Prepubertal Patients Research Articles

Hypogonadism After Treatment for Medulloblastoma: Results From the SJMB03 Trial of Risk-Adapted Radiation Therapy

Our purpose was to estimate the cumulative incidence (CI) of hypogonadism in a cohort of pediatric patients treated for medulloblastoma with surgery, risk-adapted craniospinal irradiation, and dose-intensive chemotherapy. Children and adolescents (n=156) treated between 2003 and 2013 were evaluated for evidence of hypogonadism and infertility. Clinical information and mean radiation dose to the hypothalamus and gonads and cumulative doses of chemotherapy agents were recorded to estimate CI of hypogonadism and infertility with competing risks. The 5-year CI of hypogonadism was 71.25% (±6.76%) for women and 6.48% (±3.16%) for men (P < .0001) and 50.00% (±9.70%) for puberty age and 28.99% (±5.05%) for prepuberty age at treatment (P=.0068). The 5-year CI by gonadal radiation dose exposure (GRDE) was 61.11% (±12.13%) for high (>2 Gy), 61.18% (±12.92%) for intermediate (1-2 Gy), and 21.97% (±4.76%) for low (<1 Gy) (P < .0001). Sex, puberty status, GRDE, interval from treatment to puberty, and vincristine dose were associated with hypogonadism. Hypogonadism in female sex was highly correlated with GRDE, and dose to hypothalamus was significant when included in multivariable models or when used in models restricted to patients treated after the age of puberty. CI of infertility at 10 years was 55.36% (±14.07%) for women and 23.53% (±10.64%) for men (P=.0389) in a sample of 33 patients. In the setting of intensive chemotherapy, low-dose gonadal radiation exposure has a significant effect on gonadal function. Women and those achieving age of puberty at time of radiation therapy have a higher risk of hypogonadism. GRDE > 2 Gy was associated with hypogonadism for all groups and >1 Gy in prepubertal patients. Hypothalamus dose was significant when included in multivariable models that included postpubertal patients and those with lower GRDE.

Pre-pubertal oocytes harbor altered histone modifications and chromatin configuration.

Pre-pubertal oocytes are still dormant. They are arrested in a GV state and do not undergo meiotic divisions naturally. A multitude of molecular pathways are changed and triggered upon initiation of puberty. It is not yet clear which epigenetic events occur in oocytes upon pubertal transition, and how significant these epigenetic events may be. We evaluated epigenetic marker levels in mouse pre-pubertal and post-pubertal female oocytes. In addition, we evaluated H3K9me2 levels in human oocytes collected from fertility preservation patients, comparing the levels between pre-pubertal patients and post-pubertal patients. The chromatin structure shows a lower number of chromocenters in mouse post-pubertal oocytes in comparison to pre-pubertal oocytes. All heterochromatin marker levels checked (H3K9me2, H3K27me3, H4K20me1) significantly rise across the pubertal transition. Euchromatin markers vary in their behavior. While H3K4me3 levels rise with the pubertal transition, H3K27Ac levels decrease with the pubertal transition. Treatment with SRT1720 [histone deacetylase (HDAC) activator] or overexpression of heterochromatin factors does not lead to increased heterochromatin in pre-pubertal oocytes. However, treatment of pre-pubertal oocytes with follicle-stimulating hormone (FSH) for 24h - changes their chromatin structure to a post-pubertal configuration, lowers the number of chromocenters and elevates their histone methylation levels, showing that hormones play a key role in chromatin regulation of pubertal transition. Our work shows that pubertal transition leads to reorganization of oocyte chromatin and elevation of histone methylation levels, thus advancing oocyte developmental phenotype. These results provide the basis for finding conditions for in-vitro maturation of pre-pubertal oocytes, mainly needed to artificially mature oocytes of young cancer survivors for fertility preservation purposes.

