bluuebunny/crossref_metadata_2025 huggingface dataset:
8014 Cushing’s Syndrome: Two Sides of The Spectrum
Authors: Aguilera M , VU A , Shakil J , Al-Ward R
Published: October 2024

Disclosure: M. Aguilera: None. A. Vu: None. J. Shakil: None. R. Al-Ward: None.

Introduction: Cushing’s syndrome (CS) is a rare condition with an annual incidence of 2-8 per million. Endogenous CS is mainly due to corticotroph adenoma of the pituitary followed by excessive glucocorticoid production from adrenal and ectopic sources. CS has significant morbidity and mortality hence the need for timely diagnosis. The varied presentations often pose great challenges in identifying the source of hypercortisolism. We present two unusual cases of CS with distinct clinical presentations and atypical laboratory profiles. Case 1: 25-year-old male with no medical history presented with 9 months of facial puffiness, weight gain, fluid retention, hypertension and blurred vision. Physical examination revealed round facies, bilateral supraclavicular fat pads and wide abdominal striae. Laboratory workup showed markedly elevated ACTH 537 pg/mL [7.2-63 pg/mL], serum cortisol 8.5 ug/dL [6.2-19.4 ug/dl], 24-hour urine free cortisol (UFC) 30 [5-62 ug/24H] and normal late-night salivary cortisol (LNSC). Repeat workup a month later showed serum cortisol of 56ug/dL, ACTH 874 pg/dL, 24-hour UFC of 11880ug/24H and elevated LNSC. Pituitary MRI showed a large heterogenous 3.1 cm partially cystic sellar mass with suprasellar extension. Due to significantly elevated ACTH and short duration of symptoms, we suspected an ectopic source. Due to initial negative testing, except for high ACTH level, a silent corticotroph adenoma was also considered. The patient underwent transsphenoidal resection resulting in significant decrease of cortisol and ACTH postoperatively. Pathology showed a corticotroph adenoma with Ki-67 index of <1%. Case 2: 47-year-old woman with medical history of obesity, polycystic ovary syndrome and a stable 1 cm lung nodule since 2020, presented with fluid retention, worsening acne and resistant hypertension over a 1-year period. She required hospitalization for hypertensive emergency and hypokalemia. Laboratory data showed morning serum cortisol 28 ug/dL, ACTH of 90.1 pg/mL, 24-hour UFC 346 ug/24H, elevated LNSC on two occasions and cortisol 24.3 ug/dl after a 1mg dexamethasone suppression. MRI did not show a pituitary mass. PET dotatate scan revealed a tracer avid 1 cm right upper lobe pulmonary nodule. She underwent a right upper lobe lobectomy, resulting in a significant decrease in cortisol and ACTH levels on postoperative day 1. Pathology confirmed a typical carcinoid tumor. Discussion: High ACTH levels and a short symptom duration often point to ectopic production, paraneoplastic syndromes or corticotroph carcinomas. Cushing's disease typically exhibits mildly elevated ACTH levels, but our cases deviate from this norm, complicating source identification. This atypical presentation highlights the complexity of Cushing's syndrome, challenging conventional diagnostic paradigms.

Presentation: 6/1/2024
8295 Development of Type 1 Diabetes and Primary Adrenal Insufficiency Secondary to Immunotherapy Treatment for Chordoma in a Patient With Hypopituitarism
Authors: Kesavan Chary P , Silverstein J M
Published: October 2024

Disclosure: P. Kesavan Chary: None. J.M. Silverstein: None.

Background: Cranio-cervical chordomas are rare locally aggressive, invasive, and slow-growing bone neoplasms. Treatment involves a combination of excision and radiation therapy, and sometimes immunotherapy for recurrent disease. Endocrine-related toxicities from immune checkpoint inhibitors are well recognized and include autoimmune thyroid disease, hypophysitis, and less commonly, type 1 diabetes mellitus (T1DM) and primary adrenal insufficiency (PAI). We present a case of a patient with hypopituitarism secondary to a recurrent and aggressive skull base chordoma with leptomeningeal spread who developed T1DM and PAI after treatment with nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody. Diagnosis of PAI was delayed because patient was on hydrocortisone replacement for secondary adrenal insufficiency. Case Report: A 38 year old male with history of primary hypothyroidism underwent endoscopic endonasal transsphenoidal resection and adjuvant proton beam radiation therapy for a sellar chordoma after presenting with diplopia. Testing was consistent with hypopituitarism and the patient was started on hydrocortisone, levothyroxine, and testosterone replacement. Due to recurrent disease and leptomeningeal spread, he subsequently underwent three additional surgeries and two courses of gamma knife radiosurgery. Five months after starting systemic therapy with nivolumab, the patient developed insulin dependent diabetes presumed to be T1DM secondary to immunotherapy. He was continued on nivolumab, and six months into treatment developed hyperkalemia and hyponatremia requiring inpatient admission. He was treated with diuretics and fluid restriction initially without improvement in his electrolyte abnormalities although he remained relatively asymptomatic. Laboratory evaluation showed a renin activity of 66 ng/mL/H and aldosterone < 4.0 ng/dL (<= 21) with sodium of 128 mmol/L (135-145) and potassium 5.8 mml/L (3.3-4.9). Due to suspicion for PAI secondary to checkpoint-inhibitor induced adrenalitis, 21-hydroxylase antibody was checked and was positive. It was felt that the patient had not had other signs or symptoms classic for PAI such as nausea and/or vomiting because he had already been on glucocorticoid replacement for his hypopituitarism. Ultimately, the patient was started on fludrocortisone, with resolution of his hyponatremia and hyperkalemia. Conclusion: Adrenal insufficiency from immunotherapy is most commonly caused by hypophysitis. T1DM and PAI due to adrenalitis are less common. In patients on steroid replacement for hypopituitarism, the development of electrolyte abnormalities with or without symptoms in a patient on immunotherapy should raise the suspicion for rarer endocrine side effects such as primary adrenal insufficiency.

