Aggressive Tumor Research Articles

Tackling Anticancer Drug Resistance and Endosomal Escape in Aggressive Brain Tumors Using Bioelectronics.

Resistance mechanisms in brain tumors, such as medulloblastoma and glioblastoma, frequently involve the entrapment of chemotherapeutic agents within endosomes and the extracellular expulsion of drugs. These barriers to effective treatment are exacerbated in nanotechnology-based drug delivery systems, where therapeutic nanoparticles often remain confined within endosomes, thus diminishing their therapeutic efficacy. Addressing this challenge necessitates the development of novel strategies to enhance the efficiency of cancer therapies. This study tests the hypothesis that external electrical stimuli can modulate intracellular trafficking of chemotherapeutic drugs in common malignant brain tumors in children (medulloblastoma) and adults (glioblastoma) by using gold nanoparticles (GNPs). In our experiments, alternating current (AC) stimulation ranging from 1 kHz to 5 MHz and at a strength of 1 V/cm significantly reduced cell viability in drug-resistant medulloblastoma and enhanced delivery of GNPs in glioblastoma. Low-frequency AC resulted in a 50% increase in apoptosis compared to controls and an 8-fold increase in cell death in cisplatin-resistant medulloblastoma cells, accompanied by a substantial reduction in EC50 from 2.5 to 0.3 μM. Similarly, vincristine-resistant cells demonstrated a 4-fold enhancement in drug sensitivity. Furthermore, high-frequency AC facilitated a significant increase from 20 to 75% in the endosomal escape of GNPs in glioblastoma cells. These findings underscore the potential of AC to selectively disrupt cancer cell resistance mechanisms and bolster the efficacy of nanoparticle-based therapies. The results indicate the effectiveness of AC stimulation in circumventing the limitations inherent in current nanotechnology-based drug delivery systems but also illustrates its transformative potential for treating aggressive, drug-resistant brain tumors.

The DHODH inhibitor teriflunomide impedes cell proliferation and enhances chemosensitivity to daunorubicin (DNR) in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological tumor that requires novel treatment strategies, especially for relapsed/refractory cases. Dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway, has been identified as a potential target for tumors. Besides, Teriflunomide (TRF) is a DHODH inhibitor with anticancer effects; however, its role in T-ALL remains poorly understood. Here, we investigated the potential anticancer effects of TRF on T-ALL cells, and the results showed that TRF inhibited cell proliferation, caused S-phase cell cycle arrest, and promoted apoptosis of T-ALL (MOLT4 and JURKAT) cell lines. In addition, TRF reduced the infiltration capacity of T-ALL cells in T-ALL xenograft mice while up-regulating the expression of P53 and BTG2. The BTG2 knockdown significantly attenuated the inhibitory effect of TRF on cellular growth and suppressed the TRF-mediated elevated expression of P53 in T-ALL cells. Moreover, combined treatment with TRF and daunorubicin (DNR) significantly reduced cell viability and promoted apoptosis in DNR-resistant T-ALL cells. Our study provides valuable insights into the critical role of TRF in treating T-ALL while increasing the sensitivity of DNR-resistant T-ALL cells to DNR.

Serum cyfra21-1 is a new prognostic biomarker of penile squamous cell carcinoma

ObjectiveOur study tried to evaluate the prognostic utility of preoperative serum cyfra21-1 in patients with penile squamous cell carcinoma (PSCC).MethodsThis retrospective study analyzed data from 94 patients who underwent either partial or radical penectomy accompanied by bilateral inguinal or pelvic lymphadenectomy at our institution from 2010 to 2018. The median duration of follow-up was 66.5 months. Serum cyfra21-1 concentrations were quantified through enzyme-linked immunosorbent assay, with patients classified into two groups based on cyfra21-1 levels (≤ 3.30 ng/ml and > 3.30 ng/ml). The impact of cyfra21-1 levels on clinical outcomes was evaluated.ResultsAmong the 94 patients, 68 (72.3%) had normal cyfra21-1 levels, while 26 (27.6%) exhibited elevated cyfra21-1 levels. During the follow-up period, 38 patients (40.4%) experienced relapse, and 35 patients (37.2%) died from PSCC. A significantly higher occurrence of advanced pathological grades was observed in the elevated cyfra21-1 group compared to the normal group (P = 0.029). Patients with elevated cyfra21-1 levels had significantly worse disease-free survival (DFS) and disease-specific survival (DSS) than those with normal levels (P < 0.001 and P < 0.001, respectively). In multivariate analysis, cyfra21-1 (HR: 3.938, 95% CI: 1.927–8.049, P < 0.001), lymph node involvement (HR: 8.277, 95% CI: 2.261–30.298, P = 0.001), pathological grade (HR: 2.789, 95% CI: 1.110–7.010, P = 0.029), and ECOG (Eastern Cooperative Oncology Group) performance status (HR: 1.751, 95% CI: 1.028–2.983, P = 0.039) were independent predictors of worse DFS. Similarly, CYFRA 21 − 1 (HR: 3.000, 95% CI: 1.462–6.156, P = 0.003), lymph node involvement (HR: 9.174, 95% CI: 2.010–41.862, P = 0.003), and ECOG performance status (HR: 1.856, 95% CI: 1.053–3.270, P = 0.032) were independent predictors of worse DSS.ConclusionsHigh preoperative serum cyfra21-1 levels correlate with greater tumor aggressiveness and represent a novel, effective, and convenient prognostic biomarker for PSCC.