Comparison of two prediction models in a clinical setting to predict growth in prepubertal children on recombinant growth hormone

ObjectivePrediction models that calculate the growth response in children on recombinant growth hormone (GH) have shown to be helpful tools in deciding who should start treatment, as identifying GH deficiency can be a challenge. The aim of the study is to compare two prediction models; the KIGS (Pfizer International Growth Study) prediction models which are more accessible and the Gothenburg model which has previously been clinically validated. DesignAll prepubertal patients who commenced GH treatment at Queen Silvia Children's Hospital in Gothenburg during a 13-year-period were candidates for the study. Children were excluded if suspected syndrome, malignant disease, chronic disease, or poor adherence to treatment were found. The KIGS model and the Gothenburg model were used to make predictions. Data was obtained from medical charts for the period from birth to the end of the first year of treatment. The predicted height outcome was compared against observed. ResultsThe study included 123 prepubertal children (76 males). The average age at treatment start and standard deviation (SD) was 5.7 (1.8) years. Correlation analyses were performed between predicted growth by both the Gothenburg and KIGS models versus the first year observed growth response showing strong correlations of r = 0.990 and r = 0.991 respectively with studentized residuals of 0.10 (0.81) for the Gothenburg model and 0.03 (0.96) for the KIGS model. ConclusionWe found that both the Gothenburg model and the KIGS model are equivalent when applying to our clinical cohort. Both models are very precise, hence it is encouraged to use either based on accessibility for the clinic.

Craniofacial morphology of patients with unilateral cleft lip and palate at two stages of skeletal maturation.

The aim of this retrospective cross-sectional investigation was to perform a 3D analysis of craniofacial morphology of patients with unilateral cleft lip and palate (UCLP) at two stages of skeletal maturation. Cone-beam computed tomography (CBCT) scans of 52 UCLP patients (34 prepubertal; 18 pubertal) were collected from an outpatient referral center for the treatment of craniofacial deformities. In total 15 multiplanar craniofacial landmarks were identified, 3D virtual surface models were created, and 13 variables were measured to assess the 3D Euclidean distances between landmarks and spatial position of the landmarks in the projected X, Y and Z components. Maxillary and mandibular pitch (clockwise, counterclockwise) rotation relative to the cranial base was also evaluated. The significance level was set at 5%. Maxillary retrusion value relative to the cranial base was higher and statistically significant greater (p = 0.028) in pubertal (SNA, 77.4° ± 6.2; N-ANS Y, 3.3 mm ± 3.1) than in prepubertal patients (SNA 81.0° ± 5.2; N-ANS Y, 5.8 mm ± 2.7). The posterior cranial base length (S-Ba Y) was significantly longer (p = 0.013) in pubertal (20.7 mm ± 3.4) than in prepubertal patients (18.4 mm ± 2.7). The upper facial height (N-ANS Z) was significantly greater (p = 0.01) in pubertal (46.9 mm ± 4.5) than in prepubertal patients (43.4 mm ± 3.0). Prepubertal and pubertal UCLP patients presented distinct patterns of craniofacial morphology, mainly in the sagittal component of the maxilla and in the posterior cranial base length. Pubertal patients had greater maxillary retrusion and posterior cranial base length.

