bluuebunny/crossref_metadata_2025_split huggingface dataset:
6376 Wnt/beta-catenin Pathway is Associated with Cell Proliferation in Growth Hormone-producing Pituitary Tumors
Authors: Kuwabara Saki , Kameda Hiraku , Nomoto Hiroshi , Cho Kyu Yong , Nakamura Akinobu , Ishi Yukitomo , Motegi Hiroaki , Fujimura Miki , Atsumi Tatsuya 
Published: October 2024

Abstract
Disclosure: S. Kuwabara: None. H. Kameda: None. H. Nomoto: None. K. Cho: None. A. Nakamura: None. Y. Ishi: None. H. Motegi: None. M. Fujimura: None. T. Atsumi: None.
Objective: It has been well recognized that the Wnt/β-catenin pathway regulates cell proliferation, and that translocation of β-catenin from the cytoplasm to the nucleus promotes cell proliferation. There have been, however, limited reports on the Wnt/β-catenin pathway in growth hormone-producing pituitary tumors (GHomas), and we aimed to investigate the impact of the Wnt/β-catenin pathway on cell proliferation in GHomas. Methods: We performed three types of experiments with patient pathological specimens, disease model cell lines, and primary culture of GHoma cells. 1.The intracellular localization of β-catenin was evaluated using immunofluorescence staining of pathological specimens from GHoma patients and subsequently its association with clinical data was analyzed. 2.The Wnt/β-catenin inhibitor iCRT14 was administered to rat GHoma cells GH1, using the WST-1 assay to measure cell viability and real-time PCR to assess GH and cell cycle genes expression. 3. The Wnt/β-catenin inhibitor iCRT14 was added to cultured cells obtained from GHoma patients to evaluate cell viability and gene expression. Results: 1. Samples from 26 cases (42%) exhibited strong dot-like expression of β-catenin in the nucleus (dot pattern (DP) group), and samples from 36 cases (58%) showed β-catenin expression in the cytoplasm or cell membrane (non-DP group). Tumors in the DP group had a larger size than non-DP group (diameters 18.3±9.2 vs. 13.4±7.4 mm, p&lt;0.05), and the postoperative remission rate was lower (23 vs. 50%, p&lt;0.05). 2. Viability evaluation using WST-1 assay showed a maximum decrease of 25%. Gene expression showed concentration-dependent reduction in GH gene expression by up to 40% (p&lt;0.05) and cyclin D1 gene up to 50% (p&lt;0.05) following iCRT14 administration. 3. Among 6 cases, 3 showed a tendency toward cell growth inhibition, and 4 showed a tendency toward decreased cyclin D1 gene expression. Conclusion: It is suggested that the Wnt/β-catenin pathway is activated in the DP group because of the nucleus accumulation of β-catenin, and given the larger tumor size and lower postoperative remission rate in DP group, the Wnt/β-catenin pathway may stimulate cell proliferation in GHomas. In addition, cyclin D1-mediated effects were considered. Wnt/β-catenin pathway could play a role in GHomas growth, therefore this pathway would be a potential therapeutic target for treating affected patients.
Presentation: 6/3/2024
6789 Do Obesity-Associated MRAP2 Variants Modulate MC4R and GHSR Signaling?
Authors: Rondon Alejandra Virginia Rodriguez , Volker Femke , Welling Mila Sofie , de Groot Corjan , van Haelst Mieke M , van den Akker Erica L T , van Rossum Elisabeth F C , Delhanty Patric John , Visser Jenny A 
Published: October 2024

Abstract
Disclosure: A.V. Rodriguez Rondon: None. F. Volker: None. M.S. Welling: None. C. de Groot: None. M.M. van Haelst: None. E.L. van den Akker: None. E.F. van Rossum: None. P.J. Delhanty: None. J.A. Visser: None.