Macrophages: Key Players in the Battle against Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a challenging subtype of breast cancer characterized by the absence of estrogen and progesterone receptors and HER2 expression, leading to limited treatment options and a poorer prognosis. TNBC is particularly prevalent in premenopausal African-descent women and is associated with aggressive tumor behavior and higher metastatic potential. Tumor-associated macrophages (TAMs) are abundantly present within the TNBC microenvironment and play pivotal roles in promoting tumor growth, progression, and metastasis through various mechanisms, including immune suppression and enhancement of angiogenesis. This review provides an in-depth overview of TNBC, focusing on its epidemiology, its molecular characteristics, and the critical influence of TAMs. It discusses the pathological and molecular aspects that define TNBC’s aggressive nature and reviews current and emerging therapeutic strategies aimed at targeting these dynamics. Special attention is given to the role of TAMs, exploring their potential as therapeutic targets due to their significant impact on tumor behavior and patient outcomes. This review aims to highlight the complexities of the TNBC landscape and to present the innovative approaches that are currently being pursued to improve therapeutic efficacy and patient survival.

Poorly differentiated chordoma: recognising this complex and rare aggressive tumour with characteristic immunohistochemical profile.

Poorly differentiated chordoma (PDC) is an uncommon subtype of chordoma, distinct in its occurrence in paediatric age group, location, variable epithelioid/rhabdoid/spindled histomorphology and the lack of physaliphorous cells (classical of chordoma) and immunohistochemistry (INI-1 loss, brachyury positive). We describe two cases of PDC. A3-year-old male and 4-year-old female child presented with neck stiffness and infiltrating tumour involving the skull base and upper cervical vertebral segments. Histopathology showed a tumour with sheets of cells having epithelioid to rhabdoid morphology and absence of physaliphorous cells. The tumour cells were positive for pan-cytokeratin, EMA, CD99 and vimentin and showed loss of INI-1 suggesting differentials of epithelioid sarcoma and atypical teratoid/rhabdoid tumour. On careful review of the clinical, radiological and pathological features, the additional immunohistochemistry for brachyury was performed, and its positivity clinched the diagnosis of PDC. Both the patients succumbed within a short span post-surgery. The present case study helps in creating an awareness and attempts to expand our knowledge in relation to the spectrum of chordoma (clinico-histological) and its immunohistochemical profile.

8659 Aldosterone-Secreting Adrenocortical Carcinoma: A Rare Cause Of Primary Hyperaldosteronism Associated With Dismal Outcome

Abstract Disclosure: S. Beeby: None. C.H. Huzita: None. F.Q. Aratani: None. L.S. Motomia: None. F. Coelho: None. M. Polo: None. C.R. Victor: None. A.O. Hoff: None. J. Chambo: None. V. Srougi: None. F. Ledesma: None. A. Latronico: None. M.Q. Almeida: None. B.B. Mendonca: None. M.C. Fragoso: None. Background: Adrenocortical carcinoma (ACC) is a rare and one of the most aggressive solid tumors, with an incidence of 1-2 cases per million. In adults, hormonal excess is usually manifested by ACTH-independent Cushing's syndrome or mixed endocrine syndrome due to cortisol and androgen production. Isolated aldosterone secretion is an extremely rare condition, with an estimated 2.5% of patients with ACC. We aimed to describe two patients with aldosterone-secreting ACC with poor outcomes. Case 1 - A 34-year-old male who was diagnosed with hypertension at 29 years of age, associated with hypokalemia needing intravenous potassium replacement therapy. Diagnosis of primary hyperaldosteronism was established with aldosterone levels of 72 ng/dL (RR &amp;lt; 23.1 ng/dL) and renin activity of 1.1 ng/mL/h (RR 0.3 to 5.8 ng/mL/h. An abdominal CT scan identified a tumor mass of 9.5 x 8.0 x 4.5 cm. He underwent a left adrenalectomy and histological and immunohistochemistry data suggested an adrenocortical carcinoma (modified Weiss score 5/7, Ki67 40%). Initial staging was ENSAT III and a Helsinki score of 48. There was transient improvement, however recent laboratory studies showed an increase in aldosterone (66,9 ng/dL) accompanied by new episodes of hypokalemia. CT scans on follow-up showed recurrence of disease, with the presence of nodules on the surgical site and abdominal wall. He received 3 lines of systemic chemotherapy and mitotane and underwent 2 other surgical procedures to treat the metastatic lesions. Currently, overall survival is 3 years. Case 2 - A 44-year-old female incidentally found a right adrenal mass (6.6 x 6.4 cm) on MRI during the investigation of elevated liver enzymes and abdominal pain. Laboratory studies showed hypokalemia, with potassium levels of 2 mEq/L (RR 3.5-5 mEq/L), aldosterone levels of 243 ng/dL (RR &amp;lt; 23.1 ng/dL), and renin of 12.2 uUI/mL (RR 4.4 - 46.1 uUI/mL). She underwent right adrenalectomy and histology and immunohistochemistry data showed a modified Weiss 7/7 and Ki67 of 80%. The patient had a germline pathogenic variant of TP53 (p.R337H). Initial staging was ENSAT III and a Helsinki score of 88. She received adjuvant mitotane and systemic chemotherapy. Even so, follow-up imaging showed hepatic metastatic disease, with an elevated aldosterone production surpassing 1000 ng/dL. The patient's overall survival was 2 years and she passed away during surgical procedure for resection of liver metastases. Discussion: ACC is a rare and aggressive tumor, and isolated aldosterone production by such tumors is extremely rare. We presented two cases with poor prognostic features and in which despite adjuvant mitotane and systemic chemotherapy there was disease progression. Due to the rarity of this condition, data on patient outcomes is limited, and further understanding of the molecular signature of these tumors could bring new insights on the tumorigenesis process. Presentation: 6/3/2024