ACL Reconstruction for Open Physes Patient

Introduction: Participation of young athletes contributes to increment of ACL tears cases in children and adolescence. Management of ACL tears in that age group remains debatable. Traditionally, patients with immature bone have been treated without surgery or delayed reconstructive surgery to prevent iatrogenic growth retardation due to epiphyseal injury. However, conservative management showed poor results, the patient subsequently developed recurrent knee instability leading to progressive intraarticular damage, including secondary meniscus and chondral injuries. Special reconstruction technique is required to maintain the growth plate. The purpose of this study is to point out reconstruction technique available on managing ACL rupture. Method: This presentation review does systematic evidence based on literature review of management of ACL injury in skeletal immature patient. Results: There are some techniques that can be performed for paediatric patients are physeal sparing, with iliotibial band reconstruction, ACL reconstruction with all-epiphyseal tunnels and post distal fixation, all-epiphyseal tunnels reconstruction and fixation, partial transphyseal technique, and trans-physeal technique. The surgical technique was determined based on maturity and bone age using Tanner staging and hand radiographs. In pre pubertal patients, Tanner stage 1 or 2 (boys 12 years and girls 11 years) was performed using a physeal sparing. Young adolescents are still in their infancy, Tanner stage 3 or 4, boys 13-16 years old, it is better to have ACL reconstruction done with partial transphyseal or transphyseal technique. Older adolescents with physeal closure (males 15 years and girls 14 years) ACL reconstruction were performed as in adult patients. Discussion: The choice of reconstruction technique in pediatric patients is based on the maturity and bone age of the child. In the pre-pubertal period with Tanner stage 1 or 2 experiments can be carried out non-operative measures followed by physeal sparing reconstruction, young adolescents are still in their infancy, transphyseal reconstruction is carried out, reconstruction in older adolescents is carried out as in adults. Some consideration makes decision whether not to operate or operate the patient. Concerns regarding injury to physic, leg length discrepancy, and source of graft led the innovation of the surgical technique to reconstruct the ACL.

Hızlı ve Yarı Hızlı Maksiller Genişletme Etkinliğinin İskeletsel Maturasyon Aşamalarına Göre Karşılaştırılması: Retrospektif Bir Çalışma

Objective: This study aimed to compare the skeletal and dentoalveolar effects of the expansion force created by the semi-rapid and rapid activation protocols. Material and Methods: The study comprised 54 patients (26 female and 28 male) with transverse maxillary insufficiency. Of these patients, 22 were treated with semi-rapid maxillary expansion (SRME) and 32 with rapid maxillary expansion (RME). The SRME group consisted of 6 prepubertal, 8 pubertal, and 8 postpubertal patients, and the RME group consisted of 11 prepubertal, 11 pubertal, and 10 postpubertal patients. Treatment effects with both protocols were evaluated with 11 different measurements on posteroanterior cephalograms and plaster models taken before treatment and after a retention period of 3 months. Kruskal-Wallis analysis was used for comparisons between different maturation periods. Independent sample t-test and Mann-Whitney U test with Bonferroni correction were used for pairwise comparisons between two different activation protocols. Results: The increases in nasal and dental widths in the SRME group were found to be higher than in the RME group in the prepubertal patient group (p0.05). No statistically significant difference was found among prepubertal, pubertal, and postpubertal groups for all skeletal and dental measurements (p>0.05). Conclusion: The current study represented some evidence that the SRME activation protocol might cause less tissue resistance than the conventional RME. The efficiency of maxillary expansion therapy is similar in prepubertal, pubertal, and postpubertal patients in whom sutural resistance is resolved.

Sexual function and fertility preservation in testicular cancer survivors

Testicular cancer is a common cancer among reproductive age men, with the necessary treatment options having varying impacts on fertility and sexual function. Treatment begins with orchiectomy and is often followed by a combination of chemotherapy, radiation, and/or retroperitoneal lymph node dissection, which have different effects on spermatogenesis, gonadotropin levels, and ejaculation. Alkylating agents such as cisplatin are commonly used for testicular cancer and are amongst the most spermatotoxic chemotherapeutic agents. Radiation poses gonadotoxic effects despite gonadal shielding due to a scatter effect. Suprahilar and bilateral retroperitoneal lymph node dissections can cause ejaculatory dysfunction. Options to preserve fertility vary by pubertal status. While the standard recommendation for post pubertal patients is cryopreservation, prepubertal patients rely on experimental protocols for cryopreservation of germ cells with stem cell capabilities, with the hope that these cells will one day be stimulated to produce sperm. These topics are reviewed to give insight into current literature around fertility in testicular cancer survivorship and determine best possible practices in fertility preservation among patients.

Prepubertal Children with Papillary Thyroid Carcinoma Present with More Invasive Disease Than Adolescents and Young Adults.