Melanocortin 2 receptor accessory protein 2 (MRAP2) is a membrane-bound protein expressed on hypothalamic neurons that modulate the function of appetite-regulating receptors, including melanocortin-4 receptor (MC4R) and growth hormone secretagogue receptor (GHSR). While pathogenic variants in the MRAP2 gene are associated with obesity, the mechanism for this remains unclear. The aim of this study is to investigate the functional impact of wildtype (WT) MRAP2 and MRAP2 variants on MC4R and GHSR signaling. Four MRAP2 variants (S80F, R125C, P167A and Q174X) were identified in patients with obesity by obesity gene panel analysis. The functional effects of these variants were analyzed by co-transfecting HEK293 cells with expression plasmids encoding WT or variant MRAP2 and WT MC4R or WT GHSR. Endpoint analyses included cell surface expression, and ligand-induced second messenger responses (α-MSH-induced cAMP response for MC4R and ghrelin-induced Ca2+ mobilization for GHSR), β-arrestin-2 recruitment, and internalization. WT MRAP2 significantly decreased basal MC4R cell surface expression by 68.1±4.3% (p&lt;0.001). In the absence of MRAP2, α-MSH induced MC4R internalization. However, in the presence of WT MRAP2, MC4R cell surface expression was increased by 89.4±6.9% upon α-MSH stimulation (p&lt;0.001). GHSR cell surface expression and ghrelin-induced internalization were not affected by WT MRAP2. Furthermore, in the cells expressing MC4R with WT MRAP2, the maximal α-MSH-induced cAMP and β-arrestin-2 recruitment responses were increased by 29.8±5.2% and 81.3±4.2% respectively (p&lt;0.001), compared with those lacking MRAP2. We also investigated GHSR ghrelin-induced Ca2+ mobilization and found that, in the presence of WT MRAP2, this increased significantly by 95.37±21.9%, (p&lt;0.0003). However, ghrelin-induced β-arrestin-2 recruitment was suppressed by 69.8±7.6%, (p&lt;0.001). Using these endpoints we found no effect of the variants on the ability of MRAP2 to modulate ligand-induced signaling by MC4R and GHSR. Our results indicate that WT MRAP2 enhances the cAMP response by increasing MC4R cell membrane expression upon α-MSH stimulation, and enhances GHSR Ca2+ mobilization by decreasing β-arrestin-2 recruitment upon ghrelin stimulation. The MRAP2 variants assessed in this study behaved as WT MRAP2 in α-MSH-induced MC4R and ghrelin-induced GHSR signaling, suggesting that these may be benign variants. However, since MRAP2 can modulate multiple receptors, we cannot rule out that these MRAP2 variants affect other appetite-regulating receptors and thereby influence body weight regulation via other pathways.
Presentation: 6/3/2024
7540 Recognition of Need for Optimization of Diabetes Education for Children with Type 1 diabetes: Long term Provider Experience
Authors: Begum-Hasan J 
Published: October 2024

Abstract
Disclosure: J. Begum-Hasan: None.
Title: Recognition of need for optimization of diabetes education for children with Type 1 diabetes: long term “On call provider experience “Janhanara Begum – Hasan, MD, PhD. Jacob school medicine. UBMD Pediatrics Context: Pediatric endocrinologist does provide on call service 24/7 to support patient care as needed for the family with children with diabetes. Complication of diabetes including DKA is preventable However, based on interaction with the family with children diabetes, the trend shows sub optimal education in this regard. Aim/Objective: To review case scenario and provide recommendation to optimize diabetes management with a goal of prevention of complications. Case discussion: 3 case scenarios are selected to review. Case 1: The father called at 2 am as his daughter’s (12 year F) Insulin pump is broken and BGs are elevated in upper 300s. Her urine is +ve for moderate ketone and she has nausea. He does not have any short acting pen or syringe to provide correction Insulin. He reports that he is not aware of her Insulin settings in the pump. Parents are separated and mother is more involved in her care. Short /long acting Insulin pen were prescribed with recommendations including correction dose as per weight with a plan for follow up. Case 2: The mother called at 9 pm and reported that by mistake, she did administer “Admelog” at 18 units instead of Basaglar, for her son, 11 year old with Type 1 diabetes. He was on Lantus and Humalog before. She gets confused with short and long acting Insulin particularly with changes. The mother was advised on close monitoring of BGs with recommendation of treatment of Hypoglycemia including Glucagon therapy. He was followed closely with stabilization of BGs with extra carbohydrate overnight. Case 3: The father calls to inform that his son, 14 year, with recent onset Typ1 diabetes, has been vomiting with high BG in 400s with large ketone. His Insulin dose was decreased recently as he was told to be in “Honeymoon phase” and planned for close follow up. However, the family missed endocrine FU &gt;12 months now. His BGs have been high in upper 200s to 300s for last 2-3 months. The parents are in the process of divorce. He was sent to local ED with clinical impression of DKA. He was treated for his severe DKA as found after metabolic labs. He did well after 2 days hospitalization for management of his DKA. Conclusion: -Complications of Type 1 diabetes are preventable. The family needs further education on diabetes management including review of Insulin therapy when Insulin pump does malfunction, with a copy of written instruction of Insulin doses, differences in long and short acting Insulin along with psychosocial support to optimize care of children with Type 1 diabetes.
Presentation: 6/2/2024
12333 46 XX/XY Chimerism - Positive NIPT And Post-natal Karyotype Is It Real?
