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Background: For all fertility preservation (FP) cases at our institution, a biopsy is performed for routine pathology from all gonadal tissue removed. This is not standard at all centers. We reviewed our experience with biopsy for pathological evaluation of ovarian and testicular specimens in FP cases to determine clinical utility., Methods: The medical records of individuals who underwent ovarian tissue cryopreservation (OTC) or testicular tissue cryopreservation (TTC) between 2011 and 2023 were retrospectively reviewed under an IRB-approved study at a free-standing tertiary care children's hospital. Patient demographics, diagnosis, operative characteristics, and pathology results were collected., Results: One-hundred and eighty-three patients underwent OTC, and 134 patients underwent TTC. All patients had their gonadal tissue biopsied for routine pathology. Malignancy was identified in the biopsies of 4 OTC patients (2.2%) and 2 TTC patients (1.5%). Two OTC patients (1.1%) and 2 TTC patients (1.5%) did not have germ cells identified in their biopsy. All OTC and TTC patients and families elected to continue storing tissue for FP after discussion of pathology findings., Conclusions: Pathology results provide another data point to help inform patients and their families when making decisions on ovarian or testicular tissue storage and on how tissue may be utilized in the future to restore fertility and/or hormones. There is a low rate of identifying malignancy in gonadal tissue biopsies taken from FP specimens even in patients with known malignancy. However, when malignancy was identified, it could be unexpected and alter the diagnosis and treatment plan significantly for patients., Level of Evidence: IV., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Study Objective: Isolated tubal torsion (ITT) is a surgical emergency that is less well characterized than ovarian torsion and presents with its own diagnostic challenges. We retrospectively examined patients with ITT and compared them to patients with ovarian torsion to better understand the unique features of this pathophysiologic process., Methods: The medical records of patients who were identified as having ITT or ovarian torsion intraoperatively between January 2019 and November 2022 were reviewed. Patient demographics, clinical documentation, diagnostic imaging reports, operative reports, and pathology results were collected., Results: A total of 82 patients met inclusion criteria of which 62 (75.6%) had ovarian torsion and 20 (24.4%) had ITT. Most patients (63.4%) underwent 2 or more imaging studies prior to the operating room. A diagnosis of torsion occurred more often on preoperative imaging for the ovarian torsion group (67.7% ovarian torsion vs 35.0% ITT, P = .01). Doppler flow to the ovary was expectedly absent in 65.9% of ovarian torsion patients but interestingly also absent in 25% of ITT patients (P = .01). Patients with ovarian torsion were more likely to have ovarian cysts (56.5% vs 10.0%, P < .001), while patients with ITT were significantly more likely to have a paratubal cyst (90.0% vs 38.7%, P < .001)., Conclusion: ITT is a surgical emergency that poses a risk to future fertility. Ultrasound studies, including doppler, may not be as definitive in patients with ITT and early cross-sectional imaging should be considered. When there is a high clinical suspicion for ovarian torsion or ITT, there should be a low threshold for diagnostic laparoscopy., (Copyright © 2024 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Background: Treatment for certain childhood cancers and nonmalignant conditions can lead to future infertility and gonadal failure. The risk of treatment delay must be considered when offering fertility preservation (FP) options. We examined the timeline from FP referral to return to treatment (RTT) in pediatric patients who underwent FP due to iatrogenic risk for infertility., Methods: A retrospective review was performed of patients with FP consultation due to an increased risk of iatrogenic infertility at Ann & Robert H. Lurie Children's Hospital of Chicago from 2018 to 2022. Data on diagnosis, age, treatment characteristics, and procedure were collected., Results: A total of 337 patients (n = 149 with ovaries, n = 188 with testes) had an FP consultation. Of patients with ovaries, 106 (71.1%) underwent ovarian tissue cryopreservation (OTC), 10 (6.7%) completed ovarian stimulation/egg retrieval (OSER), and 33 (22.1%) declined FP. Of the patients with testes, 98 (52.1%) underwent testicular tissue cryopreservation (TTC), 48 (25.5%) completed sperm banking (SB), and 42 (22.3%) declined FP. Median time from referral to FP consultation was short (ovaries: 2 days, range: 0-6; testes: 1 day, range: 0-5). OSER had a significantly longer RTT versus OTC and no FP (52.5 vs.19.5 vs. 12 days, p = .01). SB had a significantly quicker RTT compared to TTC or no FP (9.0 vs. 21.0 vs. 13.5 days; p = .008). For patients who underwent OTC/TTC and those who declined FP, there was no significant difference in time from consultation to treatment., Conclusions: It is feasible to promptly offer and complete FP with minimal delay to disease-directed treatment., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Turner syndrome (TS) is a genetic condition in phenotypic females in which the individual has 1 intact X chromosome and the second sex chromosome is absent or structurally altered Components of Y chromosome (eg, 45,X/46,XY) have been found in 5%-15% of patients with TS; these patients are often referred to as having "Turner syndrome with Y" (TS+Y). The presence of Y chromosome material increases risk for development of gonadal tumors. Historically, prophylactic gonadectomy has been recommended in this population to prevent malignancy, and patients were presumed infertile due to the presence of streak gonads with no germ cells (GCs). More recently, studies have reported on spontaneous puberty and menarche in TS+Y patients suggesting the presence of viable GC and ovarian function. Our institution offers patients with TS+Y the option of experimental gonadal tissue cryopreservation (GTC) at the time of gonadectomy. We present a unique case of a young girl with TS+Y who had GCs present in her gonads and underwent experimental GTC at the time of gonadectomy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Interests M.J.B. has nothing to disclose. D.F. has nothing to disclose. E.L.T. reports funding from NIH/NCI T32 CA009560, NRSA F30HD107966-01, and T32GM008152 outside the submitted work. T.B.L. has nothing to disclose. M.M.L. reports funding from National Institutes of Health U01HD110336 and National Institutes of Health R01HD104683 outside the submitted work. E.E.R. has nothing to disclose.