Introduction: Pediatric papillary thyroid carcinomas (PTCs) are more invasive than adult PTCs. No large, contemporary cohort study has been conducted to determine whether younger children are at higher risk for advanced disease at presentation compared to adolescents. We aimed to describe pediatric PTC and contextualize its characteristics with a young adult comparison cohort. Methods: The National Cancer Database was interrogated for pediatric and young adult PTCs diagnosed between 2004 and 2017. Clinical variables were compared between prepubertal (≤10 years old), adolescent (11-18 years old), and young adult (19-39 years old) groups. Multivariable logistic regression modeling for independent predictors of metastases was conducted. A subanalysis of microcarcinomas (size ≤10 mm) was performed. Results: A total of 4860 pediatric (prepubertal n = 274, adolescents n = 4586) and 101,159 young adult patients were included. Prepubertal patients presented with more extensive burden of disease, including significantly larger primary tumors, higher prevalence of nodal and distant metastases, and increased frequency of features such as lymphovascular invasion, and extrathyroidal extension (ETE). Prepubertal age was an independent predictor of positive regional nodes (adjusted odds ratio [AOR] = 1.36 [95% confidence interval {CI} 1.01-1.84], p = 0.04) and distant metastatic disease (AOR = 3.12 [CI 1.96-4.96], p < 0.001). However, there was no difference in survival between groups (p = 0.32). Prepubertal age independently predicted lymph node metastases for microcarcinomas (AOR = 2.19 [CI 1.10-4.36], p = 0.03). Prepubertal (n = 41) versus adolescent (n = 937) patient age was associated with gross ETE (p = 0.004), even with primary tumors ≤1 cm in size. Conclusions: Patients aged <11 years old present with more advanced disease than adolescents, with a higher likelihood of nodal and distant metastatic disease at time of diagnosis, although survival is high. Prepubertal children undergo more extensive treatment, likely reflective of more invasive disease at the outset, even in the setting of a subcentimeter primary tumor.

Early Growth Hormone Initiation Leads to Favorable Long-Term Growth Outcomes in Children Born Small for Gestational Age.

Early initiation of growth hormone (GH) therapy is recommended for short children born small for gestational age (SGA); however, real-world data indicate that treatment is often delayed. We aimed to assess the impact of patient age at GH therapy initiation on long-term growth outcomes and safety in short children born SGA. Analysis of pooled data from NordiNet® International Outcome Study (NCT00960128; 469 European clinics) and the ANSWER Program (NCT01009905; 207 US clinics), two large, complementary observational studies. Patients received GH as prescribed by their treating physician. Enrolled patients born SGA were categorized into three groups based on their age at GH treatment initiation: 2 to <4 years, 4 to <6 years, and ≥6 years. Patient characteristics at birth and GH initiation, auxology, and safety data were evaluated. The effectiveness analysis (treatment-naïve and prepubertal patients at GH initiation) included 3318 patients: 10.7% aged 2 to <4 years at therapy initiation, 31.6% aged 4 to <6 years, and 57.7% aged ≥6 years. Following 8 years of therapy, the mean improvement in height standard deviation score from baseline was significantly greater in the 2 to <4 years group vs the 4 to <6 years (+2.5 vs +2.2; P = 0.0054) and ≥6 years groups (+2.5 vs +1.7; P < 0.0001). No unexpected safety events were reported. Early initiation of GH therapy in short children born SGA may be an important contributor to height optimization. The data are reassuring regarding the long-term safety of GH therapy in this population.

Effectiveness of low-level laser therapy in facilitating maxillary expansion using bone-borne hyrax expander: A randomized clinical trial.

