Yasmin Gosiengfiao

Pretreatment antimüllerian hormone levels determine rate of posttherapy ovarian reserve recovery: acute changes in ovarian reserve during and after chemotherapy

OBJECTIVE To identify factors associated with ovarian reserve impairment during and immediately after chemotherapy. DESIGN Prospective cohort study. SETTING Four university hospitals. PATIENT(S) Forty-six adolescent and young adult women with a new diagnosis of cancer requiring chemotherapy. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Measurements of ovarian reserve via levels of serum follicle-stimulating hormone, luteinizing hormone, estradiol, inhibin B, and antimüllerian hormone (AMH) as well as antral follicle counts and mean ovarian volume at 3-month intervals. RESULT(S) Changes in ovarian reserve were quantified for both the acute impact of treatment using linear regression and the longitudinal recovery after therapy using mixed-effects models adjusted for baseline ovarian reserve, use of alkylating agent, and hormone use. The women had at least one pretreatment and two posttreatment study visits (mean follow-up interval: 12 months). All measures of ovarian reserve demonstrated statistically significant changes during chemotherapy. Alkylating agent exposure and baseline ovarian reserve were acutely associated with the magnitude of impairment, and pretreatment AMH levels were associated with the rate of recovery of AMH after treatment. In adjusted models, participants with a pretreatment AMH level > 2 ng/mL recovered at a rate of 11.9% per month after chemotherapy, whereas participants with pretreatment AMH levels ≤ 2 ng/mL recovered at a rate of 2.6% per month after therapy. CONCLUSION(S) Baseline ovarian reserve and alkylating agent exposure effect the magnitude of acute changes in ovarian reserve from chemotherapy. The rate of recovery of AMH is impacted by pretreatment levels. This should be considered during pretreatment fertility preservation counseling.

Successful nontransplant resection of POST-TEXT III and IV hepatoblastoma.

Liver transplantation is increasingly advocated as primary surgical therapy for children with hepatoblastoma involving 3 or 4 sectors of the liver after neoadjuvant chemotherapy. This study evaluated the results of nontransplant hepatectomy in children who might otherwise have been considered for liver transplantation.

Validation of a prognostic multi-gene signature in high-risk neuroblastoma using the high throughput digital NanoString nCounter™ system.

Microarray‐based molecular signatures have not been widely integrated into neuroblastoma diagnostic classification systems due to the complexities of the assay and requirement for high‐quality RNA. New digital technologies that accurately quantify gene expression using RNA isolated from formalin‐fixed paraffin embedded (FFPE) tissues are now available. In this study, we describe the first use of a high‐throughput digital system to assay the expression of genes in an “ultra‐high risk” microarray classifier in FFPE high‐risk neuroblastoma tumors. Customized probes corresponding to the 42 genes in a published multi‐gene neuroblastoma signature were hybridized to RNA isolated from 107 FFPE high‐risk neuroblastoma samples using the NanoString nCounter™ Analysis System. For classification of each patient, the Pearsons correlation coefficient was calculated between the standardized nCounter™ data and the molecular signature from the microarray data. We demonstrate that the nCounter™ 42‐gene panel sub‐stratified the high‐risk cohort into two subsets with statistically significantly different overall survival (p = 0.0027) and event‐free survival (p = 0.028). In contrast, none of the established prognostic risk markers (age, stage, tumor histology, MYCN status, and ploidy) were significantly associated with survival. We conclude that the nCounter™ System can reproducibly quantify expression levels of signature genes in FFPE tumor samples. Validation of this microarray signature in our high‐risk patient cohort using a completely different technology emphasizes the prognostic relevance of this classifier. Prospective studies testing the prognostic value of molecular signatures in high‐risk neuroblastoma patients using FFPE tumor samples and the nCounter™ System are warranted.

