Acute Menopausal Symptoms in Young Cancer Survivors Immediately following Chemotherapy.

PURPOSE: The aim of this study was to evaluate the prevalence of menopausal symptoms in young cancer survivors immediately following the completion of chemotherapy. METHODS: This prospective cohort study followed 124 young females with a new diagnosis of cancer requiring chemotherapy to assess symptoms of menopause before treatment and immediately following chemotherapy. Symptoms were compared before and after treatment using the McNemar test and between cancer patients and 133 similar-aged healthy controls using Pearson χ2 and Fisher's exact tests. RESULTS: Participants undergoing cancer therapy reported more menopausal symptoms compared to controls prior to the initiation of any treatment (hot flashes or night sweats 33 vs. 7%, p < 0.01, trouble sleeping 57 vs. 31%, p < 0.01, headaches 50 vs. 35%, p = 0.02, and decreased libido 36 vs. 16%, p < 0.01) and also reported a greater prevalence of symptoms immediately after cancer therapy compared to pretreatment prevalence (vasomotor symptoms, p < 0.01, vaginal dryness, p < 0.01, decreased concentration, p < 0.01, and body aches, p = 0.01). Cancer patients with lower anti-Müllerian hormone (AMH) levels after treatment (<0.10 ng/mL) had an increased risk of vasomotor symptoms (OR 2.2, p = 0.04), mood swings (OR 2.4, p = 0.03), feeling sad (OR 2.2, p = 0.04), trouble sleeping (OR 2.7, p = 0.02), and decreased libido (OR 3.0, p = 0.03) when controlled for age and cancer type, and the incidence of these symptoms was not affected by the use of systemic hormones or psychiatric medications. Treatment length, use of alkylating agents, pelvic radiation, and marital status were also not associated with the prevalence of menopausal symptoms. CONCLUSIONS: Premenopausal women with a new cancer diagnosis have more menopausal symptoms than females of similar age before and after cancer treatment, the effects of which are not mitigated by systemic hormone use. Decreased AMH levels were associated with an increased likelihood of reporting physiologic symptoms after therapy. IMPLICATIONS FOR CANCER SURVIVORS: This information is imperative for counseling; ultimately, improved symptom management during and after cancer therapies will improve quality of life in young cancer survivors.

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.

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.

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.

Is surgical resection and observation sufficient for stage I and II sacrococcygeal germ cell tumors? A case series and review.

BACKGROUND: Sacrococcygeal teratoma (SCT) is the most common germ cell tumor (GCT) of infancy. Up to 35% of infants may have malignant elements. The standard of care for SCT with malignant elements (SCT-ME) has been surgery and chemotherapy. However, cases where low-stage SCT-ME have been successfully observed following resection have been reported. PROCEDURE: To better understand the outcomes of low-stage SCT-ME that do not receive chemotherapy, we reviewed SCT pathology reports from five children's hospitals from 1999 to 2009. Information regarding staging workup, tumor markers, treatment, and outcome was collected for patients with stage I or II SCT-ME. An English language literature review was also performed. RESULTS: Seventy-four SCT were identified: 51 stage I and 23 stage II; 13 (18%) were SCT-ME: 5 stage I and 8 stage II; four stage I and four stage II tumors were not treated with chemotherapy. No stage I tumors recurred; all of the stage II tumors recurred and were successfully salvaged, two had no ME at recurrence. We identified another 10 stage I SCT-ME in the literature managed with active surveillance-two recurred and were successfully treated with surgery and chemotherapy. CONCLUSIONS: Overall, of the 14 cases of stage I SCT-ME, 12 survived with no recurrence and the two who did recur were successfully treated with platinum-based chemotherapy (EFS = 86%, overall survival [OS] = 100%); this suggests that patients with stage I SCT-ME could be observed after surgery and treated only upon recurrence. Stage II SCT-ME require further study in a clinical trial setting.

Segmental Chromosomal Aberrations in Localized Neuroblastoma Can be Detected in Formalin-Fixed Paraffin-Embedded Tissue Samples and Are Associated With Recurrence.

BACKGROUND: Array comparative genomic hybridization (CGH) analyses of frozen tumors have shown strong associations between the pattern of chromosomal aberrations and outcome in patients with advanced-stage neuroblastoma. New platforms for analyzing chromosomal aberrations using formalin-fixed paraffin-embedded (FFPE) tissue have recently been developed. We sought to determine whether chromosomal microarray analysis (CMA) using FFPE tumors is feasible and if segmental chromosomal aberrations were prognostic of recurrence in localized neuroblastoma. METHODS: Patients with MYCN nonamplified International Neuroblastoma Staging System stage 1 and 2 disease who recurred were identified. CMA was performed with diagnostic FFPE samples using OncoScan™ FFPE Express 2.0. The prognostic significance of chromosomal pattern was validated in 105 patients with available CGH results. RESULTS: In 26 evaluable patients, 11 recurred locally, nine had metastatic relapse, and six remained progression free >3 years from diagnosis. No chromosomal aberrations were identified in four tumors. Numerical chromosomal aberrations (NCAs) without segmental chromosomal aberration (SCA) were identified in 11 patients: six progressed locally, two had metastatic progression and 3 remained progression-free. Eleven patients had SCAs: four progressed locally, six developed metastatic progression and one remained progression-free. Five or more SCAs were only detected in tumors from patients who developed metastases (P = 0.0004). In the validation cohort, SCAs were associated with inferior event-free survival (EFS) compared to NCA (5-year EFS 68% ± 8.3% vs. 91% ± 3.6%, respectively; P = 0.0083). CONCLUSIONS: It is feasible to evaluate chromosomal aberrations using FFPE neuroblastoma tissue. SCA is associated with inferior EFS in localized neuroblastoma patients, and multiple SCAs may be predictive of metastatic relapse.