The objective of this randomized clinical trial was to study the skeletal and dental effects of low-level laser therapy (LLLT) along with a miniscrew-assisted expander (Hyrax) after six months of retention. After sequence generation, concealed allocation, and implementation, 24 female patients were randomly divided (1:1) into two-groups: bone-borne rapid palatal expansion (BBE) without LLLT (n = 12) and BBE with LLLT (n = 12). Eligibility criteria included female patients aged 10-13 years old with bilateral posterior crossbites. Intraoral and extraoral photographs, cone-beam computed tomography images, and digital study models were obtained before expansion and six months after retention. The 7 mm Hyrax appliance was anchored to four palatal mini-screws, which were activated twice daily for 15 days, then locked and kept in place as a retainer. LLLT was performed in the laser group during expansion and retention, according to the guidelines provided. The records of 24 patients were analyzed. According to the post-retention measurements, both groups showed a significant increase in nasal and maxillary widths and total facial height. In the laser group, the Sella-Nasion-Point A and Point A-Nasion-Point B angles and the interpremolar apical distance were significantly increased. Within the limitations of this study, the results suggest that the parameters and protocol of LLLT do not clinically affect the efficiency of BBE in prepubertal and pubertal patients.

The Vertebrae as OARs in Paediatric Radiotherapy Clinical Trials: Initial QUARTET experience

Objectives Irradiation of the vertebrae in prepubertal patients can result in growth defects and deformities, related to inhomogeneities in dose distribution. In 2019 the SIOPE-ROWG published a consensus on vertebral delineation and constraints in an effort to standardise practice across Europe. QUARTET is a SIOPe project for RTQA in Paediatric Clinical Trials across Europe. All trials incorporate specific guidelines which include recommendations on vertebral delineation and dosimetry as per the 2019 ROWG consensus. We performed an audit of the first cases enrolled in the trials using QUARTET for RTQA, aiming to identify the main protocol deviations in vertebral delineation and their impact on dosimetry. Methods All cases undergoing QUARTET review until 22/02/2022 were evaluated. Pre-pubertal patients with vertebrae in the proximity of the target volume were included. Vertebrae adjacent to the target volume (VBs_Adj) and directly cranial and caudal (VB_NAdj_S/I) were assessed for compliance to delineation and dosimetry guidelines by a second, independent reviewer. Missing or non-compliant structures were recontoured and the new DVH metrics were compared with the initial ones. Results 51 patients were included. VB_NAdj_S/I were not delineated in 49% of the cases. Dose constraints for VBs _Adj were met in 31% of initial submissions. Dosimetry compliance for VB_NAdj_S/I was 53% for photons and 16% for protons. Resubmission for vertebral delineation or dose issues was required for 20% of cases. Approximatively 70% of VBs delineations include spinal processes and spinal canal. When re-delineated, only 14% of the VBs_Adj met the dosimetry constraints. Conclusion Despite the availability of international consensus guidelines, a high variability in vertebrae delineation is observed in QUARTET cases, with impact on dosimetry. Better vertebral sparing was observed in photon cases. Guidelines will be amended to reflect these results and further improve compliance. Irradiation of the vertebrae in prepubertal patients can result in growth defects and deformities, related to inhomogeneities in dose distribution. In 2019 the SIOPE-ROWG published a consensus on vertebral delineation and constraints in an effort to standardise practice across Europe. QUARTET is a SIOPe project for RTQA in Paediatric Clinical Trials across Europe. All trials incorporate specific guidelines which include recommendations on vertebral delineation and dosimetry as per the 2019 ROWG consensus. We performed an audit of the first cases enrolled in the trials using QUARTET for RTQA, aiming to identify the main protocol deviations in vertebral delineation and their impact on dosimetry. All cases undergoing QUARTET review until 22/02/2022 were evaluated. Pre-pubertal patients with vertebrae in the proximity of the target volume were included. Vertebrae adjacent to the target volume (VBs_Adj) and directly cranial and caudal (VB_NAdj_S/I) were assessed for compliance to delineation and dosimetry guidelines by a second, independent reviewer. Missing or non-compliant structures were recontoured and the new DVH metrics were compared with the initial ones. 51 patients were included. VB_NAdj_S/I were not delineated in 49% of the cases. Dose constraints for VBs _Adj were met in 31% of initial submissions. Dosimetry compliance for VB_NAdj_S/I was 53% for photons and 16% for protons. Resubmission for vertebral delineation or dose issues was required for 20% of cases. Approximatively 70% of VBs delineations include spinal processes and spinal canal. When re-delineated, only 14% of the VBs_Adj met the dosimetry constraints. Despite the availability of international consensus guidelines, a high variability in vertebrae delineation is observed in QUARTET cases, with impact on dosimetry. Better vertebral sparing was observed in photon cases. Guidelines will be amended to reflect these results and further improve compliance.