The only fertility preservation and subsequent restoration option for many patients facing gonadotoxic treatments is ovarian tissue cryopreservation and transplantation. While this process is successful for some, there is significant room for improvement to extend the life of the transplant and to make it safe for patients that may have metastatic disease within their ovarian tissue. We need a deeper understanding of how the physical properties of the ovarian microenvironment may affect folliculogenesis to engineer an environment that supports isolated follicles and maintains primordial follicle quiescence. Bovine ovaries were used here as a monovulatory model of folliculogenesis to examine the effects of primordial follicle activation and growth under different physical conditions. We found that there were no differences in activation, growth or survival when primordial follicles were cultured in isolation or in situ (remaining in the tissue) under two significantly differently rigid alginate gels. To determine if the extra rigid environment did not affect activation in isolated follicles due to an immediate activation event, we used 5-ethynyl-2'-deoxyuridine (EdU) to track follicle activation during the isolation process. We identified EdU incorporation in granulosa cells after primordial follicles were isolated from the surrounding extracellular matrix (ECM). These findings support that isolation of primordial follicles from the ECM is an activating event and that the differentially rigid environments assessed here had no effect on follicle growth. Further work is needed to suppress activation in primordial follicles to maintain the ovarian reserve and extend the life of an ovarian tissue transplant.

Objective: To review the program and patient metrics for ovarian tissue cryopreservation (OTC) within a comprehensive pediatric fertility preservation program in its first 12 years of development., Design: Retrospective review., Setting: A tertiary children's hospital in a large urban center between March 2011 and February 2023., Patients: Pediatric patients who underwent OTC., Interventions: Unilateral oophorectomy for OTC., Main Outcome Measures: Patient demographics and clinical course information were collected for analysis., Results: A total of 184 patients underwent OTC in the first 12 years. One hundred fifteen patients were prepubertal at the time of OTC, and 69 were postpubertal. In total, 128 patients (69.6%) received part of their planned therapy before OTC. Starting in 2018, 104 participants (92.0%) donated tissue to research, 99 participants (87.6%) donated blood, and 102 (90.2%) donated media to research. There was a decrease in the median age of patients who underwent OTC from 16.4-6.6 years and an overall increase in the proportion of patients per year that were prepubertal. Forty-eight (26.0%) patients who underwent OTC were outside referrals and traveled from as far as Seattle, Washington., Conclusion: During the first 12 years of this program, oncofertility research increased, annual tissue cryopreservation cases increased, and the median age of those who underwent OTC decreased. The program was adapted to build a stand-alone gonadal tissue processing suite and specialized in prepubertal ovarian tissue processing. The program will continue to adapt to patient needs in the upcoming decades because restoration technologies advance through research supported by this and collaborating programs., Competing Interests: K.L.M. has nothing to disclose. T.K. has nothing to disclose. E.E.R. has nothing to disclose. M.M.L. has nothing to disclose., (© 2024 The Authors.)