Authors: Del Rosario Kychelle L , Sheriden Nina , Vijayakanthi Nandini 
Published: October 2024

Abstract
Disclosure: K.L. Del Rosario: None. N. Sheriden: None. N. Vijayakanthi: None.
Introduction: Non-Invasive Prenatal Testing(NIPT) using cell free fetal DNA in plasma of pregnant women has become a routine part of prenatal care in screening for fetal aneuploidies including sex chromosome abnormalities in most regions around the world. False positive results are increasingly imposing challenges in pre-natal as well as post-natal care. Case Discussion: We report a neonate born at 32+2 weeks gestation to a 42-year-old G2 P2 mother. Pregnancy was complicated by insulin dependent maternal type 2 diabetes mellitus, maternal chronic hypertension and a positive NIPT for high-risk monosomy X. Prenatal ultrasound showed male anatomy. Interestingly on physical exam after birth, the neonate had typical male external genitalia with bilateral normal male gonads. Chromosome analysis done immediately after birth revealed the presence of two cell lines: 40 of the 50 cells (80%) had a normal female 46 XX karyotype and 10 of the 50 cells (20%) had a normal male 46 XY karyotype. These findings could be due to reabsorbed twin, Klinefelter syndrome with two trisomy rescue events, maternal cell contamination or true chimerism. In addition, fluorescence in situ hybridization (FISH) analysis for X and Y probes revealed the presence of two cell lines. The first cell line (70% of the cells) had two hybridization signals for chromosome X and the second cell line (∼25% of the cells) had one hybridization signal for chromosome X and one for chromosome Y. Postnatal ultrasound showed normal testicles with no evidence of Mullerian structures. Newborn screening was negative for congenital adrenal hyperplasia (CAH). Genetics was consulted and recommended repeat chromosomal analysis, parental testing to determine sex chromosome segregation, and follow-up with pediatric endocrinology. Repeat cytogenetic testing at 2 weeks of life resulted in a normal male chromosome complement of 46,XY. Previous abnormal cytogenetics were thought to be due to maternal cell contamination. Further endocrine labs showed LH(1.16 uIU/ml) and testosterone levels ( 87 ng/dL), appropriate levels for age indicating normal Hypothalamic Pituitary Gonadal (HPG) axis and testicular Leydig cell function. Since the family was previously counseled regarding the concept of maternal cell contamination, they expressed understanding and were happy with the update of the normal karyotype result. Conclusion: False-positive results concerning for rare chimerism on NIPT can occur and should prompt a thorough history, physical exam, ultrasound studies and repeat testing to confirm its presence. Careful consideration should be taken when counseling family about the implications of these results, especially communication about gender assignment of the infant.
Presentation: 6/3/2024
7204 An Unexpected Cause of Ga-68 Dotatate PET/CT Somatostatin Receptor Avidity in a Pediatric Patient with Hereditary Paraganglioma-Pheochromocytoma Syndrome due to an SDHA Mutation
Authors: Leopold Kaitlin , Polites Stephanie , Binkovitz Larry , Casas Luis , Lteif Aida Nadim 
Published: October 2024

Abstract
Disclosure: K. Leopold: None. S. Polites: None. L. Binkovitz: None. L. Casas: None. A.N. Lteif: None.
Title: An Unexpected Cause of Ga-68 Dotatate PET/CT Somatostatin Receptor Avidity in a Pediatric Patient with Hereditary Paraganglioma-Pheochromocytoma Syndrome due to an SDHA Mutation. Introduction: Individuals with Succinate Dehydrogenase (SDHx) gene mutations have an increased risk of paragangliomas and pheochromocytomas beginning in childhood.Clinical Case: A 9 year old male with Cornelia de Lange syndrome and a paternally inherited SDHA pathogenic gene variant (c1534C&gt;T) presented with worsening migraine headaches and skin pallor with activity. 24 hour urine fractionated metanephrines were mildly elevated, with metanephrine 122 mcg/24h (29-92 mcg/24 h), normetanephrine 187 mcg/24 h (34-169 mcg/24 h), and total metanephrine 309 mcg/24 h (47-223 mcg/24 h). Ga-68 DOTATATE PET/CT showed a focus of moderately increased radiotracer activity in the anterior aspect of the distal gastric antrum with a max SUV 8.2 corresponding to a 9x7 mm nodule on CT in the same area, suggestive of underlying somatostatin receptor positive lesion such as a paraganglioma. MRI with contrast completed to further characterize the lesion showed no visible mass corresponding to the focal area of radiotracer uptake on DOTATATE PET/CT. Repeat 24 h urine metanephrines continued to show mild elevation of metanephrine (138 mcg/24h), normetanephrine (200 mcg/24h), and total metanephrines (338 mcg/24h). 24 hour urine catecholamines, 5-Hydroxyindoleacetic acid, and homovanillic acid were normal. An upper endoscopic ultrasound was completed which confirmed the presence of a lesion near the stomach but not arising from the stomach wall and not consistent with a gastrointestinal stromal tumor. CT enterography with IV contrast showed a 6x6 mm enhancing mass within the distal right lateral gastric wall. Due to ongoing symptoms, mild elevations in urine fractionated metanephrines, and a clear mass on US and CT, the patient underwent laparoscopic abdominal exploration where a 14x14x13 mm mass with surrounding gastric and duodenal serosa was excised with primary closure of the bowel. Pathology showed ectopic pancreatic tissue in the wall of the small bowel and stomach. Repeat Ga-68 DOTATATE PET/CT 5 months following surgery showed resolution of the distal gastric somatostatin receptor avidity. Clinical Lesson: This is the first case of ectopic pancreatic tissue mimicking a paraganglioma in a pediatric patient with hereditary paraganglioma-pheochromocytoma syndrome. False positive imaging should be considered in patients with SDHx mutations when the uptake is atypical in location and when the elevation in urine metanephrines is mild.