RF14 | PMON328 The Effect of Pituitary Cysts on Pituitary Volume in Patients with Growth Hormone Deficiency and Idiopathic Short Stature

Abstract Background Pituitary cysts (PCs) may be related to the development of diminished growth hormone secretion because they may limit the proliferation of somatotrophs. This study seeks to investigate the mass effect of PCs on the pituitary function. Methods Patients aged 6-18 with cysts and follow-ups between 2007–21 were compared to normal controls (NCs) aged 6-18 from a neuroradiology center. Pituitary volume (PV) is the volume of the pituitary gland including the cyst, while net pituitary volume (netPV) is the volume of the pituitary gland excluding the cyst. Since NCs did not have PCs, only PV was utilized. PVs and netPVs are reported in mm3. Data were stratified into prepubertal (age &amp;lt; 11 yrs) and pubertal (age &amp;gt; 11 yrs). The Kruskal-Wallis One Way ANOVA on Ranks was utilized to compare multiple means, and the Kruskal-Wallis Multiple-Comparison Z Value test (with Bonferroni adjustment) was utilized for pairwise comparisons. Results The mean and median PVs of prepubertal GHD (n=37), ISS (n=5), and NCs (n=58) were 290.2 ± 109.7 and 305.0, 314.4 ± 100.8 and 299.8, and 246.8 ± 63.7 and 241.6, respectively. The difference between mean PVs of prepubertal GHD, ISS, and NCs was not significant. The mean and median PVs of pubertal GHD (n=58), ISS (n=33), and NCs (n=112) were 391.5 ± 163.5 and 370.2, 409.2 ± 215.8 and 382.9, and 424.2 ± 138.9 and 402.7, respectively. The difference between mean PVs of pubertal GHD, ISS, and NCs was not significant. For netPV, the mean and median values for prepubertal GHD and ISS patients were 252.2 ± 83.3 and 272.2, and 245.2 ± 85.7 and 244.9, respectively. The difference between mean netPVs of prepubertal GHD, ISS, and NCs was not significant. For netPV, the mean and median values for pubertal GHD and ISS patients were 332.7 ± 121.3 and 346.4, and 333.9 ± 146.1 and 330.7, respectively. The mean netPVs of pubertal GHD and ISS patients were both significantly lower than the mean PV of pubertal NCs. The mean and median PVs for cyst patients were 364.8 ± 170.0 and 347.8 which was not significantly different from the NCs. The mean and median netPVs for cyst patients were 307.3 ± 122.9 and 289.0 which was significantly different from the NCs (p&amp;lt;0.001). Conclusion When considering the functional component of the pituitary gland, cyst volume should be subtracted from the overall pituitary gland. Presentation: Sunday, June 12, 2022 12:36 p.m. - 12:41 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Testicular microlithiasis in paediatric patients with Klinefelter syndrome from infancy till adolescence: early start of degenerative process in the testes—preliminary results