Study Question: Does a chemically defined maturation medium supplemented with FGF2, LIF, and IGF1 (FLI) improve in vitro maturation (IVM) of cumulus-oocyte complexes (COCs) obtained from children, adolescents, and young adults undergoing ovarian tissue cryopreservation (OTC)?, Summary Answer: Although FLI supplementation did not increase the incidence of oocyte meiotic maturation during human IVM, it significantly improved quality outcomes, including increased cumulus cell expansion and mitogen-activated protein kinase (MAPK) expression as well as enhanced transzonal projection retraction., What Is Known Already: During OTC, COCs, and denuded oocytes from small antral follicles are released into the processing media. Recovery and IVM of these COCs is emerging as a complementary technique to maximize the fertility preservation potential of the tissue. However, the success of IVM is low, especially in the pediatric population. Supplementation of IVM medium with FLI quadruples the efficiency of pig production through improved oocyte maturation, but whether a similar benefit occurs in humans has not been investigated., Study Design, Size, Duration: This study enrolled 75 participants between January 2018 and December 2021 undergoing clinical fertility preservation through the Fertility & Hormone Preservation & Restoration Program at the Ann & Robert H. Lurie Children's Hospital of Chicago. Participants donated OTC media, accumulated during tissue processing, for research., Participants/materials, Setting, Methods: Participants who underwent OTC and include a pediatric population that encompassed children, adolescents, and young adults ≤22 years old. All participant COCs and denuded oocytes were recovered from media following ovarian tissue processing. IVM was then performed in either a standard medium (oocyte maturation medium) or one supplemented with FLI (FGF2; 40 ng/ml, LIF; 20 ng/ml, and IGF1; 20 ng/ml). IVM outcomes included meiotic progression, cumulus cell expansion, transzonal projection retraction, and detection of MAPK protein expression., Main Results and the Role of Chance: The median age of participants was 6.3 years, with 65% of them classified as prepubertal by Tanner staging. Approximately 60% of participants had been exposed to chemotherapy and/or radiation prior to OTC. On average 4.7 ± 1 COCs and/or denuded oocytes per participant were recovered from the OTC media. COCs (N = 41) and denuded oocytes (N = 29) were used for IVM (42 h) in a standard or FLI-supplemented maturation medium. The incidence of meiotic maturation was similar between cohorts (COCs: 25.0% vs 28.6% metaphase II arrested eggs in Control vs FLI; denuded oocytes: 0% vs 5.3% in Control vs FLI). However, cumulus cell expansion was 1.9-fold greater in COCs matured in FLI-containing medium relative to Controls and transzonal projection retraction was more pronounced (2.45 ± 0.50 vs 1.16 ± 0.78 projections in Control vs FLIat 16 h). Additionally, MAPK expression was significantly higher in cumulus cells obtained from COCs matured in FLI medium for 16-18 h (chemiluminescence corrected area 621,678 vs 2,019,575 a.u., P = 0.03)., Limitations, Reasons for Caution: Our samples are from human participants who exhibited heterogeneity with respect to age, diagnosis, and previous treatment history. Future studies with larger sample sizes, including adult participants, are warranted to determine the mechanism by which FLI induces MAPK expression and activation. Moreover, studies that evaluate the developmental competence of eggs derived from FLI treatment, including assessment of embryos as outcome measures, will be required prior to clinical translation., Wider Implications of the Findings: FLI supplementation may have a conserved beneficial effect on IVM for children, adolescents, and young adults spanning the agricultural setting to clinical fertility preservation., Study Funding/competing Interest(s): This work was supported by Department of Obstetrics and Gynecology startup funds (F.E.D.), Department of Surgery Faculty Practice Plan Grant and the Fertility & Hormone Preservation & Restoration Program at the Ann & Robert H. Lurie Children's Hospital of Chicago (M.M.L. and E.E.R.). M.M.L. is a Gesualdo Foundation Research Scholar. Y.Y.'s research is supported by the internal research funds provided by Colorado Center of Reproductive Medicine. Y.Y., L.D.S., R.M.R., and R.S.P. have a patent pending for FLI. The remaining authors have no conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Tumors of the breast and reproductive organs that occur in children, adolescents, and young adults (AYA) have different biological features and can present special challenges. Although prognosis for these tumors is generally favorable, the long-term effects of treatment can be debilitating. Treatments are often multimodal and may include surgery as well as chemotherapy and/or radiation, which can cause considerable distress and anxiety related to loss of femininity or masculinity, concern over future fertility, or sexual dysfunction. Thus, tumors of the reproductive organs in pediatric/AYA patients require special consideration of the treatment effects beyond the intended oncologic outcome. Multidisciplinary teams should be involved in their care and address issues of fertility, sexual dysfunction, and psychosexual concerns before treatment begins. This review addresses histology, risk factors, prognosis, staging and treatment of gynecologic, breast and testicular cancers in pediatric and AYA patients., (© 2021 Wiley Periodicals LLC.)