7166 EFFECT OF ANTI-NEOPLASTIC THERAPIES ON CARCINOMA AND AGGRESSIVE PITUITARY TUMORS : A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract 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

8308 Up-regulation of Diacylglycerol kinase gamma (DGKG) in aggressive recurrent pituitary tumors could be targeted by Dasatinib reducing cell proliferation and induced apoptosis

Abstract Disclosure: K. Taniguchi-Ponciano: None. I. Remba: None. M. Loza-Mejia: None. J. Salazar: None. A. Mendez-Perez: None. C. Aguilar-Flores: None. A. Chavez-Gonzalez: None. E. Ortiz-Reyes: None. L. Bonifaz: None. D. Marrero-Rodríguez: None. M. Mercado: None. Pituitary tumors (PT) represent 15% of all intracranial tumors. Some PTs exhibit an aggressive behavior, growing rapidly and invading surrounding tissues, and are frequently resistant to multimodal treatment showing multiple recurrences. Pituitary tumors often recur after initial surgery, particularly when invasive, precluding complete resection of the lesion, which can only be achieved in ∼40-50% of all patients.We have previously characterized transcriptome and exome from 22 tumor lesions from 11 patients by RNA- and DNAseq and methylome profile by microarrays of aggressive, both primary and recurrent PT from the same patient to identify molecular pharmacological targets.Among the differentially expressed genes in most recurrent tumors we found those related to fatty acid biosynthesis and metabolism, phosphatidylinositol, glycerophospholipid and phospholipase D signaling. Importantly, one gene found in most of the lipid-related pathways was diacylglycerol kinase gamma (DGKG). DGKG gene expression was confirmed by immunofluorescence and did not seem to be regulated by DNA methylation. And DGKG showed allelic c.G947A:p.R316K variant in all primary and recurrent tumor tissues analyzed, more research is needed to understand genetic variant impact on protein function. We then performed DGKG molecular docking for FDA-approved drug repurposing. Human DGKG tridimensional model was downloaded from AlphaFold and Autodock Vina, Molegro Virtual Docker, PyMol v2.5.2 program and the Protein-Ligand Interaction Profiler web tool were used. The in silico ADMET profiles were generated in ADMETLab 2.0 using only FDA approved drugs. We identified Dasatinib as a strong candidate for DGKG targeting. We then exposed GH3 cell line to increasing concentrations of Dasatinib (1, 2.5 y 5 μM) using DMSO as vehicle. After cell viability was assessed, approximatively 31% of all live GH3 cells were at proliferative state without any treatment, that was taken as our basal quantity to compare the GH3 cells treated with the TKI’s. Dasatinib reduced approximatively 28% the cell proliferation at 1 μM (p=0.0048), at 2.5 μM reduced nearly 50% of cell proliferation (p=0.003) and at 5 μM inhibited nearly 98% of cell proliferation (p=0.0395) by means of Click-iT EdU Cell proliferation Kit. We then, evaluated Dasatinib apoptosis induction capacity. Interestingly, the 1 μM Dasatinib concentration induced apoptosis (p=0.0001) as concentrations increased, cell death also increased considerably (p=0.0001) measured by Anexin V-FITC and DAPI assay. The RNAseq data from GH3 cells exposed to Dasatinib show diminished gene expression of cell cycle related genes and glycolysis.In conclusion, we observed DGKG upregulated in recurrent aggressive pituitary tumors participating in lipid metabolism pathways and could be targeted by Dasatinib at very low doses. Presentation: 6/3/2024