Presentation: 6/3/2024
7960 Clinical Outcomes of Image-Guided Therapies In Patients With Adrenocortical Carcinoma: A Tertiary Referral Center Retrospective Study
Authors: Chahla Brenda , Pal Koustav , Balderrama Brondani Vânia , Yaylaci Mert Feyza , Campbell Matthew , Sheth Rahul , Amir Habra Mouhammed 
Published: October 2024

Abstract
Disclosure: B. Chahla: None. K. Pal: None. V. Balderrama Brondani: None. F. Yaylaci Mert: None. M. Campbell: None. R. Sheth: None. M.A. Habra: None.
Background: Image-guided therapies (IGTs) such as cryoablation or embolization are commonly used in oncology, but their role in adrenocortical carcinoma (ACC) is not well-defined. Materials and Methods: A retrospective review of ACC patients treated with IGTs. We assessed time to next line of systemic therapy, disease control rate (DCR), local tumor progression-free survival (LTPFS), and complications of IGTs.Treatment efficacy was assessed based on RECIST v1.1. Complications were categorized based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: The study cohort included 26 patients (median age 56 years [range 38-76]; n=18 female) who had 51 IGT sessions to treat 86 lesions. The median Ki-67 is 20 (range 2-79), and median Weiss score is 6 (range 3-9). Seventeen patients received systemic therapy including mitotane, chemotherapy, immunotherapy, and other treatments prior to the first IGT and 10 patients received systemic therapy concurrently with first IGT. IGT modalities included cryoablation (n = 49), microwave ablation (n = 21), combined microwave and bland transarterial embolization (n = 8), bland transarterial embolization alone (n = 3), radioembolization (n = 3), and radiofrequency ablation (n = 2). Treated sites included the liver (n=37), intraperitoneal (n=11), adrenalectomy bed (n=10), lung (n=6), lymph nodes (n=6), retroperitoneal soft tissue (n=6) and other soft tissues (n=10). The median largest pre-IGT anteroposterior tumor dimension was 2.3 cm (range 0.5-8.6). DCR was 81.4% (70 out of 86), of which 66.3% of tumors showed complete response, 18.6% showed progressive disease, 8.1% showed partial response, and 7.0% showed stable disease. LTPFS rates were 73% and 63% at 1 and 2 years, respectively. Fourteen lesions needed re-ablation. Ten patients did not require systemic therapy while 16 patients (61.5%) received new systemic therapy following IGT, with a median time from first IGT to systemic therapy of 12.5 months (95% CI: 8.6 months- upper limit not reached). There was 1 reported CTCAE grade 3 adverse event (biloma) following IGT. Conclusion: IGT use in properly selected ACC lesions is safe and associated with prolonged disease control and delay in the need for systemic therapy.
Presentation: 6/2/2024
7202 CPP with Rapid Pubertal Progression in a 9-Year-Old Boy with Hypothalamic Teratoma
Authors: Robilliard R , Tung G , Svokos K , Lulla R , Quintos J Q 
Published: October 2024

Abstract
Disclosure: R. Robilliard: None. G. Tung: None. K. Svokos: None. R. Lulla: None. J.Q. Quintos: None.