Objective: To outline our experimental gonadal tissue cryopreservation (GTC) protocol that does not disrupt the standard of care in medically-indicated gonadectomy for patients with differences of sex development, including highlighting the multidisciplinary collaborative protocol for when neoplasm is discovered in these cases., Methods: Two patients with complete gonadal dysgenesis who were undergoing medically-indicated prophylactic bilateral gonadectomy elected to pursue GTC. Both were found to have germ cell neoplasia in situ on initial pathologic analysis, requiring recall of the gonadal tissue, which had been cryopreserved., Results: Cryopreserved gonadal tissue was successfully thawed and transferred to pathology for complete analysis. No germ cells were identified in either patient nor were found to have malignancy, so further treatment beyond gonadectomy was not indicated. Pathologic information was communicated to each family, including that long-term GTC was no longer possible., Conclusion: Organizational planning and coordination between the clinical care teams, GTC laboratory, and pathology were key to handling these cases with neoplasia. Processes that anticipated the possibility of discovering neoplasia within tissue sent to pathology and the potential need to recall GTC tissue to complete staging included (1) documenting the orientation and anatomical position of tissue processed for GTC, (2) defining parameters in which tissue will be recalled, (3) efficiently thawing and transferring GTC tissue to pathology, and (4) coordinating release of pathology results with verbal communication from the clinician to provide context. GTC is desired by many families and at the time of gonadectomy and is (1) feasible for patients with DSD, and (2) did not inhibit patient care in 2 patients with GCNIS., Competing Interests: DECLARATION OF COMPETING INTEREST Authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Eighty percent of children diagnosed with cancer in childhood survive into adulthood. Fertility preservation (FP) is an important consideration, and procedures are available to reduce the risk of infertility following gonadotoxic therapies. Discussing FP options eases decision-making and minimizes regret; however, poor comprehension of these topics remains a challenge. This study evaluates if video-based educational tools increase understanding of FP options among pediatric patients and families. Videos were first tested among participants not at risk of infertility to ensure objective utility and optimize quality. In part 1, parents of pediatric surgical patients were randomized to view 2 publicly available educational videos on FP in differing orders. Each group completed pre-surveys and post-surveys assessing the comprehension and perception of video quality. In part 2, the parent and patient participants completed a comprehension assessment before and after viewing our institution-specific educational video, designed based on participant feedback from part 1. Part 1 results demonstrated a significant increase in participant knowledge and perceived understanding after viewing the videos ( P <0.001), regardless of order. In part 2, the post-test comprehension scores were significantly improved for all participants and all subgroups, P <0.01. Results suggest that video-based educational tools may help to reduce barriers to FP in pediatric oncology., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To study ovarian gross morphologic and subanatomic features across pubertal development., Design: Prospective cohort study., Setting: An academic medical center with specimens collected from 2018-2022., Patients: Tissue was obtained from prepubertal and postpubertal participants (0.19-22.96 years) undergoing ovarian tissue cryopreservation before treatment that put them at a significantly or high increased risk of developing premature ovarian insufficiency. Most participants (64%) had not received chemotherapy at tissue collection., Interventions: None., Main Outcome Measures: Ovaries procured for fertility preservation were weighed and measured. Ovarian tissue fragments released during processing, biopsies used for pathology, and hormone panels were analyzed for gross morphology, subanatomic features, and reproductive hormones. Graphical analysis of best-fit lines determined age at maximum growth velocity., Results: Prepubertal ovaries were significantly (1.4-fold and 2.4-fold) smaller than postpubertal ovaries by length and width and 5.7-fold lighter on average. Length, width, and weight grew in a sigmoidal pattern with age. Prepubertal ovaries were less likely to display a defined corticomedullary junction (53% vs. 77% in postpubertal specimens), less likely to have a tunica albuginea (22% vs. 93% in postpubertal specimens), contained significantly more (9.8-fold) primordial follicles, and contained primordial follicles at significantly deeper depths (2.9-fold) when compared with postpubertal ovaries., Conclusions: Ovarian tissue cryopreservation is a resource to study human ovarian biology and pubertal development. Maximum growth velocity occurs late within the pubertal transition (Tanner 3+) after changes in subanatomic features. This ovarian morphology model adds to foundational knowledge of human ovarian development and supports ongoing transcriptomics research., (© 2023 The Author(s).)

Decisions about fertility preservation can be difficult in general but the recent application of preservation techniques to pediatric patients has ushered in a host of new ethical considerations. Fertility preservation (FP) may be considered for all patients who are at risk for infertility due to their medical diagnosis or treatment, including those undergoing gonadotoxic chemotherapy, those with differences of sex development (DSD) undergoing gonadectomy, 1-3 and transgender patients undergoing gender affirming surgery. The focus of this paper is to review the ethical issues involved in offering FP to pediatric oncology patients and, to a lesser extent, the new ethical issues that apply to patients with DSD. Some of the techniques and approach to counseling will also apply to transgender individuals, although that is beyond the scope of this work. We aim to discuss several barriers to offering FP and to advise how to counsel families in the setting of rapid changes in this field. Families should be educated about:Specific guidance for clinicians regarding some of these points was recently published in an American Academy of Pediatrics Clinical Report, 1 and we will illustrate the use of these guidelines in four case presentations., (Copyright © 2021. Published by Elsevier Inc.)