8024 A Case of Smoldering Clinically Silent Cushing’s Disease

Abstract Disclosure: C. Bheeman: None. I. Shafiq: None. Aggressive pituitary adenomas account for about 10% of all pituitary adenomas. These aggressive tumors are noted to have unusually rapid tumor growth rate despite optimal standard therapies including surgery, medical therapy and radiotherapy. We present a case of a 39-year-old female with no prior past medical history who initially presented with complaint of amenorrhea. She had reported she had not menstruated for the past 6 months. She also endorsed galactorrhea with nipple stimulation. A pituitary dedicated MRI revealed a pituitary adenoma measuring 2.5 x 1.7 x 1.7 cm. Hormonal work-up showed salivary cortisol on two consecutive nights that was 66 ng/dL and 52 ng/dL (reference range: 0 - 99 ng/dL) and a prolactin that was slightly elevated at 44.9 ng/mL (reference range: 4.8-23.3 ng/mL). This elevation in prolactin was thought to be due stalk effect and since her hypothalamus-pituitary-gonadal axis was suppressed, patient had a transsphenoidal resection of what was thought to be a nonfunctioning adenoma. However, the pathology of her tumor was significant for extensive ACTH staining and a Ki-67 of 11 - 15%. Her clinical course proved to be challenging as her tumor reoccurred multiple times and she eventually developed biochemical and clinical evidence of Cushing’s disease and had visual defects due to compression of the tumor on the optic nerves. This tumor was refractory to multiple surgeries, radiation treatment and chemotherapy. Through the presentation of this case, we aim to highlight the factors associated with aggressive pituitary adenomas, the current treatment guidelines and emerging medical therapies. Presentation: 6/1/2024

7466 The Effects Of Various Forms Of Diabetes On Features Of Tumor Aggressiveness In Thyroid Cancer

Abstract Disclosure: R.D. Paparodis: None. E. Karvounis: None. A. Kapezanou: None. S. Livadas: None. G. Simeakis: None. D.P. Askitis: None. I. Androulakis: None. N.G. Angelopoulos: None. D. Zianni: None. A. Rizoulis: None. A. Boniakos: None. I. Perogamvros: None. D. Bantouna: None. J.C. Jaume: None. Introduction: Diabetes has been linked to increased risk for several cancers and aggressiveness of tumor behavior. A link between thyroid cancer and diabetes appears controversial in the literature as of yet. We designed the present study to assess whether autoimmune (type 1 + LADA = DM1) or type 2 diabetes (DM2) are associated with more aggressive thyroid cancers compared to those found in non-diabetic (non-DM) individuals. Methods: We retrospectively reviewed data from patients undergoing thyroid surgery in 10 Endocrinology and Endocrine Surgery Clinics throughout Greece over 2 years. We collected data on history and type of diabetes, pre-existing to the thyroid surgery, its treatments and duration, the preoperative thyroid function tests and the surgical pathology findings. We compared the incidence of various histological types of thyroid cancer and the features of tumor aggressiveness between patients with diabetes and those with normal glucose homeostasis (non-DM) (DM1 vs. DM2 vs. non-DM). Results: Overall, n=808 subjects with thyroid cancer were included: n=571 were females (70.7%), age 47.3 ± 14.3 years, BMI 27.0 ± 5.0 Kg/m2, mean TSH 1.99 ± 2.21 mIU/L; n= 692 were non-DM, n=10 had DM1 and n=107 had DM2. Histology revealed n=5 poorly differentiated / anaplastic, n=13 medullary, n=12 Hürthle cell, n=17 follicular and n=773 papillary thyroid cancers (PTC); n=20 (2.5%) with aggressive histological subtypes of PTC, n=5 (0.6%) with distant metastases (MET), n=199 (24.6%) with extrathyroidal extension (ETE), n=419 (51.9%) with capsular invasion (CI), n=225 (27.8%) with lymph nodes involvement (LNi) and n=23 with cancer recurrence (CR) (2.8%). The incidence of aggressive histological types, CR, MET or number of I-131 treatments were not different between groups (p&amp;gt;0.05). ETE, CI and LNi were significantly more common in non-DM compared to both diabetes groups, while gross ETE was more common in DM2 over DM1 and non-DM (p&amp;lt;0.001). Conclusions: More DM1 than DM2 seem to confer a protective effect on several features of cancer aggressiveness in affected individuals. On the other hand, more DM2 than DM1 seems to significantly promote gross ETE. No effect was observed pertaining to the risk for more aggressive tumors or histological subtypes of PTC. Although aggressiveness of thyroid cancer seems controlled in DM1 and to a lesser degree in DM2 the complex interplay between autoimmunity, hyperglycemia and thyroid cancer biology requires larger sample size to better determine causative effects. Presentation: 6/2/2024