To present the results of testicular ultrasonography supported by clinical and hormonal aspects in paediatric patients with Klinefelter syndrome (KS). Prospective analysis of medical files of 20 patients diagnosed with KS between 2016 and 2022. Assessed data included analysis of causes of referral, ultrasound, and clinical characterisation with hormonal evaluation of serum FSH, LH, testosterone, inhibin B, and anti-Müllerian hormone. Non-mosaic Klinefelter syndrome (47, XXY) was diagnosed in 65% of cases (13/20) by the geneticist (including 7 cases prenatally), in 25% (5/20) by the endocrinologist and in 10% (2/20) by the hematologist. Ultrasound assessment revealed bilateral testicular microlithiasis (TM) in all patients. The youngest KS patient with TM was 3 months old. TM patterns have not changed during follow-ups of up to 6 years in any of the patients. In all KS patients markedly reduced echogenicity and in pubertal KS patients, also irregular echostructure of the testes was observed. The hormonal patterns observed in the study group were typical for those already described in KS. Sertoli and Leydig cell function was intact in prepubertal patients and deteriorated after the start of puberty.Conclusion: Although the degenerative process in the testicular tissue starts very early in the testes in KS and is reflected in morphological changes seen in ultrasonography, Sertoli and Leydig cell hormonal function is normal in prepubertal KS patients.What is Known:• So far, normal Leydig and Sertoli cell function was observed in infants and prepubertal KS patients.What is New:• The morphological changes in the testes in KS may already be seen in early infancy.

Automatic Evaluation for Bioengineering of Human Artificial Ovary: A Model for Fertility Preservation for Prepubertal Female Patients with a Malignant Tumor.

Introduction: The in vitro culture of primordial follicles is the only available option for preserving fertility in prepubertal girls with malignant tumors. The cultivation of primordial follicles in scaffolds as artificial ovaries is a promising approach for this. Methods: Dissociated follicles were placed into an artificial ovarian scaffold composed of fibrinogen and thrombin. The follicles were cultured in a dish dedicated to live cell imaging and observed for growth using immunofluorescence and development via optical microscopy. The morphology of the follicles in the scaffold was three-dimensionally reconstructed using the Imaris software. Growth and development were also quantified. Results: The morphology of artificial ovaries began to degrade over time. Within approximately 7 days, primordial follicles were activated and grew into secondary follicles. A comparison of optical and confocal microscopy results revealed the superior detection of live cells using confocal microscopy. The three-dimensional reconstruction of the confocal microscopy data enabled the automatic enumeration and evaluation of the overall morphology of many follicles. Conclusions: The novel artificial ovary-enabled primordial follicles to enter the growth cycle after activation and grow into secondary follicles. The use of a fibrin scaffold as a carrier preserves the developmental potential of primordial germ cells and is a potentially effective method for preserving fertility in prepubertal girls.

TRANS 202: ADVANCED PRACTICE IN THE CARE OF GENDER-DIVERSE YOUTH

This Extended Workshop offers providers with an interest in the care of gender-diverse youth the opportunity to expand knowledge and build comfort in the assessment and treatment of both prepubertal and adolescent patients and their families.

Precocious puberty due to intracranial germ cell tumors: a case–control study

Children with intracranial germ cell tumors may present premature sexual development via either gonadotrophin-releasing hormone (GnRH)-dependent cause or GnRH-independent cause. We conducted a single-center retrospective study on 37 precocious puberty (PP) patients with intracranial germ cell tumors and 25 age-matched prepubertal patients with elevated human chorionic gonadotropin (hCG) levels. Classification of PP was derived from hCG, gonadotropin and sex steroid levels and their changes. Five boys were assigned to GnRH-dependent group (G1). Thirty-one boys and one girl were assigned to GnRH-independent group (G2) with a median hCG of 76.75 (8.29-2747) IU/L. Seven boys and 18 girls were conducted as controls, with a median hCG of 17.12 (2.91-1062) IU/L. Patients in G1 had constant pubertal LH and testosterone levels after tumor complete response. Patients in G2 had hCG levels that decreased simultaneously with testosterone/estradiol levels, prior to tumor regression. The differences in hCG levels and the gender ratio were significant between G2 and controls (P = 0.006 and P < 0.001, separately). Among intracranial germ cell tumor patients with positive hCG, boys with significantly higher hCG levels more easily developed PP. Our results suggest that GnRH-independent PP commonly regresses together with tumor regression. In comparison, results were inconclusive in tying tumor regression to the regression of GnRH-dependent PP.