Presentation: 6/3/2024
8785 Does Somatostatin Receptor Expression Intensity Impact Prognosis in Non Pituitary Neuroendocrine Tumors Treated with Somatostatin Analogues?
Authors: Jouneghani Nasrin Saleh , Fazeli Sasan , Chang Sue , Hosseini Alireza , Marandi Roghayeh , Siddiqui Abdullah , Talley Min , Salehian Behrouz
Published: October 2024

Disclosure: N. Saleh Jouneghani: None. S. Fazeli: None. S. Chang: None. A. Hosseini: None. R. Marandi: None. A. Siddiqui: None. M. Talley: None. B. Salehian: None.

Does Somatostatin Receptor Expression Intensity Impact Prognosis in Non Pituitary Neuroendocrine Tumors Treated with Somatostatin Analogues? Introduction: Non-pituitary neuroendocrine tumors (NETs) show different somatostatin receptor subtype (SSTR) expression, but their role in tumor progression and prognosis is not well known. We hypothesized that NETs with higher expression of SSTR2, SSRT5, or co-expression of SSTR2 and SSTR5 will have better outcome when treated with Somatostatin Analogues (SSA). Method: Retrospectively, patients with non-pituitary neuroendocrine tumors, followed for more than one year between 1985 and 2022, and treated with SSA (Octreotide or Lanreotide) who had available tissue were selected. Tissue immunostaining performed for SSTR2 and SSTR5 with use of monoclonal antibodies. Expression analysis of the SSTR2 and SSTR5 were evaluated by the validated semi-quantitatively method, reported by an intensity score of 0 -3. The progression free survival and overall survival were calculated by Kaplan Meier and compared in different subgroups with SSTR expression intensity. Response evaluation was assessed using RECIST v1.1. Results: Of 279 non-pituitary neuroendocrine tumors, 51 meet the criteria and tissue sent for analysis. The median age at diagnosis was 62; male 49%, with median follow up 7 years, 85% stage IV at diagnosis, most common primary tumor was in gut 54% followed by pancreas 33%. Positive SSRT5 tumors had 93% SSRT2 co-expression. There were no significant differences in progression-free survival (PFS) observed between tumors with low or high SSTR2 intensity expression (P=0.62). The presence or absences of SSRT5 expression did not have any impact on PFS (p=0.57) or overall survival (p=0.3). Conclusion: in the patient with non-pituitary neuroendocrine tumors, higher SSTR2 expression intensity or having SSRT5 co-expression, did not correlate with a better PFS or overall survival in response to SSA, in our study. Further prospective studies are needed to clarify if higher expression intensity of SSRTs correlates with better response to SSAs in NETs.

Presentation: 6/1/2024
7166 EFFECT OF ANTI-NEOPLASTIC THERAPIES ON CARCINOMA AND AGGRESSIVE PITUITARY TUMORS : A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Nunes-Nogueira Vania dos Santos , Cardoso Ana Beatriz Ribeiro , Zimmermann Amanda Cristina
Published: October 2024

Disclosure: V.D. Nunes-Nogueira: None. A.R. Cardoso: None. A.C. Zimmermann: None.

Introduction: Approximately 10% of the pituitary adenomas can have an aggressive behavior and 0.2% can present metastasis, being classified as pituitary carcinomas. Objective: Evaluate the tumor control obtained by anti-neoplastic therapies that are still little explored in the context of carcinoma and aggressive pituitary tumors. Methods: A systematic review according to the Joanna Briggs Institute has been conducted. We have included studies that evaluated patients with carcinoma or aggressive pituitary tumors who underwent treatment with at least one of the following therapies: Temozolomide, VEGF Inhibitors, Peptide Receptor Radionuclide Therapy (PRRT), Everolimus, Immune Checkpoint Inhibitors, EGFR Inhibitors, Capecitabine and temozolomide (CAPTEM). The main outcome assessed by the study was the frequency of tumor response according to the RECIST protocol classification. Embase, Medline, LILACS, and CENTRAL were our source databases. Proportional meta-analyses were performed to calculate the overall frequencies of complete remission (CR), partial remission (PR; minimum shrinkage of 30%), stable disease (SD) and progression disease (PD). We used Stata Software 18, the updated command “metaprop_one” and fit the logistic normal random effect model. Results: None clinical trial was found, and sixty case report/case series were included. The most frequent therapy used was temozolomide (101 patients), followed by PRRT, pembrolizumab, lapatinib, CAPTEM, bevacizumab, ipilimumab/ nivolumab and everolimus, with respectively 9, 6 ,6, 6, 4, 3 and 1 individuals. The majority of patient in temozolomide studies had prolactinomas (40/101), followed by Cushing’s disease (25/101), the overall frequency of CR with this drug was 1% (ch^2=2.7; p=0.049, Predictive Interval (PI) 1% to 93%, 7 events), PR was 45% ( ch^2=1.8, p=0.091, PI= 8-89%, 46 events), SD 14% (CI 95%=5 a 33%, 20 events), and PD was 25% (95%CI: 14-40%, 28 events). Two patients receiving CAPTEM presented CR, no other studies presented this outcome. In the PRRT studies, the overall frequency of PR was 22% (95%CI 6 to 58%) and PD was 44% (95%CI 18 to 75).Conclusion: Temozolomide has been the therapy most frequent used in the management of carcinoma and aggressive pituitary tumor, being PR the most frequent outcome, followed by PD and SD, with low percentage of CR. The other drugs approached by this review showed similar poor response although they were less tested in the context of this neoplasms.

Presentation: 6/2/2024
8142 Endocrine Considerations Prior to Pituitary Tumor Resection
Authors: Einafshar Parastou , Delibasi Tuncay
Published: October 2024

Disclosure: P. Einafshar: None. T. Delibasi: None.