7466 The Effects of Various Forms of Diabetes on Features of Tumor Aggressiveness in Thyroid Cancer

Abstract Disclosure: R.D. Paparodis: None. E. Karvounis: None. A. Kapezanou: None. S. Livadas: None. G. Simeakis: None. D.P. Askitis: None. I. Androulakis: None. N.G. Angelopoulos: None. D. Zianni: None. A. Rizoulis: None. A. Boniakos: None. I. Perogamvros: None. D. Bantouna: None. J.C. Jaume: None. Introduction: Diabetes has been linked to increased risk for several cancers and aggressiveness of tumor behavior. A link between thyroid cancer and diabetes appears controversial in the literature as of yet. We designed the present study to assess whether autoimmune (type 1 + LADA = DM1) or type 2 diabetes (DM2) are associated with more aggressive thyroid cancers compared to those found in non-diabetic (non-DM) individuals. Methods: We retrospectively reviewed data from patients undergoing thyroid surgery in 10 Endocrinology and Endocrine Surgery Clinics throughout Greece over 2 years. We collected data on history and type of diabetes, pre-existing to the thyroid surgery, its treatments and duration, the preoperative thyroid function tests and the surgical pathology findings. We compared the incidence of various histological types of thyroid cancer and the features of tumor aggressiveness between patients with diabetes and those with normal glucose homeostasis (non-DM) (DM1 vs. DM2 vs. non-DM). Results: Overall, n=808 subjects with thyroid cancer were included: n=571 were females (70.7%), age 47.3 ± 14.3 years, BMI 27.0 ± 5.0 Kg/m[2], mean TSH 1.99 ± 2.21 mIU/L; n= 692 were non-DM, n=10 had DM1 and n=107 had DM2. Histology revealed n=5 poorly differentiated / anaplastic, n=13 medullary, n=12 Hürthle cell, n=17 follicular and n=773 papillary thyroid cancers (PTC); n=20 (2.5%) with aggressive histological subtypes of PTC, n=5 (0.6%) with distant metastases (MET), n=199 (24.6%) with extrathyroidal extension (ETE), n=419 (51.9%) with capsular invasion (CI), n=225 (27.8%) with lymph nodes involvement (LNi) and n=23 with cancer recurrence (CR) (2.8%). The incidence of aggressive histological types, CR, MET or number of I-131 treatments were not different between groups (p&amp;gt;0.05). ETE, CI and LNi were significantly more common in non-DM compared to both diabetes groups, while gross ETE was more common in DM2 over DM1 and non-DM (p&amp;lt;0.001). Conclusions: More DM1 than DM2 seem to confer a protective effect on several features of cancer aggressiveness in affected individuals. On the other hand, more DM2 than DM1 seems to significantly promote gross ETE. No effect was observed pertaining to the risk for more aggressive tumors or histological subtypes of PTC. Although aggressiveness of thyroid cancer seems controlled in DM1 and to a lesser degree in DM2 the complex interplay between autoimmunity, hyperglycemia and thyroid cancer biology requires larger sample size to better determine causative effects. Presentation: 6/2/2024

8295 Development of Type 1 Diabetes and Primary Adrenal Insufficiency Secondary to Immunotherapy Treatment for Chordoma in a Patient With Hypopituitarism

Abstract 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 &amp;lt; 4.0 ng/dL (&amp;lt;= 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

8716 Late Onset of Temozolomide in Aggressive Pituitary Tumors: Insights From a Leading Oncology Center in Latin America

Abstract 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

8203 A Solitary Fibrous Tumor Mimicking a Non-functional Pituitary Macroadenoma

Abstract Disclosure: L. Bernacet Rivera: None. S. Omay: None. A. Huttner: None. S.E. Inzucchi: None. Background: A solitary fibrous tumor (SFT), also known as hemangiopericytoma (HPC), is a rare subset of soft tissue tumors of mesenchymal origin. This type of tumor tends to have aggressive behavior and a high risk of recurrence. Approximately less than 1% of central nervous system (CNS) tumors have been identified as part of this subtype. Case Presentation: A 73-year-old female with medical history of primary hypothyroidism, myelodysplastic syndrome (MDS), and IgM kappa MGUS initially presented to her primary care physician for evaluation of progressive visual loss over several weeks, accompanied by worsening headaches. Ophthalmologic exam revealed bitemporal hemianopsia which prompted urgent imaging. Pituitary MRI with IV contrast revealed a solid sellar mass with suprasellar extension measuring 1.8 x 1.3 x 1.9 cm. The lesion was noted to superiorly displace the optic chiasm as well as to cause mild impingement of the anterior cerebral arteries. Patient was urgently referred to neurosurgery and endocrinology for further evaluation. Initial neuroendocrine laboratory assessment, performed at 8 am, revealed a cortisol 16.5 ug/dL, free T4 1.2 ng/dL, TSH 0.77 mIU/L, prolactin 9.9 ng/mL, IGF-1 17 ng/mL, the latter value consistent with adult growth hormone deficiency. Her LH and FSH were 4.3 mIU/mL and 12.6 mIU/mL, respectively, lower than expected for a post-menopausal woman. She underwent a transnasal transsphenoidal resection of the sellar lesion. Surgery was difficult due to the fibrous nature of the tumor, for which complete resection was not achieved. Post-operative course was complicated by thrombocytopenia due to MDS. Hormonal workup following surgery was consistent with central adrenal insufficiency, hypogonadotropic hypogonadism, and central hypothyroidism. Pathology showed densely cellular spindle cell neoplasm with a collagenous background consistent with hemangiopericytoma. She underwent fractionated radiotherapy and tumor has since remained stable in size. Her visual symptoms resolved quickly following surgery. Discussion: SFT is an aggressive mesenchymal tumor which rarely appears in the sellar region. There are no identified brain MRI findings that would suggest the nature of this tumor. As a result, endocrinologists should be aware of this rare condition while evaluating pituitary neoplasms. Presentation: 6/3/2024