Survivors of pediatric cancer are at increased risk for infertility and premature hormonal failure. Surgeons caring for children with cancer have an important role to play in understanding this risk, as well as advocating for and performing appropriate fertility preservation procedures. Fertility preservation options in males and females vary by pubertal status and include nonexperimental (oocyte harvest, ovarian tissue cryopreservation, sperm cryopreservation) and experimental (testicular tissue cryopreservation) options. This review summarizes the basics of risk assessment and fertility preservation options and explores unique considerations in pediatric fertility preservation., Competing Interests: Disclosure The authors have no commercial or financial conflicts of interest to disclose. The authors have no sources of funding to report., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Laparoscopic oophorectomy with tissue cryopreservation (OTC) for fertility preservation is usually performed prior to therapy. When fertility preservation is considered after prior open abdominopelvic tumor surgery there may be a perceived barrier to laparoscopic OTC. This study evaluates the feasibility of OTC with a laparoscopic approach after open surgery., Methods: This is a single institution retrospective study from 2011 to 2019., Results: Planned laparoscopic OTC was performed after open surgery in 17 of 113 patients. Median age was 4.2 years. The most common diagnoses were Wilms Tumor (35%) and neuroblastoma (35%). The most common procedures were nephrectomy (41%) and exploratory laparotomy with biopsy (35%). The median amount of time between open surgery and OTC was 29 days. Sixteen (94%) had a laparoscopic OTC. Regardless of operative technique, patients resumed therapy a median of 3 days after OTC., Conclusions: Prior abdominopelvic surgery should not be a barrier to OTC. Laparoscopic OTC is feasible after a variety of open oncologic operations, regardless of time-interval between the procedures and without incurring a significant delay in resuming oncologic therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Many individuals with differences of sex development experience subfertility. We describe a novel gonadal tissue cryopreservation protocol for those individuals., Materials and Methods: Before 2018 patients with differences of sex development electing gonadal tissue cryopreservation were enrolled in a cancer focused protocol. Thereafter, our hospital developed a protocol specifically for these patients undergoing gonadectomy due to neoplasia risk. Protocol development steps and procedures are reported. A retrospective chart review was conducted for patient characteristics and cryopreservation choices., Results: During the institutional review board approval process there were multidisciplinary meetings with stakeholders. The main concerns discussed included preoperative counseling, pathological evaluation and final tissue disposition. Detailed multidisciplinary preoperative counseling is provided regarding potential gonadal tissue cryopreservation for patients undergoing gonadectomy. For enrolled patients the gonad is bisected after removal, with half being sent to pathology and half being processed for cryopreservation. If neoplasia is noted, cryopreserved tissue is recalled for further pathological analysis. Postoperative counseling is performed after pathology results are available, and the final gonadal tissue cryopreservation decision is made. During the study period 7 patients with 5 diagnoses and a median age of 10.99 years (IQR 1.29 to 14.84) elected to attempt gonadal tissue cryopreservation. Of the patients 4 (57%) had germ cells and elected to store tissue., Conclusions: Gonadal tissue cryopreservation at the time of gonadectomy is feasible for patients with differences of sex development at risk for gonadal neoplasia. The protocol described represents a template for institutions wishing to offer gonadal tissue cryopreservation to patients electing gonadectomy. More than half of patients thus far have cryopreserved gonadal tissue.

Purpose: The significant reduction in childhood cancer mortality has allowed for greater emphasis on survivorship issues, including infertility. This study evaluated the participation of pediatric surgery training programs in fertility preservation (FP) and exposure of fellows to adnexal cases. Materials and Methods: A survey was distributed to pediatric surgery fellowship program directors in the United States and Canada through email. Questions focused on FP participation, operative cases, FP program limitations, and fellow completion of adnexal cases. Results: Survey participation was 49% (28/57). Overall, 43% (12/28) of training programs report participation in FP initiatives. Of those who participated, the most common procedures performed were testicular tissue biopsy (58%) and testicular sperm extraction (42%) in males, and surgical transposition of the ovaries (83%) and laparoscopic oophorectomy (67%) in females. The greatest cited limitations on participation were that FP was another department's responsibility (50%) and lack of multidisciplinary team (31%). Notably, lack of operative experience in benign ovarian and testicular procedures (0%) was not a limitation. All programs, regardless of participation in FP, noted that their fellows performed benign and malignant adnexal cases. Conclusion: Less than half of pediatric surgery training programs participate in FP initiatives, despite adequate advanced minimally invasive training of fellows to perform these procedures.

Background: The only pre-treatment fertility preservation option for prepubertal girls, who are at risk for infertility due to their diagnosis or treatment, is surgical removal of ovarian tissue for cryopreservation (OTC). We investigated ovarian tissue health following isolation with an ultrasonic advanced energy device (UAED), that has a previously reported thermal spread of ≤2 cm., Methods: The ovaries of eight Yucatan minipigs were isolated by laparoscopy (1) close dissection with the UAED located up to 2 mm away from the ovarian capsule, (2) far dissection with the UAED located >2 cm away, or by (3) laparotomy for control ovaries using cold scissors. Ovarian cortex tissues were cultured for 4 days to assess tissue health., Results: Ovarian cortex tissue isolated using a UAED produced an altered metabolic ratio in both the far and close dissection compared to control (p < 0.001). There was an increase in folliculogenesis in the control samples over samples isolated with far and close dissection (p < 0.0001), and a reduction in estradiol production in experimental groups (p < 0.0001)., Conclusions: This model defines differences in ovarian tissue health among different isolation techniques. Ongoing work will further define the standard of care surgical technique for OTC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Survival for children with cancer has improved significantly in recent decades, prompting an increasing emphasis on minimizing late effects of therapy, including infertility and premature gonadal insufficiency. The time interval after diagnosis and before therapy initiation can be stressful and overwhelming for patients and their families coming to terms with the implications of the diagnosis, but is also the optimal time to address oncofertility options. Pediatric surgeons are often an integral part of the care team for these patients during this vulnerable time period and play a key role in advocating for and performing oncofertility procedures. Children with cancer have both non-experimental and experimental fertility preservation options available depending on their pubertal status and a risk assessment performed based on their anticipated therapy. This review provides an oncofertility toolkit for pediatric surgeons to perform a risk assessment, counsel families on fertility preservation options, and establish an oncofertility program tailored to the resources available at their institutions., (Copyright © 2019. Published by Elsevier Inc.)