What is New in Rhabdomyosarcoma Management in Children

Optimal management of rhabdomyosarcoma requires establishing the correct pathologic diagnosis, histologic sub-type, primary site, extent of disease (Stage), and extent of resection (Group). Based on these features, cooperative groups in North America and Europe have defined risk-adapted treatments that include surgery, chemotherapy, and usually radiotherapy. This article focuses on recent findings that can impact or have already impacted rhabdomyosarcoma treatment guidelines and highlights controversies that should be addressed in order to improve outcome for children with rhabdomyosarcoma.Rhabdomyosarcoma is currently sub-classified in children based on histology into the favorable embryonal/botryoid/spindle cell types and the unfavorable alveolar form. Risk group assignment depends in part on histologic sub-type. Alveolar rhabdomyosarcoma is sometimes associated with chromosomal translocations, which impact clinical behavior. An important ongoing debate is whether molecular diagnostic tools to identify chromosomal translocations and/or define gene expression profiles should be used to sub-classify rhabdomyosarcoma rather than histology. Clinical trials continue to evaluate retrospective as well as prospective cohorts in order to carefully determine the impact of histology versus biologic features on outcome in the context of specific therapeutic regimens.Most rhabdomyosarcoma recurrences involve the primary site or adjacent region. Cooperative groups continue to investigate new approaches to local control in order to reduce local recurrences and sequelae associated with local therapy. Delaying primary resection until after chemotherapy has started appears to increase the number of tumors that can be completely resected with acceptable morbidity in some primary sites. Radiation dose reductions following delayed primary resection have been investigated. Although outcomes appear similar to the conventional approach of full-dose radiotherapy without delayed primary resection, long-term effects of the two approaches have not been rigorously compared. Early evidence suggests that newer methods of delivering radiotherapy, including intensity-modulated radiotherapy (IMRT), proton beam radiotherapy, and brachytherapy maintain efficacy but may reduce long-term sequelae compared with 3-dimensional conformal radiotherapy.Chemotherapy regimens defined by the cooperative groups vary by risk group. The most commonly used regimens include vincristine and dactinomycin in combination with an alkylating agent, either cyclophosphamide or ifosfamide. In order to improve outcomes, recent clinical trials have introduced new chemotherapeutic agents (e.g. topotecan, carboplatin, or epirubicin) into the treatment regimens. However, outcomes have not been significantly impacted. Novel chemotherapy administration schedules have been tested in patients with metastatic rhabdomyosarcoma, including interval compressed dosing or maintenance therapy, and may be promising. Molecularly targeted agents are currently under investigation in combination with chemotherapy for patients with recurrent or metastatic rhabdomyosarcoma. It is hoped that these novel agents will benefit all patients with rhabdomyosarcoma in the future.

Pediatric Oncology Providers' Attitudes and Practice Patterns Regarding Fertility Preservation in Adolescent Male Cancer Patients.

Background:The aim of this study was to evaluate pediatric oncology providers’ attitudes toward fertility preservation (FP), their use of educational materials, their approach to FP discussion, and their FP knowledge specifically pertaining to adolescent males. Methods:A 40-item online survey was distributed to physicians, advanced practice nurses (APN), and nurses within pediatric oncology. Results:About 78.7% of physicians, 81.4% of APN, and 51.9% of nurses reported high levels of comfort in discussing FP options with adolescent males (P<0.05). Fifty-one percent of physicians and 54.2% of APN reported using educational materials, compared with 38.9% of nurses (P<0.05). Regarding knowledge of FP technologies, 48.7% of physicians, 52.5% of APN, and 81.1% of nurses reported being unfamiliar with intracytoplasmic sperm injection (P<0.05). An overwhelming majority (92.9%) of respondents reported having no formal training in discussing FP. Finally, 84.8% of respondents believed formal training on this issue would be useful to them. Conclusions:This study illustrates an unmet need in the education of pediatric oncology providers, as knowledge gaps and discomfort are common themes reported by health care professionals within the context of adolescent male FP care. In addition, this study reveals a high level of receptiveness to FP training by these same providers.

Gemcitabine with or without docetaxel and resection for recurrent osteosarcoma: the experience at Children's Memorial Hospital.

It remains unclear how to optimally incorporate gemcitabine and docetaxel into the management of patients with recurrent osteosarcoma. We describe 4 pediatric patients with recurrent osteosarcoma who were treated with gemcitabine±docetaxel and resection. One patient had a partial response and 2 had stable disease. Two patients subsequently underwent surgical resections. Median duration of response was 8 months and was longer for patients who underwent resection. One patient remains disease-free 57 months from recurrence. Our limited series provides additional support for the use of gemcitabine±docetaxel for recurrent osteosarcoma and suggests benefit of concurrent local control measures if possible.

Presence of Germ Cells in Disorders of Sex Development: Implications for Fertility Potential and Preservation

Purpose: We sought to determine the presence of germ cells in the gonads of patients with disorders of sex development to establish whether preservation of germ cells for future fertility potential is possible. We hypothesized that germ cells are present but vary by age and diagnosis. Materials and Methods: We reviewed histology from patients with disorders of sex development who underwent gonadectomy/biopsy from 2002 to 2014 at a single institution for pathological classification of the gonad, composition of gonadal stroma and germ cell presence. Results: A total of 44 patients were identified and germ cells were present in 68%. The presence and average number of germ cells per mm2 were analyzed by gonad type and diagnosis. By gonad type all ovotestes, most testes, ovaries and dysgenetic testes, and 15% of streak gonads had germ cells present. By diagnosis germ cells were present in all patients with complete androgen insensitivity syndrome, Denys‐Drash syndrome, SRY mutation, mixed gonadal dysgenesis, ovotesticular conditions and StAR (steroid acute regulatory protein) deficiency, in some patients with persistent müllerian duct syndrome, XO/XY Turner syndrome and disorders of sex development not otherwise specified, and in none with complete or partial gonadal dysgenesis. Germ cells were present in the gonads of 88% of patients 0 to 3 years old, 50% of those 4 to 11 years old and 43% of those older than 12 years. Conclusions: Germ cells were present in the majority of our cohort and the presence decreased with age. This novel, fertility driven evaluation of germ cell quantity in a variety of disorders of sex development suggests that fertility potential may be greater than previously thought. Further studies must be done to evaluate a larger population and examine germ cell quality to determine the viability of these germ cells.