8078 TERT Positive Thyroid Nodule in the Setting of Metastatic Melanoma

Abstract Disclosure: E. Langnas: None. S. Chao: None. K.M. Gomes: None. A. Bhan: None. Metastatic disease to the thyroid gland is uncommon with a reported incidence of up to 4% in post-surgical specimens. Lung cancer is the most common primary tumor site in autopsy series. Clinically, renal cell carcinoma is the most common primary tumor site. Metastatic melanoma to the thyroid gland is clinically rare, however, in autopsy series, it has been reported with incidence of up to 39%. A 61-year-old man presented to the endocrinology clinic for an incidentally detected thyroid nodule. He had recently presented with a chronic cough, prompting a chest x-ray that revealed pulmonary nodules. Subsequent computed tomography (CT) showed numerous bilateral lung nodules measuring up to 2.5 cm and an incidental thyroid nodule. Ultrasound of the thyroid identified a 2.7 cm mixed cystic-solid right thyroid nodule. No risk factors for thyroid cancer were identified. His TSH was 3.51uIU (0.45 - 5.33 uIU/mL). The thyroid nodule was biopsied, and pathology revealed atypical spindle cells with irregular nuclear membranes and scattered histiocytes. A further review with cytopathology suggested non-thyroidal origin of the cells. Molecular testing with AFIRMA reported a telomerase reverse transcriptase (TERT) promoter mutation at C228T. The sequencing was negative for TERT C250T, BRAF, RET, PETC1, PTC3 and MTC. Due to concerns about metastatic disease, a positron-emission tomography (PET)-CT was conducted, revealing hypermetabolic lesions in numerous bilateral lung nodules, right thyroid nodule, porta hepatis lymph node, and a soft tissue nodule within the greater curvature of the gastric body. Subsequent biopsies of the right lung and gastric body confirmed the diagnosis of metastatic melanoma. On further questioning, it was found that the patient had a history of a skin lesion on his back that was excised several years ago with pathology reporting tumoral melanosis. Malignant melanoma has a poor prognosis due to high recurrence and metastatic rates. In melanoma, TERT promoter mutations are the most common mutations in noncoding regulatory regions. TERT C228T mutations and C250T mutations are seen in malignant melanoma and studies have shown that TERT promoter mutations are associated with aggressive clinical behavior. These TERT promoter mutations can also be seen in various other cancers including primary thyroid cancers with a similar association with more aggressive thyroid tumor characteristics. Our case describes a patient with a thyroid nodule and molecular testing noting a TERT promoter mutation. Both primary thyroid cancer and metastatic disease to the thyroid should be considered in these cases. This case also highlights the importance of obtaining a thorough history of prior malignancy in patients with thyroid nodules to assess the risk of metastatic disease. Presentation: 6/1/2024

6791 Pituitary Apoplexy as Presentation of Atypical Teratoid/Rhabdoid Tumor

Abstract Disclosure: S.I. Babli: None. H. Alkubedan: None. N.M. Ali: None. R. Alqawahmed: None. M.M. Elhassan: None. Introduction: Pituitary apoplexy occurs in a pituitary adenoma; it migh occur in other less common types of tumors. The atypical teratoid/rhabdoid tumor (ATRT) is a very aggressive malignant tumor of the central nervous system and has a poor prognosis. It is rare to occur in adult and in the sellar region. Clinical Case: 32 years old male presented to ER with 4 days history of fever, headache and vomiting. He was conscious but confused. Vital signs Temperature 39 C, BP 120/80, HR 110 beats/min and Saturation of 95 %, Possibility of meningoencephalitis was raised, patient Brain CT showed Sellar and suprasellar mass with compression over the optic chiasma and invasion to the left cavernous sinus. Patient suddenly developed Generalize tonic-clonic convulsion and hypotension. He received IV midazolam, intubated and was started on noradrenaline and hydrocortisone, he was admitted to ICU as a case of meningoencephalitis and started on Ceftriaxone, Vancomycin and Acyclovir. Cerebrospinal fluid analysis showed RBC 175/cumm, WBC 20/cumm with 20% polymorph and 80% mononuclear cells, Protein 1.38 g/l (0.24-0.49) glucose 7.9 mmol/l with plasma glucose of 10 mmol/l. Repeated Brain CT showed Sellar and suprasellar mass with compression over the optic chiasma and invasion to the left cavernous sinus and with minimal heterogenicity and increased density suggestive of hemorrhagic components. Endocrine history revealed weight gain but no history to suggest acromegaly, Cushing’s syndrome or hypogonadism . Examinations: Patient was intubated and sedated BP 90/60 on Maximum inotropic support. Left oculomotor nerve palsy, Bilateral papilledema, he was having acanthosis nigricans with no signs of acromegaly, CS or hypogonadism. Laboratory finding: WBC17 with neutrophilia, Hgb 14.7 g/dl plt 360 Na 140 mmol/l, creatnin 180 mmol/, FT4 6.2 pmol/l, TSH 0.015, PROLACTINE 22, IGF1 29 ng/ml (41-246) Free testosterone index 2.13 (33-106), LH 0.5, FSH 0.3 .Patient had TTS and histopathology showed: SMARCB1 deficient malignant neoplasm, consistent with sellar atypical teratoid rhabdoid tumor. Post OP, patient had Ventilator associated pneumonia and recurrent attacks of seizures despite multiple antiepileptic medications. Patient was evaluated by medical and radiation oncologists but due to his general condition the treatment was postpone. One month after TSS, he developed intractable seizure new Brain CT showed interventricular haemorrhage with hydrocephalus and marked enlargement of hyperdense pituitary lesion which suggests haemorrhage. External ventricular drain was inserted but patient arrested and died. Conclusions: ATRT of the CNS usually affects young children. In the literature review performed in adults, only nine cases have occurred in the sellar or suprasellar region. Survival is variable in the different cases reported in the literature, with a mean of 26 months. Presentation: 6/2/2024