Endocrine Considerations in Pituitary Tumor Resection Introduction: Diabetes Insipidus (DI) is an endocrine condition involving a disturbance to the action of Anti-Diuretic Hormone (ADH) resulting in polyuria, and polydipsia with complications such as severe water and electrolyte disturbances. It can be classified into Central DI which affects the secretion of ADH or Nephrogenic DI which affects peripheral ADH receptors in Distal Convoluted Tubules (DCTs) in the renal system. Both subtypes however present similarly and are usually known to be transient. It is important to consider the most common etiologies contributing to both central and nephrogenic DI as severe complications may arise if not diagnosed and treated promptly. The most important step is to monitor and manage water and electrolytes and avoid excessive water loss which can lead to irreversible complications. This can be accomplished by introducing synthetic ADH called DDAVP or Desmopressin. Case Description: A 57-year-old female was admitted in preparation for a supra-orbital resection of a suprasellar mass. Two hours post-procedure, she was found to have an increase in urine output with her labs notable for a significant acute increase in serum sodium and a decrease in urine osmolality. Upon emergent Endocrinology evaluation, due to concerns of Acute Diabetes Insipidus in the setting of insult to the pituitary stalk, she was started on emergent treatment with IV DDAVP. Her course was complicated with persistent DI resulting in a case of permanent DI requiring out-patient daily treatments with DDAVP. Discussion: Injury to the pituitary stalk resulting in various endocrine abnormalities has been studied involving a trans-sphenoidal resection of pituitary tumors, but there is a paucity of cases reported when patients undergo a supra-orbital surgical approach. It is vital for Endocrinology and Neurosurgical services to be aware of this phenomenon, and a multi-disciplinary approach to patient management should be considered. Furthermore, close follow-up of pituitary hormones in the post-operative setting is imperative in order to avoid severe complications, such as brain damage or poor mental status. We hope to educate residents and fellows about this phenomenon that is rarely reported in the literature but can have profound effects on patient’s quality of life if not considered by the consulting Endocrinology team. References Christ-Crain, M., Winzeler, B., & Refardt, J. (2021). Diagnosis and management of diabetes insipidus for the internist: an update. Journal of internal medicine, 290(1), 73-87. Mutter, C. M., Smith, T., Menze, O., Zakharia, M., & Nguyen, H. (2021). Diabetes insipidus: pathogenesis, diagnosis, and clinical management. Cureus, 13(2).

Presentation: 6/1/2024
9377 Exploring Strategies To Reverse Cellular Characteristics Of Succinate Dehydrogenase B-loss Immortalized Chromaffin Cells
Authors: Rahimi Leili , Al-Khazal Fatimah , Becker Nicole A , James Maher L
Published: October 2024

Disclosure: L. Rahimi: None. F. Al-Khazal: None. N. Becker: None. L. Maher, III: None.

Carriers of loss-of-function alleles in genes encoding the four succinate dehydrogenase (SDH) subunits exhibit a heightened risk for pheochromocytoma/paraganglioma (PPGL), a rare neuroendocrine tumor of chromaffin cells. Tumorigenesis begins with the somatic loss of the remaining functional gene copy, resulting in a cell devoid of functional SDH. Compared to wild-type immortalized chromaffin cells (WT imCCs), SDHB-KO immortalized chromaffin cells (SDHB-KO imCCs) are larger, grow more slowly, display deformed mitochondria, show strikingly heightened succinate accumulation, and altered metabolism. Among several mechanisms proposed to link SDH deficiency with PPGL tumorigenesis, the accumulation of succinate as an oncometabolite is a leading hypothesis. We describe two attempts to suppress succinate accumulation in SDHB-KO imCCs. First, riboflavin has previously been shown to enhance residual SDHA flavinylation and enzymatic function, possibly reducing succinate levels by supporting conversion of accumulated succinate to fumarate in the absence of SDHB. We tested this by treating WT and SDHB-KO imCCs with 5 µM riboflavin for 2 weeks. Metabolomic analysis did not show decreased succinate, suggesting that enzyme activity of any remaining SDHA subunit was not rescued by increased flavinylation. Second, we envisioned a gene therapy approach to replace defective SDHB with a rescuing transgene. SDHB-KO imCCs received DNA encoding SDHB or SDHC cDNAs via transposon technology, confirmed by PCR and analyzed by western blot analyses. These studies showed that whereas WT imCCs successfully expressed processed transgene products in mitochondria, SDHB-KO imCCs could not process or transport rescuing SDH subunits into mitochondria. This shows that transposed SDHB-KO imCCs cannot properly express a rescuing SDHB subunit and do not revert to a wild-type phenotype. It is likely that the severely damaged mitochondria of SDHB-KO imCCs are incompetent to process and import rescuing SDHB subunits, so unprocessed protein accumulates without effect. This defect may lie in the mitochondrial targeting peptide recognition system because the targeting peptide of rescuing SDHB protein is not removed in SDHB-KO imCCs as judged by western blotting. In summary, we show the failure of two conceptually simple tactics to suppress succinate accumulation in SDHB-KO imCCs with highly defective mitochondria: rescue of SDHA by supporting flavinylation, or rescue of SDHB with a replacement gene copy. Further research may allow screening for small molecules that suppress succinate accumulation by other mechanisms. It remains to be determined if blocking succinate accumulation would be therapeutic in SDH-loss PPGL tumors.

Presentation: 6/1/2024
12562 Extraocular Muscle Enlargement With Proptosis In A Patient With Non Thyroidal Disease
Authors: Bantu S S , Kabir P N , Gondhi A , Vaughan T B
Published: October 2024

Disclosure: S.S. Bantu: None. P.N. Kabir: None. A. Gondhi: None. T.B. Vaughan: None.