Safety and Efficacy of Pediatric Growth Hormone Therapy: Results From the Full KIGS Cohort.

The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings. This work aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort. Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin [somatropin]; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (≥ 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth. The full KIGS cohort (N = 83 803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and death in 0.4%. The most common SAEs were recurrence of craniopharyngioma (n = 151), neoplasm (n = 99), and cancer (n = 91); and scoliosis (n = 91). Median first-year delta height-SD score (SDS) (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), and 0.71 (SGA). Median gains in NAH-SDS were 1.79 (IGHD), 1.37 (ISS), and 1.34 (SGA) for boys, and 2.07 (IGHD), 1.62 (ISS), 1.07 (TS), and 1.57 (SGA) for girls. Data from KIGS, the largest and longest running international database of rhGH-treated children, show that rhGH is safe and increases short-term height gain and adult height across GHD and non-GHD conditions.

Ovarian Tissue Cryopreservation in Children and Adolescents.

Cancer during childhood and adolescence remains a major public health issue, affecting a significant portion of this age group. Although newer anti-cancer treatments have improved survival rates, this comes at a cost in terms of gonadotoxic effects. As a result, the preservation of fertility is important. Ovarian tissue cryopreservation, one of the newest methods, has some advantages, especially for prepubertal patients: no need for ovarian stimulation, thus, no further risk for estrogen-sensitive cancer types, and preservation of more and better-quality primordial follicles of the ovarian cortex. The most frequent indications include treatment with alkylating agents, ovarian-focused radiotherapy, leukemias, lymphomas, brain and neurological tumors, as well as Turner syndrome and benign hemoglobinopathies. An expected survival exceeding 5 years, the absence of systematic disease and an overall risk of premature ovarian insufficiency over 50% are among the criteria that need to be fulfilled in order for a patient to undertake this method. Orthotopic transplantation is more frequently used, since it can allow both live birth and the recovery of endocrine function. Reimplantation of malignant cells is always a major risk and should always be taken into consideration. Histological analysis, as well as immunohistochemical and molecular methods, are needed in order to improve the search for malignant cells before transplantation. Ovarian tissue cryopreservation appears to be a method with specific benefits, indications and risks which can be an important tool in terms of preserving fertility in younger women.

Commentary to: Validation of testicular workup for ischemia and suspected torsion score in patients with acute scrotum

Barbosa et al. described the TWIST score in 2013 and reported 100% NPV and PPV for low-risk and high-risk groups respectively. They suggested that color Doppler ultrasound (CDUS) may not be needed in 80% of patients with acute scrotum. At least 5 studies (Table 3) have since attempted to validate the TWIST score and none had a perfect NPV or PPV. The NPV for low-risk group has ranged from 77% to 99% and PPV for high-risk group has ranged from 56% to 93% with results worse in prepubertal patients.

Factors Influencing Appliance Wearing Time during Orthodontic Treatments: A Literature Review

This review aims to analyze the multiple factors affecting patients’ level of compliance (how much they wear removable devices/clear aligners) during orthodontic treatments and to investigate the available methods and devices to monitor the appliance wearing time and to improve it. A literature search was conducted on electronic databases (Pubmed, Scopus, and Google Scholar). The results of the present study suggest that compliance indicators may misestimate the intraoral wearing time. Compliance is affected by patient-related factors (age, personality traits, the importance of personal appearance, self-perception of malocclusion), appliance-related factors (visibility, pain/discomfort), and clinician-related factors (trust, clear and complete communication, motivation). The motivation of pre-pubertal patients is mostly external, while adolescents/young adults have intrinsic motivation for orthodontic treatment. Patients’ self-reports tend to overestimate the appliance wearing time. Even if there is a lack of evidence, teledentistry might improve patients’ awareness of being monitored, thus increasing the time for which orthodontic devices are worn. Compliance is a key factor for clear aligner treatments, but high-quality studies focusing on this aspect are missing. Further studies should focus on how to handle the lack of cooperation and how to increase compliance in order to maximize the treatment’s results.