There were no local failures in irradiated lesions for patients who received a BED10≥100 Gy. Patients who were treated with SBRT who had ≤5 metastatic lesions at first recurrence had a superior 1 year OS of 100 vs 50% for those with >5 lesions. One patient (6.3%) experienced a Grade 3 central nervous system toxicity. CONCLUSION: LC was excellent with SBRT delivered to metastatic disease, particularly for lesions receiving a BED10≥100 Gy. High-grade toxicity was rare in our patient population. Patients with five or fewer metastatic sites have a significantly better OS compared to >5 sites. ADVANCES IN KNOWLEDGE: This study demonstrates that SBRT is safe and efficacious in the treatment of pediatric oligometastatic disease.

Heterozygous M1V variant of ELA-2 gene mutation associated with G-CSF refractory severe congenital neutropenia.

Severe congenital neutropenia is an autosomal recessive disorder characterized by maturation arrest at the promyelocyte/myelocyte phase in the bone marrow, absolute neutrophil count <0.5 × 10(9) /L and recurrent bacterial infections. Homozygous mutations of either HAX-1 or ELA-2 have been described. We report the case of a premature male infant with congenital neutropenia, associated with multiple infections, refractory to treatment with granulocyte colony stimulating factor who subsequently underwent matched sibling donor stem-cell transplant. He was found to be heterozygous for the M1V variant of the ELA-2 gene that we postulate to be causative for his severe neutropenia

Evaluating Perspectives of a Smartphone Medication Application in the Adolescent and Young Adult Oncology Population: A Qualitative Study.

Purpose: Medication adherence research involving adolescent and young adult (AYA) oncology patients has consisted of small, retrospective studies demonstrating poor adherence rates. Technology plays an active role in attempt to improve medication adherence. There is a growing body of literature investigating the role of smartphone applications (apps). We hypothesized a medication phone app, MedActionPlan Pro (MPP), leads to perceived improvement in medication adherence. Methods: Thirty AYA oncology patients actively receiving treatment (AYA defined as 15-30 years) at Nationwide Children's Hospital were enrolled. Participants downloaded the MPP app on their smartphone for 3 months, during which time participants were provided text messages and alerts to encourage medication adherence. Post-app use, participants completed semi-structured interviews. Interviews were audio-recorded, transcribed, and independently coded to determine consensus thematic content. Results: Thirty AYA oncology participants (16 male), median age 17.5 (range: 15-30 years), participated in the study, with 22 participants (55% male) with a median age of 18 years (range: 15-30 years) participated in the final qualitative survey interview. Participants reported positive views about app utilization and perceived improved medication adherence. Additional themes included perceived decreased forgetfulness, improved organization, and identified customization for medications within the app was most important to AYAs. Conclusion: AYA oncology patients reported improvement in perceived medication adherence utilizing MPP and identified several features they thought would lead to improved medication adherence. These findings, integrated with previous literature, support the further need to investigate the utility of medication adherence apps that fit the unique needs of AYA oncology patients.

Satisfaction with Fertility Preservation Decisions among Adolescent Males with Cancer: A Mixed Methods Study.

Half of male childhood cancer survivors experience treatment-related fertility impairment, which can lead to distress. Survivors often regret forgoing fertility preservation (FP), and decisional dissatisfaction is associated with a lower quality of life. This mixed methods study examined short-term FP decisional satisfaction among families of male adolescents newly diagnosed with cancer who received an initial fertility consult and completed an FP values clarification tool. One-two months after the FP decision, thirty-nine families completed the Brief Subjective Decision Quality measure. Decisional satisfaction was compared for participants (mothers, fathers, adolescents) who did and did not attempt to bank. Semi-structured interviews included the following question: How do you/your family feel about the banking decision now/in the future? Decisional quality scores were moderate-high (M = 5.74-6.33 out of 7), with no significant differences between non-attempter (n = 15) and attempter (n = 24) families (adolescents: p = 0.83, d = 0.08; mothers: p = 0.18, d = 0.45; fathers: p = 0.32, d = 0.44). Three qualitative themes emerged among non-attempter families: (1) satisfaction with decision (50% of participants), (2) acceptance of decision (60%), and (3) potential for future regret (40%). Satisfaction with decision was the only theme identified in attempter families (93%). Quantitively, short-term decisional satisfaction was high regardless of the banking attempt. However, the qualitative findings suggest that the experiences of families who did not bank may be more nuanced, as several participants discussed a potential for future regret, highlighting the importance of ongoing support.