Extraocular muscle enlargement with proptosis in a patient with Nonthyroidal disease Introduction: Majority of cases with extraocular muscle enlargement (EOME) is due to Graves’ disease, commonly in about 95% cases and another 5% make up other causes including inflammatory, neoplastic, vascular, infectious and acromegaly. We present a patient with sudden loss of vision, retroorbital pain with visual field deficits found to have EOME and subsequently a pituitary macroadenoma on imaging. Case: We present a 54-year-old male with history of hypertension, obstructive sleep apnea and morbid obesity who presented to us with complains of left sided vision loss. Patient was evaluated by ophthalmology and noted to have unilateral, left-sided, change in visual acuity. Physical exam was notable for macrognathia, skin tags, enlarged hands, excessive sweating. MRI brain revealed bilateral EOME with proptosis and a pituitary macroadenoma measuring 1.5x1.7x1.3cm, abutting the pre-chiasmatic left optic nerve. On biochemical evaluation he was noted to have elevated IGF1 of 979 confirming the diagnosis of acromegaly. ((hemoglobin A1C of 5.5%, prolactin 5.1, FT4 0.89, TSH 0.692, total testosterone 61, IGF1 level was 979)). He underwent transsphenoidal resection of the pituitary macroadenoma. Pathology showed sparsely granulated somatotroph adenoma. Discussion: Acromegaly has an incidence of 3-4 cases per million per year. The characteristics of the disease are due to chronic growth hormone hypersecretion resulting in the excessive growth of tissue due to the stimulation of insulin-like growth factor 1 (IGF-1). EOME with proptosis in acromegaly is seen rarely. Visual symptoms may manifest as visual field deficits due to compression of the optic pathway in 18-25% cases, increased intraocular pressure, increase in corneal thickness and a diffuse symmetrical enlargement of the extraocular muscles which cannot be distinguished from thyroid orbitopathy on imaging. The degree of enlargement appears to correlate with the duration of the disease rather than the levels of IGF1. EOME improves with the treatment of acromegaly. Although visual symptoms may be a rare presentation of acromegaly, if the clinical suspicion exists, one may consider obtaining an IGF-1 level to complete the evaluation of EOME if the thyroid levels are normal.

Presentation: 6/3/2024
12580 Factitious Cushing’s Syndrome Secondary To Indiscriminate Use Of Brazilian Herbal Medicine: Case Report
Authors: Warszawski Leila , de Marca Seidel Karen F , Padilla Carlos , de Souza Valéria Priscila Neves , Calmon Júlia Ribeiro
Published: October 2024

Disclosure: L. Warszawski: None. K.F. Seidel: None. C. Padilla: None. V.N. de Souza: None. J.R. Calmon: None.

Background: Herbal medicines are obtained exclusively from active plant raw materials, which leads people to believe that these medications are safer and free from side effects. Moreira milk is a Brazilian herbal medicine used mainly for its supposed anti-inflammatory properties. This medication is not regulated by The Brazilian Health Regulatory Agency (Anvisa). Herein we report a case of exogenous Cushing's Syndrome (CS) caused by continuous use of Moreira milk. Case report: A 53-year-old female patient was seen in October 2018 at the endocrinology clinic due to progressive weight gain, mood swings, edema and weakness of the lower limbs, violet streaks on the flanks, easy bruising and dorsocervical fat pad. She brought tests to our specialized consultation that showed low basal cortisol (0.4 mcg/dL - RR 5 to 25 mg/dL) and ACTH ( %lt; 5 pg/ml - RR 10 to 60mg/dL), two HbA1c values above 6.5% and a sella turcica MRI revealing normal-sized pituitary gland with a hypo-enhancing contrast area, possibly corresponding to a microadenoma. New tests were carried out which showed the maintenance of low basal cortisol and ACTH. The patient reported background use of losartan and Moreira milk for 2 years - as a phytotherapy to control joint pain after Chikungunya. She denied use of topical, inhalatory or oral corticoids. Exogenous CS was suspected and the use of Moreira milk was interrupted. We proceeded to use prednisone for weaning, which had to be gradual, but the patient progressed with clinical improvement. Conclusion: There are some cases of hypercortisolism associated with herbal medicines, the majority of which are due to contamination with synthetic glucocorticoids, as is believed to occur with Moreira milk. Despite being widely sold in Brazil, because it is not approved by ANVISA, the production cannot be inspected, therefore, can be contaminated. Those cases of exogenous CS are challenging, and misidentifying Cushing's syndrome can result in a series of improper treatments with severe repercussions.

Presentation: 6/1/2024
12530 Inferior Petrosal Sinus Sampling In Cushing’s Disease
Authors: Gondhi A , Antharam S , Moledina I
Published: October 2024

Disclosure: A. Gondhi: None. S. Antharam: None. I. Moledina: None.