Background/purpose: Testicular tissue cryopreservation (TTC) provides an experimental option for fertility preservation for male children at significant risk for azoospermia owing to high-risk gonadotoxic treatments., Methods: A single institution, retrospective review of TTC cases from 2015 to 2017. Children at significant risk for azoospermia were eligible for study inclusion. A unilateral wedge biopsy of the testis was performed for TTC., Results: TTC was performed in 23 patients. Average age was 10 years old (5 months to 18 years). Diagnoses included solid tumor (74%, n = 17), hematologic malignancy (17%, n = 4), and benign hematologic disease (13%, n = 3). Six patients had TTC at the time of disease relapse. Nine patients were referred for TTC prior to stem cell transplantation. The majority (70%, n = 16) of patients had an additional procedure at the time of TTC. One patient developed postoperative scrotal cellulitis that was treated with antibiotics. The majority of patients (96%, n = 22) had normal testicular tissue with the presence of germ cells on histopathological analysis. Median time to start of medical therapy was seven days with no unanticipated treatment delays., Conclusions: Testicular wedge biopsy for TTC can be performed safely, coordinated with other necessary procedures, and does not delay the start of treatment. TTC remains an experimental option for fertility preservation for children, as no spermatogenic recovery or pregnancies from cryopreserved testicular tissues have been reported to date., Level of Evidence: IV., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Study Question: Is it feasible to disseminate testicular tissue cryopreservation with a standardized protocol through a coordinated network of centers and provide centralized processing/freezing for centers that do not have those capabilities?, Summary Answer: Centralized processing and freezing of testicular tissue from multiple sites is feasible and accelerates recruitment, providing the statistical power to make inferences that may inform fertility preservation practice., What Is Known Already: Several centers in the USA and abroad are preserving testicular biopsies for patients who cannot preserve sperm in anticipation that cell- or tissue-based therapies can be used in the future to generate sperm and offspring., Study Design, Size, Duration: Testicular tissue samples from 189 patients were cryopreserved between January 2011 and November 2018. Medical diagnosis, previous chemotherapy exposure, tissue weight, and presence of germ cells were recorded., Participants/materials, Setting, Methods: Human testicular tissue samples were obtained from patients undergoing treatments likely to cause infertility. Twenty five percent of the patient's tissue was donated to research and 75% was stored for patient's future use. The tissue was weighed, and research tissue was fixed for histological analysis with Periodic acid-Schiff hematoxylin staining and/or immunofluorescence staining for DEAD-box helicase 4, and/or undifferentiated embryonic cell transcription factor 1., Main Results and the Role of Chance: The average age of fertility preservation patients was 7.9 (SD = 5) years and ranged from 5 months to 34 years. The average amount of tissue collected was 411.3 (SD = 837.3) mg and ranged from 14.4 mg-6880.2 mg. Malignancies (n = 118) were the most common indication for testicular tissue freezing, followed by blood disorders (n = 45) and other conditions (n = 26). Thirty nine percent (n = 74) of patients had initiated their chemotherapy prior to undergoing testicular biopsy. Of the 189 patients recruited to date, 137 have been analyzed for the presence of germ cells and germ cells were confirmed in 132., Limitations, Reasons for Caution: This is a descriptive study of testicular tissues obtained from patients who were at risk of infertility. The function of spermatogonia in those biopsies could not be tested by transplantation due limited sample size., Wider Implications of the Findings: Patients and/or guardians are willing to pursue an experimental fertility preservation procedure when no alternatives are available. Our coordinated network of centers found that many patients request fertility preservation after initiating gonadotoxic therapies. This study demonstrates that undifferentiated stem and progenitor spermatogonia may be recovered from the testicular tissues of patients who are in the early stages of their treatment and have not yet received an ablative dose of therapy. The function of those spermatogonia was not tested., Study Funding/competing Interest(s): Support for the research was from the Eunice Kennedy Shriver National Institute for Child Health and Human Development grants HD061289 and HD092084, the Scaife Foundation, the Richard King Mellon Foundation, the Departments of Ob/Gyn & Reproductive Sciences and Urology of the University of Pittsburgh Medical Center, United States-Israel Binational Science Foundation (BSF), and the Kahn Foundation. The authors declare that they do not have competing financial interests., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)

Purpose of Review: Rapid advancement in the field of pediatric surgery has resulted in unprecedented opportunities to advance the care of children. However, assuring that the highest quality, most appropriate care is available to all pediatric patients remains challenging. Regionalization of care has been proposed as a means of obtaining this critical goal. In this review, we discuss the ethical challenges associated with regionalization of pediatric surgical care., Recent Findings: Regionalization of pediatric surgical care is associated with improved patient outcomes. Over half of pediatric surgeons favor regionalization of care. Despite these findings, regionalization of care may be associated with inequitable distribution of resources, financial and emotional burdens for patients and families, and surgeon dissatisfaction and technical decline., Summary: Regionalization of pediatric surgical care is fraught with complex ethical issues. Development of a system of pediatric surgery networks may offer a solution to these challenges.