7205 Anaplastic Thyroid Carcinoma Presenting as New-Onset Thyrotoxicosis and Hypoparathyroidism in a Young Patient: A Diagnostic Dilemma between Hashitoxicosis and Anaplastic Thyroid Cancer

Abstract Disclosure: M. Sulehri: None. E.G. Bustamante: None. A. Elmaaz: None. A. Chaudhuri: None. Introduction: This case report explores the complex diagnostic challenges encountered in a young patient presenting with anaplastic thyroid carcinoma (ATC) manifested by thyrotoxicosis and hypoparathyroidism. Case report: A 29-year-old male who sought multiple emergency room visits for shortness of breath, was initially misdiagnosed with pneumonia. On the third visit, exacerbated respiratory distress led to intubation, CT of the neck and thyroid US unveiling an infiltrative mass centered within the region of the thyroid gland. Initial thyroid function tests showed TSH &amp;lt;0.02 uIU/mL, free thyroxine 6.91 ng/dL, and total T3 204 ng/dL indicating hyperthyroidism, promptly managed with Methimazole and beta blockade. Elevated TPO antibodies (194 unit/mL) were observed, whereas thyroglobulin antibodies and thyroid receptor antibodies were undetected. Concurrently, hypoparathyroidism was noted, marked by low calcium levels (7.9 mg/dL) with albumin of 3.4 g/dL (corrected Calcium 8.4), and low parathyroid hormone (PTH) (&amp;lt;6 pg/mL). Other labs showed ionized calcium 4.30 mg/dL, phosphate 4.6 mg/dL, magnesium 1.8 mg/dL, and vitamin D 54 ng/dl. The patient received calcium carbonate supplement, calcitriol and IV calcium gluconate. Thyrotoxicosis then transitioned to hypothyroidism and levothyroxine replacement therapy was initiated. Definitive diagnosis was delayed due to the patient's overall condition and a low suspicion of malignancy. Left thyroidectomy and tracheostomy were performed, revealing dense subplatysmal necrosis with tumor involvement of both thyroid lobes and isthmus with multiple enlarged nodes. Final surgical pathology confirmed the presence of anaplastic thyroid carcinoma. Due to poor prognosis, the patient was transferred to hospice care where the patient succumbed to his condition within a day. Conclusion: Anaplastic thyroid cancer is considered one the most aggressive and fastest growing tumors. Although it is usually seen in patients after the age of 60, we present a very rare case of ATC in a young patient in the third decade who was presented with infiltrative thyroiditis and hypoparathyroidism. The case underscores the importance of considering rare etiologies in patients with atypical clinical presentation. Presentation: 6/1/2024

8744 Genomic Variant Landscape In Aggressive &amp; Treatment Resistant Prolactin-Secreting Tumors

Abstract Disclosure: D. Marrero-Rodríguez: None. K. Taniguchi-Ponciano: None. F. Martinez-Mendoza: None. E. Peña-Martinez: None. S. Vela-Patiño: None. S. Hinojosa-Alvarez: None. J. Hernandez-Perez: None. R. Chavez-Santoscoy: None. E. Sosa-Eroza: None. P.E. Espinosa Cardenas: None. M. Mercado: None. Pituitary tumors (PT) represent the second most frequent intracranial tumor and this neoplasm arises from adenohypophyseal cells. Prolactin-secreting tumor (PRL-tumors) are the most commonly neoplasm of the pituitary gland and arises from lactotrophs, and account for 50% of all pituitary tumors. Pituitary tumors are highly heterogeneous lesions and many of them are invasive in up to 45%, with up to 15% being clinically aggressive. Aggressive PRL-tumors are defined as invasive tumors with unusually rapid growth rate despite maximal tolerated dopamine agonist dose and requiring additional therapy and presenting multirecurrent potential. Predicting pituitary tumor behavior remains a challenge, therefore we performed whole exome sequencing to identify genomic variant landscape from aggressive and treatment-resistant prolactin-secreting pituitary tumors. Interestingly one tumor showed one hotspot mutation in splicing factor gene SF3B1 (c.C1873T:p.R625C), a second tumor showed an stop codon in SF3B1 (c.C496T:p.R166*). We then evaluated known hereditary-related pituitary tumor genes, identifying three patients with two different GNAS allelic variants the first one showed c.A3059G:p.N1020S and two tumors with c.C1307A:p.A436D variants. PRKAR1A gene did not showed any allelic variants in our cohort, while all tumors presented c.A1636G:p.T546A variant in MEN1 gene, in AIP gene allelic variant c.C682A:p.Q228K was present in all tumors. PAX6 gene is related to pituitary gland development and function, we found a deletion (c.980delA:p.K327Rfs*29) causing frameshift present in all tumors. The target coding-gene for cabergoline, first line of treatment, DRD2 di not showed any allelic variant. Also XRCC1 and ABCB1 genes, which are related to drug and therapy response showed c.A1196G:p.Q399R and c.T2887G:p.S963A allelic variants in 100% and 88% of tumors, respectively. Together this genomic landscape could represent higher risk to harbor aggressive non-responsive PRL secreting tumor. Presentation: 6/1/2024