Inferior Petrosal Sinus Sampling in Cushing’s Disease Introduction: Cushing's disease (CD) is the most common cause of endogenous Cushing syndrome( CS) caused by ACTH secreting pituitary tumor. MRI is typically used for imaging, but standard MRI may only detect 50% of microadenomas. In these cases, inferior petrosal sinus sampling (IPSS) is the gold standard in detecting pituitary source of ACTH. Case presentation:A 53-year-old man presented with signs and symptoms of CS: fatigue, weight gain, decreased libido, mood swings, new onset prediabetes. Physical examination revealed cushingoid appearance with facial flushing, easy bruising, abdominal purple striae. Initial work up revealed ACTH dependent CS: elevated late night Salivary cortisol 0.39 mcg/dL (<0.09 mcg/dL), 24hr urine free cortisol 192 mcg/24 hour (4 – 50 mcg/24 hour)Non suppressed cortisol 8.1 mcg/dL (<1.8 mcg/dL) after 1mg dexamethasone suppression test8 AM ACTH 56 pg/ml (7.2 – 63 pg/ml), DHEAS 491 mcg/dL (38-318 mcg/dL)Pituitary hormonal work up: normal Prolactin 7.8 ng/mL (2.6-13.1 ng/mL)Low TSH 0.29 ng/ml (0.45-5.3 ng/ml) with normal Free T4 0.76 ng/dl (0.58-1.6 ng/dl)Low Total Testosterone 150 ng/dl (175-781 ng/dl), Low FSH<0.7 mInt units/ml(1.27-19.26 mInt units/ml), Low LH 1 mInt units/ml (1.24- 8.62 mInt units/ml), Normal IGF 180 ng/mL (65-222 ng/mL), A1C 6% (Prediabetes – 5.7-6.4) MRI Brain showed normal pituitary gland. IPSS was performed with DDAVP: +2, +5, +10, +15: Right/ periphery ratio- 31.8, 10.75, 7.6, 5.3. left/periphery ratio- 26.6, 18.8, 8.3, 7.5. All the ratios >=3, which showed clear central to peripheral gradient. and no left or right difference consistent with Cushing's disease. Subsequently, a transsphenoidal pituitary gland resection was performed. Suspicious tissue was excised from both sides during the surgery, showing positive ACTH immunostaining, consistent with pituitary microadenoma. Post-operative labs showed significant improvement with normalization of Cortisol 3.2 mcg/dl, ACTH 45 pg/ml, TSH 3.14 ng/ml, FT4 0.61 ng/dl, FSH 1.7 mInt units/ml, LH 2.4 mInt units/ml, Prolactin 7.1 ng/ml, A1C 5.4 %He was discharged on physiological dose of Hydrocortisone and passed cortisol stimulation test (3.4 mcg/dl ---> 18.1 mcg/dl) Conclusion: Distinguishing between CD and ectopic ACTH secretion is crucial due to the differing treatment options. The most accurate method for differentiation is IPSS, which boasts high sensitivity and specificity compared to other analyses. Despite its invasiveness, IPSS is associated with rare adverse events, making it a valuable tool in clinical practice.

Presentation: 6/3/2024
8716 Late Onset of Temozolomide in Aggressive Pituitary Tumors: Insights From a Leading Oncology Center in Latin America
Authors: de Macedo Camila Regina Pereira Batista , de Magalhães Isabelle Pinheiro Amaro , Glezer Andrea , da Cunha Neto Malebranche Berardo Carneiro , de Castro Musolino Nina Rosa , Feher Olavo , Batista Rafael Loch
Published: October 2024

Disclosure: C.R. de Macedo: None. I.P. de Magalhães: None. A. Glezer: None. M. Berardo Carneiro da Cunha Neto: None. N.R. de Castro Musolino: None. O. Feher: None. R.L. Batista: None.

Introduction: Temozolomide (TMZ) is an oral alkylating agent used in management of glioblastoma multiforme. Since 2006, TMZ is used in patients with pituitary tumors (PITNets) with yielded promising outcomes as an alternative for aggressive PITNets. Objective: To evaluate the response to TMZ in patients with aggressive or metastatic PITNets within the largest tertiary oncology service in Latin America. Patients and Methods: We screened all cases that received TMZ at our institution between 2008-2023 (n=661, primarily glioblastoma cases). We identified 7 cases that TMZ was employed for treating PITNets. We assessed for PITNet characteristics, functionality, timelines of treatment initiation, correlation with radiotherapy, duration of TMZ usage and treatment response utilizing the RECIST criteria. Results: At the time of diagnosis, all patients presented with macro-PITNets and 6 were giant (size greater than 4 cm). In terms of hormonal production, 4 cases were prolactinomas and 3 were non-functioning PITNets. Over the follow-up period, these tumors exhibited an aggressive behavior, manifesting rapid tumor growth despite optimized treatments and one case was recategorized as metastatic PitNET. All cases demonstrated a Ki-67 index greater than or equal to 3%. The initiation of TMZ occurred on average 9.48 years after diagnosis and subsequent to multiple surgical interventions (average of 1.8 surgeries). In 5 cases, TMZ followed radiotherapy. Among the cohort, 3 of 7 patients underwent 6 cycles of TMZ, one underwent 5 cycles, another had an extended treatment of 10 cycles and 2 patients received only 3 cycles due to adverse effects. In terms of treatment response, 4 patients exhibited stable disease, one achieved a partial response (PR) and 2 had disease progression. The most commonly side effect was mild nausea and vomiting and one patient required dose adjustment due to thrombocytopenia. A second course of TMZ was warranted in 2 cases that previously demonstrated a PR (on average one year after the initial treatment). While one case sustained the PR, the other experienced disease progression. Conclusion: The administration of this treatment was often postponed, potentially attributed to the significant disparities in opinions regarding the optimal timing of treatment initiation and the most suitable duration of usage. However, TMZ demonstrated its efficacy in maintaining disease stability for the majority of cases, with good tolerability and safety, even when used later, after multiple surgical procedures, and in patients with high Ki67 levels.

Presentation: 6/2/2024
8611 Maternal Immune Activation During Mid-Gestation Leads to Impaired Neuroendocrine Stress Response and Blood-Brain Barrier Integrity in a Sex-Dependent Manner
Authors: Sheng J A , Tobet S A
Published: October 2024

Disclosure: J.A. Sheng: None. S.A. Tobet: None.