Infertility is known to decrease quality of life among adults. In some cases, infertility is caused by medical conditions and/or treatments prescribed in childhood, and using methods to protect or preserve fertility may expand future reproductive possibilities. Structured programs to offer counseling about infertility risk and fertility preservation options are essential in the care of pediatric patients facing fertility-threatening conditions or treatments, yet multiple barriers to program development exist. This report was developed from the institutional experiences of members of the Pediatric Initiative Network of the Oncofertility Consortium, with the intent of providing guidance for health care providers aiming to establish programs at institutions lacking pediatric fertility preservation services. The mechanics of building a fertility preservation program are discussed, including essential team members, target populations, fertility preservation options (both established and experimental), survivorship issues, research opportunities, and ethical considerations. Common barriers to program development and utilization, including low referral rates and financial concerns, are also discussed, and recommendations made for overcoming such barriers., (Copyright © 2018 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background/purpose: Many survivors of childhood cancer will experience premature gonadal insufficiency or infertility as a consequence of their medical treatments. Ovarian tissue cryopreservation (OTC) remains an experimental means of fertility preservation with few reports focused on the surgical technique and postoperative outcomes for OTC in children., Methods: This is a single institution, retrospective review of OTC cases from January 2011 to December 2017. Children were eligible for OTC if they had a greater than 80% risk of premature ovarian insufficiency or infertility owing to their anticipated gonadotoxic medical treatment., Results: OTC was performed in 64 patients. Median age was 12 years old (range: 5 months-23 years). Nearly half (48%) of the patients were premenarchal. Laparoscopic unilateral oophorectomy was performed in 84% of patients. There were no surgical complications. In 76% of patients, OTC was performed in conjunction with an ancillary procedure. The majority (96%) of patients were discharged within 24 hours. Median time from operation to medical therapy was six days, with no unanticipated treatments delays attributable to OTC., Conclusions: Laparoscopic unilateral oophorectomy for OTC can be performed safely, in combination with other ancillary procedures, as an outpatient procedure without delaying medical therapy for children facing a fertility-threatening diagnosis or treatment., Level of Evidence: IV., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Infertility is common for individuals with differences of sex development (DSD) and is a significant concern to these individuals. Fertility potential in many DSD conditions is poorly understood. Gonadal tissue cryopreservation (GTC) for fertility preservation (FP) is offered to children with cancer undergoing gonadotoxic therapy. Our team sought to expand the field of FP by offering and evaluating the success of GTC for individuals with DSD., Materials and Methods: GTC was offered to patients with DSD undergoing prophylactic gonadectomy, after extensive multidisciplinary counseling. For those who elected to attempt GTC, data were retrospectively abstracted, including: DSD diagnosis, age at gonadectomy, indication for gonadectomy, pathology results, and final decision about long-term gonadal tissue storage., Results: Ten patients were enrolled to attempt GTC, with a mean age of 11.5 years (range 1-18). Five of the 10 patients had germ cells (GCs) present. Diagnoses (age at gonadectomy) for patients with GCs included ovotesticular DSD (13 months), mixed gonadal dysgenesis (17 months), partial gonadal dysgenesis (3 years), partial androgen insensitivity syndrome (11 years), and mixed gonadal dysgenesis (12 years). Four of the 5 subjects with GCs elected for GTC. One opted against GTC, citing immature gametes that did not match gender identity., Conclusion: GTC at the time of gonadectomy for patients with DSD is feasible. In many patients, GCs are present. While questions remain about the timing of gonadectomy, quality of GCs, and future success for use of the tissue based on technological advancement, GTC represents a novel approach to experimental FP for individuals with DSD., (© 2019 S. Karger AG, Basel.)

Background: Children with chronic conditions, including cancer, have been shown to have high-intensity end-of-life care. We assessed the frequency and timing of invasive procedures that children with cancer undergo during their terminal hospital admission (THA)., Methods: The Pediatric Health Information System database was queried from 2011 to 2015 for patients ages 1-18 years with a "malignancy" flag who died in the hospital. Patient demographics, admission details, procedures codes, and date of service were extracted. Invasive procedures were categorized into 'major operations' or 'minor procedures'., Results: 2210 children with cancer were identified as having a THA. During the THA, 1423 (64.4%) patients underwent an invasive procedure and 856 (60.1%) of those children underwent three or more procedures. 466 (21.1%) patients underwent a total of 780 major operations. The most common operations were ventriculostomy/ventriculoperitoneal shunt (n = 211), intracranial mass excision (n = 60), bowel resection (n = 56), and exploratory laparotomy/laparoscopy (n = 46). 