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.

Treatment of neuroblastoma in congenital central hypoventilation syndrome with a PHOX2B polyalanine repeat expansion mutation: New twist on a neurocristopathy syndrome.

Neuroblastoma in patients with congenital central hypoventilation syndrome (CCHS) as part of a neurocristopathy syndrome is a rare finding and has only been associated with paired-like homeobox 2b (PHOX2B) non-polyalanine-repeat-expansion mutations. To the best of our knowledge, we report the first case of a child with CCHS and Hirschsprung disease who had a PHOX2B polyalanine-repeat-expansion mutation (PARM) (genotype 20/33) and developed high-risk neuroblastoma. We further describe his treatment including chemotherapy and therapeutic I(131) -metaiodobenzylguanidine. This case highlights the need to consider neuroblastoma in patients with CCHS and the longest PHOX2B PARMs and to individualize treatment based on co-morbidities.

A Pilot Study of Circulating Endothelial and Hematopoietic Progenitor Cells in Children With Sarcomas.

Utilizing a multiparametric flow cytometry protocol, we assessed various cell types implicated in tumor angiogenesis that were found circulating in the peripheral blood of children with sarcomas (cases) based on their cell surface antigen expression. Circulating endothelial cells (CECs), endothelial colony-forming cells (ECFCs), and the ratio of 2 distinct populations of circulating hematopoietic stem and progenitor cells (CHSPCs), the proangiogenic CHSPCs (pCHSPCs) and nonangiogenic CHSPCs (nCHSPCs) were enumerated. Multiparametric flow cytometry was analyzed in cases at baseline and at 4 additional timepoints until the end of treatment and levels compared with each other and with healthy controls. At all timepoints, cases had significantly lower levels of CECs, but elevated ECFCs and a pCHSPC:nCHSPC ratio compared with controls (all P-values <0.05). There was no significant difference in any of the cell types analyzed based on tumor histology, stage (localized vs. metastatic), or tumor size. After treatment, only the CECs among the complete responders were significantly lower at end of therapy (P<0.01) compared with nonresponders, whereas the ECFCs among all cases significantly increased (P<0.05) compared with baseline. No decline in the pCHSPC:nCHSPC ratio was observed despite tumor response. On the basis of these results, a validation of CECs as prognostic biomarker is now warranted.

Irinotecan and temozolomide for treatment of neuroblastoma in a patient with renal failure on hemodialysis.

Renal failure is a rare complication of neuroblastoma or its therapy. To our knowledge, no reports describe treatment of children with neuroblastoma with chemotherapy in the setting of renal failure and maintenance hemodialysis. We report a 6-year-old child with high-risk neuroblastoma who developed renal failure requiring long-term hemodialysis. She was subsequently treated with 13 cycles of intravenous irinotecan 20 mg/m(2)/day and oral temozolomide 100 mg/m(2)/day for 5 days before disease progression without any dose adjustments, transfusions, febrile neutropenia or diarrhea. This case demonstrates that irinotecan and temozolomide can be safely administered in children with renal failure requiring hemodialysis.

Progression-free survival of two cases of high-risk neuroblastoma with refractory/relapsed disease following surgery alone.

Outcome for the vast majority of high-risk neuroblastoma patients with refractory or relapsed disease is dismal. We report two high-risk patients who remain progression-free for more than 113 and 18 months following the diagnosis of refractory/relapsed disease who were treated with surgery alone. Complete resolution of a refractory thoracic mass and relapsed liver nodules was observed in one patient. The refractory/relapsed disease in the second patient has remained stable. In both cases, the tumor showed histologic evidence of neuroblastoma maturation. These cases demonstrate that refractory/relapsed neuroblastoma is clinically heterogeneous and highlight the need for better biomarkers to optimize patient care.

Transient partial response to sorafenib treatment in an adolescent patient with MEN2B syndrome and end-stage medullary thyroid carcinoma.