Background and Hypothesis: Maternal immune activation (MIA) has been associated with increased risk for neuropsychiatric diseases in the offspring. Recently, our lab demonstrated toll-like receptor 7 (TLR7) activation during impaired stress-related behaviors (anxiety-, anhedonia-, social-like) (Sheng et al., 2023, Front. Neurosci.). Stress-related behaviors are regulated by neurons in the paraventricular nucleus of the hypothalamus (PVN), an anatomic region involved in the hypothalamic-pituitary-adrenal (HPA) stress response. We hypothesize immune system activation by TLR7 during mid-gestation impairs PVN neuroendocrine stress response and brain vasculature. Methods: Timed-pregnant female mice were administered the TLR7 agonist Resiquimod (RQ) or vehicle saline on embryonic day 12.5. Adult offspring underwent 20-minute acute restraint stress with 80-minutes of recovery to examine plasma corticosterone (ELISA assay) as an indicator of HPA function. Mice were transcardially perfused with fluorescein isothiocyanate (FITC; 100mg/mL) to visualize blood vessel integrity (FITC leakage; Frahm & Tobet, 2015, Brain Struct. Funct.). Sections through the PVN of offspring were also immunolabeled for Glial Fibrillary Acidic Protein (GFAP; astrocytic end feet) and IBA-1 (microglia). Only data from brains of offspring that did not undergo restraint stress are presented for baseline changes in blood-brain barrier components by MIA. Results: Plasma corticosterone was elevated in RQ-offspring (males p<0.0001, females p<0.01 vs. VEH) following stressor and recovery, suggesting delayed negative feedback to the HPA axis. Blood-brain barrier integrity diminished in RQ-adult offspring who showed greater FITC leakage in the PVN as indicated by an increase in the ratio of extravascular to intravascular FITC (males p<0.001, females p<0.01). GFAP+ coverage of FITC-labeled vessels was greater in the PVN only in RQ males compared to VEH (p<0.001). Microglia were examined in relation to vasculature, and data show more IBA-1+ cells in the PVN with close proximity (within 2µm) to blood vessels after maternal injection of RQ in females compared to VEH (p<0.05). In RQ-adult males, the average size of IBA-1+ cells in the PVN were greater than VEH counterparts (p<0.05), but number and proximity of IBA-1+ cells to blood vessels were unchanged. No changes in these measures were seen in control brain regions. Conclusions: This study provides support for sex-dependent influences of fetal immune antecedents on brain development and adult neuroendocrine function that could indicate a locus for increased susceptibility to adult neuropsychiatric disorders. While the current experiments found significant post-pubertal changes selectively in adult PVN, ongoing studies are examining whether these effects are evident prior to puberty. Supported by ORWH-NIMH U54 SCORE-MH118919.

Presentation: 6/1/2024
8637 Pituicytoma mimicking Craniopharyngioma
Authors: Araoye Olubusayo , Delibasi Tuncay , Chaugule Akshata Satish , Dhillon Shabnam Kaur , Fuller Christine
Published: October 2024

Disclosure: O. Araoye: None. T. Delibasi: None. A. Chaugule: None. S.K. Dhillon: None. C. Fuller: None.

Pituicytoma, a rare low-grade glial tumor originating from the neurohypophysis or infundibulum of the pituitary gland, poses diagnostic challenges due to its propensity to mimic other sellar or suprasellar lesions. We present a case of a 51-year-old male with a history of a suprasellar mass initially suggested to be a craniopharyngioma, incidentally discovered. Opting for elective surgery, the patient underwent transsphenoidal resection, revealing a highly vascular tumor adherent to the optic chiasm and pituitary stalk. While the tumor was successfully removed, sacrifice of the pituitary stalk led to postoperative complications, including cerebrospinal fluid (CSF) leak and central diabetes insipidus (DI).Histopathological examination characterized the tumor as oncocytic pituicytoma/spindle cell oncocytoma, a subtype of pituicytoma. The anti-mitochondrial antibody staining at an external laboratory displayed diffuse granular cytoplasmic staining supporting oncocystic pituicytoma/spindle cell oncocytoma.Postoperatively, the patient developed central DI treated initially with desmopressin (DDAVP), complicated by subsequent hyponatremia necessitating salt tablets and fluid restriction. Additionally, central adrenal insufficiency was managed with hydrocortisone, and central hypothyroidism with levothyroxine. A history of testosterone deficiency was addressed through testosterone injections every 10 weeks.Pituicytoma's diagnostic complexity arises from nonspecific radiological features, requiring reliance on histology and immunohistochemistry for definitive diagnosis. The expression of TTF1 emerges as a characteristic marker. Surgical resection, the primary treatment modality, proves curative in most cases, albeit with associated morbidity including CSF leak, DI, and panhypopituitarism. The role of adjuvant radiotherapy remains uncertain, potentially considered in cases of incomplete resection or recurrence.This case emphasizes three key aspects: first, the potential misdiagnosis of a lobulated suprasellar mass as craniopharyngioma when it could be pituicytoma; second, the development of postoperative DI due to pituitary stalk involvement; and third, the importance of considering pituicytoma in the differential diagnosis of sellar and suprasellar masses.In conclusion, pituicytoma, though rare, demands a nuanced diagnostic approach and comprehensive postoperative management to address potential complications and optimize patient outcomes.

Presentation: 6/2/2024
7102 Pituitary Apoplexy with Eventual Complete Tumour Involution
Authors: Ng Aaron , Lai Ray
Published: October 2024

Disclosure: A. Ng: None. R. Lai: None.

Pituitary apoplexy is an endocrinological emergency resulting from infarction or haemorrhage of the pituitary gland. We present a case of pituitary apoplexy from a non-functioning pituitary macroadenoma, complicated by pituitary insufficiency and subsequent tumour involution. An 80-year-old gentleman presented to the Emergency Department with sudden severe headaches and persistent vomiting and admitted for further evaluation. Computed tomography (CT) imaging of the brain showed a prominent pituitary gland and magnetic resonance imaging (MRI) confirmed a large sellar hyperintense lesion containing blood and proteinaceous material. It measured 1.6 cm by 1.2 cm by 1 cm and indented the optic chiasm. CT angiography did not reveal any aneurysms or intracranial haemorrhage. There were no neurological or visual field deficits at presentation. There was no indication for surgery upon neurosurgical consultation. Initial evaluation of the pituitary axis was consistent with central hypocortisolism (cortisol 75 nmol/L, adrenocorticotropic hormone 1.4 pmol/L [reference range (RR) 1.6-13.9]) and hypoprolactinaemia (prolactin 56 mIU/L, RR 73-351). Luteinising hormone levels were < 1 IU/L (RR 1-9); follicle stimulating hormone levels were 3 IU/L (RR 1-19) and testosterone levels were < 1 nmol/L (RR 5 to 30) as the patient was on androgen deprivation therapy for prostate cancer. Hydrocortisone was started and he was monitored for development of frank diabetes insipidus. He did not require regular desmopressin. He later developed anti-diuretic hormone mediated hyponatraemia (serum sodium nadir of 125 mmol/L, serum osmolality 275 mmol/kg, urine osmolality 390 mmol/kg) that was managed with fluid restriction and solute loading. He also developed central hypothyroidism on day 19 of admission (free thyroxine 11 pmol/L, thyroid stimulating hormone 0.49 mIU/L, RR 0.45-4.5) and oral levothyroxine was started. He was discharged with oral hydrocortisone and levothyroxine replacement. A repeat MRI of the pituitary 2 months later showed complete resolution of the mass and resolution of the mass effects. He was kept on oral hydrocortisone and levothyroxine replacement with regular follow-up.Most pituitary macroadenomas are non-functional, and can present with complications of apoplexy, mass effects or hormonal disturbances. However, the natural history of non-functional macroadenomas is not well known as most are operated on. Spontaneous regression of the tumour can rarely occur, notably in the setting of apoplexy and lymphocytic hypophysitis. Recovery of the pituitary axis may also accompany tumour regression. As spontaneous remission of pituitary macroadenomas may occur, close observation of tumours without visual field defects or significant mass effects may be an alternative to surgery.