Background: Central Precocious Puberty (CPP) in males is rare, with incidence of 0.01-2/10,000. The most common identifiable cause of CPP in young children is hypothalamic hamartoma. No case hypothalamic teratoma has been reported to cause CPP in males. Clinical Case: At the age of 10-years and 5-months, a boy presented to the pediatric endocrinology with signs of precocious puberty including facial hair development, voice deepening, and increased growth velocity that began at 9 years old. There was no significant past medical history and he denied headache, blurry vision, or diplopia. Physical examination showed height of 140.4 cm (47%), Tanner 4 genitalia, Tanner 3 pubic hair, and testicular volumes of 15 cc (left) and 12-15cc (right). Bone age (BA) determined by radiography was 13.5 years with a predicted adult height (PAH) of 63 inches. The mid-parental target height was 67 +/- 4 inches. Evaluation including TSH, glucose, serum and CSF β-HCG, DHEA, CSF AFP was normal. Serum LH was 2.9 IU/L and testosterone level was 109 ng/dl, consistent with CPP. MRI of the pituitary showed a small, heterogeneous and fat-containing lesion extending inferiorly from the tuber cinereum consistent with teratoma. Treatment included GnRH agonist Lupron (30mg) every 3 months. Laboratory evaluation 8 months after initial presentation showed suppressed LH of 0.9 IU/L and FSH 0.5 mIU/mL, and testosterone of 57 ng/dL. Repeat radiography for BA one year after GnRHa suppression showed BA of 14 years at CA of 11 years 6 months and PAH of 64.4 inches. Growth velocity slowed to 5.3 cm/year. At the most recent follow-up visit at CA of 12 years, height was 151.5 cm (61%), growth velocity 6.3 cm/year (74% for age), Tanner 5 penis and pubic hair, left testicular volume of 15-20cc and right testicular volume of 15 cc. Most recent radiographic BA is14 years, and PAH is 65.9 inches. Given response to GnRH agonist injections every 3 months, the absence of CNS symptoms referable to the teratoma and no change in MR imaging, no surgical intervention is recommended. Conclusion: This is the first case of a hypothalamic teratoma reported in a male associated with CPP. Despite this rare cause, the patient has responded to standard treatment with GnRH agonist therapy alone.
Presentation: 6/1/2024
7959 Combination Therapy Of Multi-Targeted Tyrosine Kinase Inhibitors And Immune Checkpoint Inhibitors In Advanced Adrenocortical Carcinoma
Authors: Yaylaci Mert Feyza , Balderrama Brondani Vânia , Marcal Leonardo P , Campbell Matthew , Jimenez Camilo , Varghese Jeena , Yogesh Shah Amishi , Amir Habra Mouhammed 
Published: October 2024

Abstract
Disclosure: F. Yaylaci Mert: None. V. Balderrama Brondani: None. L.P. Marcal: None. M. Campbell: None. C. Jimenez: None. J. Varghese: None. A. Shah: None. M.A. Habra: None.
Background: Adrenocortical carcinoma (ACC) is a rare cancer with limited response to systemic chemotherapies. Monotherapy with multi-targeted tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) in ACC patients has limited efficacy. Combining TKIs with ICIs increased response rates in other malignancies but the efficacy of this approach in ACC is still unknown. This retrospective study aims to evaluate the efficacy and safety of the combined use of TKIs and ICIs in patients with advanced ACC. Methods: A single-center, retrospective cohort study in patients with advanced ACC treated with the combination of TKIs and ICIs. Response rates, progression-free survival (PFS), overall survival (OS) calculated from the time of combination, disease control rate (DCR), and safety profile were the main study objectives. Results: Seventeen patients were treated with combination therapy of TKI (lenvatinib or cabozantinib) and ICI (pembrolizumab) between January 2017 and December 2023. Eleven patients were women, the median age was 43.4 years (range 21.9-66.6), and 8 (47.1%) patients presented cortisol-producing tumors. All patients had prior systemic therapy, median of 3 (range 1-9) lines of therapy. The median duration of TKI+ICI therapy was 7.1 months (range 0.7-69.7). The treatment was discontinued in one patient due to a grade 3 adverse event (gastrointestinal fistula) after 1.6 months of treatment. Best overall responses were as follows: partial response 2 (13%), stable disease 8 (53%), and progressive disease 5 (34%). DCR was 58.8%. Median PFS was 7.1 months (range 0.7-66.4). One death occurred during the study due to disease progression. The median OS was 21.3 months (range 3.3-70.3). At the time of this report, 7 patients (41%) were still alive. Conclusion: The combined use of TKIs and ICIs in heavily treated ACC patients is associated with occasional durable responses and has a predictable and manageable side effect profile. This combination is worthy of a prospective clinical trial to validate the findings and establish new lines of therapy for this rare disease.
Presentation: 6/2/2024