Metastatic medullary thyroid carcinoma (MTC) is an aggressive malignancy with an extremely poor prognosis. Currently no effective conventional systemic therapies exist to treat pediatric MTC. We describe an adolescent female with newly diagnosed MEN2B syndrome who presented with advanced stage metastatic MTC and demonstrated a partial transient response to sorafenib monotherapy. This clinical result supports further research into the use of sorafenib in the treatment of pediatric MTC.

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.

Long-term survival in a pediatric patient with supratentorial primitive neuro-ectodermal tumor and extraneural metastasis at diagnosis.

Extraneural metastases of central nervous system (CNS) tumors are rare occurrences most commonly observed in medulloblastomas. Survival outcomes are generally dismal. Supratentorial primitive neuroectodermal tumors (stPNET) are rare childhood tumors with few documented cases of extraneural metastases. We present a rare occurrence of a 23-month-old patient with long-term survival after diagnosis of stPNET with metastases to the lungs. This patient was treated with surgical resection, induction chemotherapy, tandem autologous hematopoietic cell rescues, and focal radiotherapy. We report long-term survival for a patient with a stPNET and extraneural metastases at diagnosis following an intensive approach to treatment.

Recall of Fertility Discussion by Adolescent Female Cancer Patients: A Survey-Based Pilot Study.

Many adolescent female cancer patients will survive into their reproductive years. Pediatric oncologists are advised to discuss oncofertility during treatment planning. In this pilot study, 19 adolescent females completed a retrospective survey assessing recall of a fertility discussion, satisfaction with fertility knowledge, and multiple factors that may influence recall, including parental involvement in decision-making. Eleven respondents (58%) remembered a discussion about infertility risk and 9 (47%) about fertility preservation. Most who recalled a discussion were satisfied with their fertility knowledge (10/11, 90.9%). In this study, we validated the feasibility of survey administration and identified trends in oncofertility counseling at our center.

Proximal Hypospadias and a Novel WT1 Variant: When Should Genetic Testing Be Considered?

We present a case of an infant with proximal hypospadias, penoscrotal transposition, and bilaterally descended testes found to have a clinically significant WT1 gene alteration on a customized disorder of sex development genetic panel in which 62 genes associated with 46, XY disorders of sex development were evaluated. This diagnosis led to early screening for and diagnosis and treatment of Wilms tumor. Patients with proximal hypospadias are not routinely evaluated by genetic testing, and when initial hormonal analyses are within normal ranges for a typical male patient, the genital atypia is usually attributed to an isolated anatomic abnormality. There is no consensus among urologists, endocrinologists, or geneticists regarding when genetic testing is warranted in these patients or the extent of genetic testing that should be pursued. However, given advances in genetic testing and the discovery of more genetic variants, the genetic evaluation of infants with proximal hypospadias should be considered on an individual patient basis. Only with continued evaluation and the identification of further genetic variants can we establish future parameters for genetic evaluation in patients with proximal hypospadias and more appropriately counsel patients and their families regarding the implications of these variants.

Transcription factors GATA-1 and Fli-1 regulate human HOXA10 expression in megakaryocytic cells.

HOXA10 is a member of the HOX family of regulatory genes that are involved in hematopoiesis. Its role in megakaryopoiesis has been suggested by its expression in immature megakaryocytes and by the proliferation of megakaryocyte-primitive blast colonies upon HOXA10 overexpression. We sought to understand the role of HOXA10 in megakaryopoiesis better, by investigating its transcriptional regulation. Analysis of the 5' untranslated region and transfection of promoter/plasmids into human tissue culture cell lines identified transcriptionally active sequences that contain GATA-1 and Ets-1 sites and a putative binding site for its neighboring gene, HOXA11. Gel shift assays confirmed protein-DNA interactions at these sites. Mutation of the GATA-1 and the Ets-1 motifs amplified the expression of HOXA10 in HEL and K562 cells, confirming the importance of these cis-acting elements in regulating HOXA10 expression in megakaryocytic cells. Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression. These data taken together give insight into the regulation of HOXA10 expression in megakaryocytic differentiation.

Proceedings of the Working Group Session on Fertility Preservation for Individuals with Gender and Sex Diversity.

Children and adolescents with gender and sex diversity include (1) gender-nonconforming and transgender individuals for whom gender identity or expression are incongruent with birth-assigned sex (heretofore, transgender) and (2) individuals who have differences in sex development (DSD). Although these are largely disparate groups, there is overlap in the medical expertise necessary to care for individuals with both gender and sex diversity. In addition, both groups face potential infertility or sterility as a result of desired medical and surgical therapies. The Ann & Robert H. Lurie Children's Hospital of Chicago (Lurie Children's) gender and sex development program (GSDP) provides specialized multidisciplinary care for both transgender and DSD patients. In response to patient concerns that recommended medical treatments have the potential to affect fertility, the Lurie Children's GSDP team partnered with experts from the Oncofertility Consortium at Northwestern University to expand fertility preservation options to gender and sex diverse youth. This article summarizes the results of a meeting of experts across this field at the annual Oncofertility Consortium conference with thoughts on next steps toward a unified protocol for this patient group.

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.