Presentation: 6/1/2024 12:15:00 PM
6374 Prevalence and risk factor of complications in patients with adult growth hormone deficiency: A retrospective database study
Authors: Fukuoka Hidenori , Fujio Shingo , Endo Takaaki , Tsuboi Satoshi
Published: October 2024

Disclosure: H. Fukuoka: None. S. Fujio: None. T. Endo: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. S. Tsuboi: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk.

Though adult growth hormone deficiency (AGHD) is known to lead to increased prevalence of complications, large database studies on AGHD have not been conducted. We investigated the clinical characteristics and prevalence of AGHD-related complications in Japanese patients. We identified 8,809 GH-untreated patients with AGHD from Medical Data Vision claims database between April 2008 and September 2022. In 2020, 3,420 AGHD patients were identified, and their prevalence of complications adjusted for sex and age was higher than that of Japanese general population, 9.3% vs 3.6% for diabetes mellitus (DM), 4.8% vs 1.3% for osteoporosis, and especially 22.0% vs 3.9% for dyslipidemia. We explored the risk factors for the onset of complications using Cox proportional hazard model. Age was significant risk factor for most complications and being female was significant risk factor for osteoporosis. DM was a significant risk factor for dyslipidemia, ischemic heart disease, cerebrovascular disease, and all cause death. AGHD increases the overall risk of metabolic complications, risk factors of these complications were similar to those in general population. Comprehensive treatment approach needs to be considered to alleviate the risk of complications.

Presentation: 6/3/2024
6705 Sheehan syndrome: a case report
Authors: Rodrigues Fernanda S , Silva Camila C , Da Silva Wilson , Caldas Talita M , Rocha Luis Klaus
Published: October 2024

Disclosure: F.S. Rodrigues: None. C.C. Silva: None. W. Da Silva: None. T.M. Caldas: None. L. Rocha: None.

Introduction: Sheehan's Syndrome, or postpartum hypopituitarism, is characterized by hyperplasia and an increase in the number of prolactin-secreting cells, secondary to a major hemorrhagic event occurring during or after childbirth. In this situation, the anterior pituitary gland can increase in size and suffer ischemia due to vascular hypoflow. Consequently, there is low production of one or more of the hormones produced by the gland, which can generate heterogeneous clinical presentations. As a preventive treatment, polytransfusion is recommended in cases of large hemorrhage. OBJECTIVE: To present a case of Sheehan’s Syndrome, which developed after a birth complicated by a major hemorrhagic event, even after receiving polytransfusion. CASE REPORT: A woman, 45 years old, being monitored at the endocrinology outpatient clinic for 2 years. As a history, there was a severe hemorrhage during her cesarean section, which occurred 30 years ago, in which she received a blood transfusion of a total of 1.2 liters of packed red blood cells. 7 years ago, she was diagnosed with hypothyroidism and 2 years ago with hyperprolactinemia. In 2022, she was also diagnosed with adrenal insufficiency. At that time, she underwent a magnetic resonance imaging (MRI) scan of the sellaturcica region, which was found to be partially empty. The patient's recent exams showed TSH: 3.15 μUI/mL (0.4-4.0); Free T4: 0.88 ng/dL (0.93-1.7); Cortisol 8h: 8 μg/dL (5-25); LH: 15 mIU/mL (1.1-14.7); FSH: 43 mIU/mL (2.8-9); Estradiol: 8 ng/dL (12.4-398); Prolactin: 28 ng/mL (1.9-25), basal GH 0’ 0.054/30’ 2.51/60’ 2.48/90’ 3.74 ng/mL (up to 10), ACTH 17 pg/mL (up to 46). Since then, she has been undergoing endocrinological monitoring for hormone replacement therapy to treat the hormonal changes caused by late-diagnosed Sheehan Syndrome. DISCUSSION: Sheehan's Syndrome is a rare disease, characterized by low blood flow and necrosis of the pituitary gland due to postpartum hemorrhage. The diagnosis results from obtaining a good clinical history associated with hormonal levels. This patient presented significant bleeding after cesarean section requiring transfusions. However, despite transfusions, the patient developed hypothyroidism, hyperprolactinemia, and adrenal insufficiency. The MRI confirmed the suspected diagnosis, showing the partially empty sellaturcica. Conclusion: The diagnosis of Sheehan Syndrome is based on very broad clinical manifestations, with MRI of the sellaturcica contributing to confirming the diagnosis. Although the preventive treatment is blood transfusion, the patient developed the disease, highlighting the need for continued monitoring of pregnant women with a history of significant bleeding during childbirth. Therefore, outpatient monitoring of the patient is necessary with a focus on hormonal levels so that clinical complications are avoided.