Pediatric and Teen Ovarian Tissue Removed for Cryopreservation Contains Follicles Irrespective of Age, Disease Diagnosis, Treatment History, and Specimen Processing Methods

PURPOSE Fertility preservation in a pediatric and teen female population is challenging because standard technologies of egg and embryo freezing may not be possible due to premenarcheal status. Ovarian tissue cryopreservation (OTC) with the intent of future ovarian tissue transplantation or in vitro follicle growth may be the only option to preserve fertility. The purpose of this study was to add to the general understanding of primordial follicle dynamics in young patients. METHODS First, the unique infrastructure of the Oncofertility Consortium National Physicians Cooperative (OC-NPC) is described, which simultaneously drives clinical fertility preservation and basic research to explore and expand the reproductive options for those in need. Then, the OC-NPC research resource is used to perform a histological evaluation of ovarian tissue from 24 participants younger than 18 years of age. RESULTS Primordial follicles, which comprise the ovarian reserve, were observed in all participant tissues, irrespective of variables, including age, diagnosis, previous treatment history, tissue size, and tissue processing methods. Primordial follicles were present in ovarian tissue, even in participants who had a previous history of exposure to chemotherapy and/or radiation treatment regimens, which placed them at risk for iatrogenic infertility or premature ovarian failure. CONCLUSION Primordial follicles were observed in ovarian tissue from all participants examined, despite population and tissue heterogeneity. These results increase the understanding of human follicle dynamics and support OTC as a promising fertility preservation modality in the young female population. Future studies to evaluate follicle quality within these tissues are warranted.

Fertility Preservation for Pediatric Patients: Current State and Future Possibilities

Purpose: This review provides an overview of pediatric fertility preservation. Topics covered include the patient populations who could benefit, the current state of fertility preservation options and research, and considerations related to ethics and program development. Materials and Methods: A broad Embase® and PubMed® search was performed to identify publications discussing investigational, clinical, ethical and health care delivery issues related to pediatric fertility preservation. Relevant publications were reviewed and summarized. Results: Populations who could benefit from fertility preservation in childhood/adolescence include oncology patients, patients with nononcologic conditions requiring gonadotoxic chemotherapy, patients with differences/disorders of sex development and transgender individuals. Peripubertal and postpubertal fertility preservation options are well established and include cryopreservation of oocytes, embryos or sperm. Prepubertal fertility preservation is experimental. Multiple lines of active research aim to develop technologies that will enable immature eggs and sperm to be matured and used to produce a biological child in the future. Ethical challenges include the need for parental proxy decision making and the fact that fertility preservation procedures can be considered not medically necessary. Successful multidisciplinary fertility preservation care teams emphasize partnerships with adult colleagues, prioritize timely consultations and use standardized referral processes. Some aspects of fertility preservation are not covered by insurance and out‐of‐pocket costs can be prohibitive. Conclusions: Pediatric fertility preservation is an emerging, evolving field. Fertility preservation options for prepubertal patients with fertility altering conditions such as cancer and differences/disorders of sex development are currently limited. However, multiple lines of active research hold promise for the future. Key considerations include establishing a multidisciplinary team to provide pediatric fertility preservation services, an appreciation for relevant ethical issues and cost.

Late Effects in Pediatric High-risk Neuroblastoma Survivors after Intensive Induction Chemotherapy Followed by Myeloablative Consolidation Chemotherapy and Triple Autologous Stem Cell Transplants

Multimodal treatment in high-risk neuroblastoma has modestly improved survival; limited data exist on the late effects from these regimens. We report the sequelae of treatment incorporating 3 consecutive cycles of high-dose therapy and autologous stem cell transplants (ASCTs) without the use of total body irradiation (TBI). We reviewed the medical records of 61 patients treated on or following the Chicago Pilot 2 protocol between 1991 and 2008. Of the 25 patients who are alive (41%), 19 had near complete data to report. Specific treatment modalities and therapy-related side effects were collected. Fourteen of these 19 patients (74%) received 3 cycles of high-dose therapy with ASCT; follow-up occurred over a median of 13.9 years (range, 5.8 to 18.8 y). The majority of late effects were endocrine-related, including growth failure, hypothyroidism, and hypogonadism. Patients also developed secondary neoplasms and skeletal deformities. The most frequent sequela was hearing loss, seen in 17/19 patients. We found a high prevalence of various late effects in survivors of high-risk neuroblastoma using a non–TBI-based regimen including 3 cycles of high-dose therapy with ASCTs. As current treatment regimens recommend tandem ASCT without TBI, it is imperative that we understand and monitor for the sequelae from these modalities.