101 (21.7%) patients who underwent a major operation died within 48 h of surgery., Conclusions: Children who have cancer and die in the hospital face a large procedural burden prior to their death. This study highlights the need for open, multidisciplinary discussions regarding the necessity of these procedures and for surgeon involvement in complex end-of-life care decisions., Type of Study: Retrospective cohort review., Level of Evidence: Level IV., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Ovarian tissue cryopreservation is increasing as a preferred option for fertility preservation for prepubertal and young adolescent females facing a fertility threatening diagnosis or treatment., Data Sources: Ovid MEDLINE and PubMed searches for terms related to ovarian tissue removal for fertility preservation revealed there is no current consensus on operative technique for surgical ovarian cortical tissue removal in adult females. Additionally, there are limited published reports of surgical approach and outcomes in the pediatric population. In total, 22 publications were reviewed for their operative approach, ovarian tissue harvesting techniques, complications and outcomes., Conclusions: Reported operative approaches and techniques for ovarian tissue cryopreservation for pediatric and adolescent patients are variable. Further investigations into operative technique and tissue harvesting that maintains healthy ovarian follicles for transplant will help establish standard technical principles for surgery in pediatric and adolescent females undergoing fertility preservation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Uterine leiomyoma is the most common uterine tumor in adult females but is rare in the pediatric population with only 10 previous cases reported. We describe the unique case of a 15-year-old girl who presented with abdominal pain and menometrorrhagia and was found to have a uterine leiomyoma as well as a mature ovarian teratoma that required surgical resection. We review diagnostic imaging and optimal management for the 2 gynecologic masses in this teenage girl., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A 14-year-old boy was seen at an outside hospital after falling over the handlebar of his bicycle and was discharged home. He was subsequently seen in our emergency department with complaints of persistent abdominal pain. A computed tomography scan of the abdomen revealed disruption of the muscles of the upper right abdominal wall containing the hepatic flexure of the colon, with a small amount of intraperitoneal free fluid noted. The patient underwent laparoscopic exploration using 3 ports (2-5 mm and 1-12 mm) and 2 separate stab incisions. The traumatic abdominal wall hernia was repaired with interrupted sutures placed with an ENDO CLOSE (Covidien, Mansfield, MA) device, and a mesenteric defect in the colon was approximated with intracorporeal sutures. The trocar sites were sutured closed. The patient recovered well and was discharged home. Follow-up examination revealed no abdominal wall defect and resolution of his symptoms. Laparoscopic repair of a traumatic abdominal wall defect and exploratory laparoscopy after trauma is feasible and safe in the pediatric patient. It should be considered as an alternative approach with potentially less morbidity than an exploratory laparotomy for handlebar injuries in a stable patient., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Certain forms of the heavy metals arsenic and chromium are considered human carcinogens, although they are believed to act through very different mechanisms. Chromium(VI) is believed to act as a classic and mutagenic agent, and DNA/chromatin appears to be the principal target for its effects. In contrast, arsenic(III) is considered nongenotoxic, but is able to target specific cellular proteins, principally through sulfhydryl interactions. We had previously shown that various genotoxic chemical carcinogens, including chromium (VI), preferentially altered expression of several inducible genes but had little or no effect on constitutive gene expression. We were therefore interested in whether these carcinogenic heavy metals might target specific but distinct sites within cells, leading to alterations in gene expression that might contribute to the carcinogenic process. Arsenic(III) and chromium(VI) each significantly altered both basal and hormone-inducible expression of a model inducible gene, phosphoenolpyruvate carboxykinase (PEPCK), at nonovertly toxic doses in the chick embryo in vivo and rat hepatoma H411E cells in culture. We have recently developed two parallel cell culture approaches for examining the molecular basis for these effects. First, we are examining the effects of heavy metals on expression and activation of specific transcription factors known to be involved in regulation of susceptible inducible genes, and have recently observed significant but different effects of arsenic(III) and chromium(VI) on nuclear transcription factor binding. Second, we have developed cell lines with stably integrated PEPCK promoter-luciferase reporter gene constructs to examine effects of heavy metals on promoter function, and have also recently seen profound effects induced by both chromium(VI) and arsenic(III) in this system. These model systems should enable us to be able to identify the critical cis (DNA) and trans (protein) cellular targets of heavy metal exposure leading to alterations in expression of specific susceptible genes. It is anticipated that such information will provide valuable insight into the mechanistic basis for these effects as well as provide sensitive molecular biomarkers for evaluating human exposure.

Mitomycin C (MMC) is a DNA crosslinking agent that is used in cancer chemotherapy. Unlike the DNA crosslinks formed by cisplatin or psoralen, which significantly distort the DNA helix, the MMC crosslink does not significantly disturb the B-DNA helical structure. Nonetheless, MMC interstrand crosslinks and total MMC adducts are rapidly removed in vivo. We investigated whether mammalian nuclear proteins can recognize and bind to a model 23 bp DNA duplex containing a single MMC lesion. Electrophoretic mobility shift assays identified two complexes in nuclear extracts from rodent cell lines and three complexes in human cell lines, containing proteins that appeared to specifically recognize the MMC interstrand crosslink. Nuclear extracts from normal and excision repair-defective mutant Chinese hamster ovary (CHO) cell lines, from human Xeroderma Pigmentosum (XP) complementation group A and E cell lines, and a Fanconi's Anemia cell line were also examined. The UV-20 CHO line, defective in ERCC-1, was missing one of the two rodent complexes. Two of the three human complexes were also absent in the XPA human cell line and the intensity of the third complex was significantly diminished. Based on these results, a model for MMC crosslink recognition is proposed in which ERCC-1 and XPA each participate in formation of one or more multimeric complexes on the crosslinked DNA and XPA also aids in the formation, but is not a component of a higher molecularweight multimeric complex that may contain ERCC-1.