Presentation: 6/2/2024
6520 Stimulated Copeptin Measurement in the Evaluation of a Patient Presenting Hypernatremia and Adipsia
Authors: Assunção Beatriz R , Freire Magda M , De Castro Margaret , Moreira Ayrton Custodio , Elias Paula C L
Published: October 2024

Disclosure: B.R. Assunção: None. M.M. Freire: None. M. De Castro: None. A.C. Moreira: None. P.C. Elias: None.

Introduction: Hypernatremia (hyperNA) in patients submitted to neurosurgery involving the hypothalamic region prompts the diagnosis of vasopressin deficiency (AVP-D), typically accompanied by increased thirst, polydipsia and polyuria. Classic adipsic AVP-D is characterized by hypotonic polyuria and no thirst in response to hyperNA. Clinical Case: A 21 yo male patient, followed since he had a surgery for a pilocytic astrocytoma of the third ventricle at 12 yo, presented hyperNA (154 mEq/L) with mild dehydration. He denied increased thirst, polyuria or polydipsia. Further evaluation showed elevated plasma and urinary osmolalities (pOsm: 317 mOsm/Kg; uOsm: 878 mOsm/Kg). The patient was admitted for hydration and fluid balance. Oral water intake (2500-3000L/day) was prescribed. Serum sodium (Na+) decreased from 158 to 133 mEq/L within 72h, and no polyuria was detected at hyper or normonatremic states. A 3% saline infusion test (SIT) was performed with thirst visual scale and plasma copeptin (CP) assessment. Na+ rose from 139 to 150 mEq/L and pOsm from 295 to 321 mOsm/kg, with no rise in thirst scale (4,2 to 4,8 cm). Basal and maximal 3% SIT CP levels were 3.1 and 3.2 pmol/L, respectively, also displaying subnormal values. CP assessed under hypovolemic hyperNA (Na+: 158 mEq/L) was 4.1 pmol/L, suggesting that this patient might have an adispic disorder with subnormal thirst and AVP osmotic responses, explaining the lack of polyuria. Patient was treated with fixed daily fluid intake with a last follow-up Na+ of 141 mEq/L.Discussion: Adipsic AVP-D is characterized by hypotonic polyuria and no thirst in response to hyperNA. However, polyuria, a hallmark of clinical presentation, was not observed in the present case. Other adipsic disorders include upward resetting of the osmotic thresholds for both thirst and AVP release (Type A); sub-normal thirst and AVP responses to osmotic stimuli (Type B); and intact osmoregulation of AVP release with absent thirst response (Type D). The lack of polyuria even in normovolemic conditions and the subnormal thirst and CP responses to normovolemic hyperNA and dehydrate states suggest the present case to be a Type B adipsic disorder. In those patients, the secretion of small amounts of AVP in response to osmotic stimulation explains why they retain the ability to concentrate urine, limiting free water excretion. Treatment is based on a fixed fluid intake of around 2 liters per day. Conclusions: Adipsic AVP-D and other adipsic disorders are extremely rare, presenting a great challenge in the diagnosis and management. To our knowledge, this is the first description of CP assessment in a patient with hyperNA and adipsia. CP might be an important diagnostic approach to adipsic disorders.

Presentation: 6/2/2024
7483 The Pharmacokinetic Profile of Lanreotide Autogel® Improved Long-Term Arrhythmia Fluctuations in Acromegalic Cardiomyopathy
Authors: Iwabuchi Masayasu
Published: October 2024

Disclosure: M. Iwabuchi: None.

Background: The prognosis of acromegaly is related to the status of cardiac complications. Ventricular premature contractions (VPC) are frequently observed in acromegaly, and it is very important to suppress fatal arrhythmias to improve long-term prognosis. Somatostatin analogs are widely used as pharmacotherapy for acromegaly, and they have been reported to improve cardiac prognosis. In comparison to LAR, lanreotide Autogel® has a unique property of self-aggregation under favorable conditions, leading to a stable structure of highly organized nanotubules and has a long half-life after subcutaneous injection determined by pseudo-first order kinetics. CASE: 55-year-old man visited a cardiologist for the treatment of PVCs and heart failure. Because of his acromegalic features, endocrinological and image examinations were performed, and diagnosis of acromegaly was confirmed. His GH was 7.17 ng/mL, IGF-1 566 ng/mL (Normal range: 59-215). Concerning excess of GH may cause nonischemic cardiomyopathy, administration of 20 mg of LAR once a month was started. GH and IGF-1 improved to1.52 ng/mL and 217 ng/mL respectively. The dose of LAR was increased to 30mg because of a remaining fluctuation of VPCs. Considering a possibility of the problem of bioavailability due to method of injection and the pharmacokinetics of LAR, administration of lanreotide Autogel® was started instead of LAR, with the result that an improvement of the fluctuation of the symptom was observed without remarkable change in GH and IGF-1. Arrhythmia status was assessed over time using Holter electrocardiography. Pretreatment Holter electrocardiogram showed 18% of total heart rates in PVCs. After LAR injection, the frequency of PVCs decreased to 3%, and 6 years after changing LAR to lanreotide, the frequency of PVCs decreased to 2%. Clinical Lessons: Simulated steady state pharmacokinetic profiles of LAR and lanreotide Autogel® differ significantly. During LAR treatment, serum concentrations of the drug are approximately stable, whereas the characteristic first-order kinetics of lanreotide Autogel® is superimposed on levels just before the next administration. The pharmacokinetic differences indicate that LAR can be better tailored to therapeutic levels, whereas serum levels of lanreotide must be high for part of the interval between injections to be effective in the period before the next administration. Lanreotide Autogel® has similar clinical effects compared to LAR for the treatment of cardiomyopathy of acromegaly and has the advantage of being available in a convenient pre-filled syringe and no necessity of injection by healthcare professionals. It is suggested that the pharmacokinetic profile of Lanreotide Autogel® resulted in decreased arrhythmia fluctuation in acromegalic hearts, which has been maintained for the past 6 years.

Presentation: 6/3/2024