12405 A Severe Case Of Virilization Of Premenopausal Woman Secondary To A Rare Testosterone Producing Sertoli Cell Tumor

Abstract Disclosure: S. Waheed: None. N.J. Vernetti: None. S. Nakhle: None. Introduction: We present a case of a premenopausal woman with elevated testosterone who was diagnosed with an aggressive Sertoli cell tumor of the ovary. Case Description: A 49-year-old multiparous female presented to the clinic with hirsutism and markedly elevated testosterone levels. Her symptoms started a year before the presentation with diffuse alopecia, acne, and increased muscle mass. Last menstrual periods were 3 years, prior to the presentation.Denies any exposure to testosterone herself or indirectly through family. On physical exam, blood pressure 170/122 coarse features, oily skin, and muscular build. She had terminal hair loss and increased hair growth on face and arms. Laboratory data revealed testosterone levels of 9280 ng/dl (reference range premenopausal 18-55 ng/dl), free testosterone &amp;gt; 50 ng/dl (premenopausal0-4.2 ng/dl), LH &amp;lt;0.3 mIU/mL (2.4-12.6 mIU/mL), FSH &amp;lt;0.3 mIU/mL (3.6-12.5 mIU/mL), 17-OHP 2270 ng/dl (15-70 ng/dl), DHEA-S 71 ug/dl (&amp;lt;229 ug/dl), LDL 128 mg/dl, Creatinine 1.29 and hematocrit 56% (34-44.6%). CT abdomen/pelvis showed 10 cm ovarian mass. She underwent Total Abdominal Hysterectomy-Bilateral Salpingo Oophorectomy (TAH-BSO). After the surgery, her testosterone levels normalized and features of hyperandrogenism resolved. Pathology report revealed sex cord stromal tumor Not otherwise specified (NOS) with cellular atypia and possible aggressive behavior. Discussion: Androgen-producing tumors in women are rare neoplasms that can cause secondary virilizing characteristics. Of patients presenting with symptoms of hyperandrogenism, these tumors are found in ∼0.2% of cases. Androgen-producing tumors can arise from the ovary or the adrenal gland. Those arising from the ovary are rare, accounting for &amp;lt;5% of all ovarian tumors. Few cases of steroid cell tumors, not otherwise specified, have been reported in the literature.Testosterone elevation of more than 2 times upper normal limit increases the suspicion for cancer. In our patient, testosterone was 180 times above the normal range for women and 15 times above the normal range for men. With rapid virilization and significant elevation in testosterone, an androgen producing ovarian tumors should be considered. Presentation: 6/2/2024

7856 In Pursuit of Solutions: Exploring Novel Therapeutic Strategies in the Treatment of a Rare, Aggressive Macroprolactinoma Post-Temozolomide: A Case Report

Abstract Disclosure: N. Konindala: None. H. Darapu: None. K. Ruddiman: None. Introduction: Prolactinomas comprise 40-60% of all pituitary tumors. Most prolactinomas respond well to dopamine agonist treatment. About 10% of these tumors are aggressive prolactinomas (APRL). Although rare, APRLs pose a significant challenge in clinical practice as treatment beyond dopamine agonists, surgery and radiotherapy is limited. A fourth-line therapy called temozolomide may be needed. After temozolomide failure, treatment options are minimal, as there are no evidence-based therapies available for such aggressive pituitary tumors. The efficacy of novel treatment agents remains to be explored. Notably, our case is one of the few where investigational agents, including Pembrolizumab and Pazopanib have been used. We present a case report that contributes to the evolving understanding of potential therapeutic options and highlights the ongoing challenges in refractory prolactinoma management. Case Presentation: A 77-year-old male was diagnosed with a macroprolactinoma in 2001 and was started on cabergoline with a good therapeutic response. In 2011, there was hormonal and imaging evidence of progression, and the patient underwent transsphenoidal hypophysectomy with gross resection followed by gamma knife radiation. The patient was found to have a recurrence of his tumor five years later and underwent repeat transsphenoidal resection. He continued to show evidence of recurrence and was recommended for chemoradiation and adjunct temozolomide (TMZ). After 12 cycles of TMZ, a repeat MRI was done, which showed radiographic recurrence. The patient had a third transsphenoidal surgery done in August 2022, followed by the initiation of a PARP-1 inhibitor, Olaparib. The development of adverse effects complicated this, and treatment was transitioned to capecitabine and TMZ in Jan 2023. The patient had persistent tumor burden symptoms, and a VEGF inhibitor Avastin was initiated. His symptoms initially improved, but unfortunately, his prolactin levels rose from 895 mg/dL to 1,547mg/dL, indicating evidence of disease progression. Immunotherapy with pembrolizumab was started on 6/2023, and he was given three doses before a follow-up MRI showed continued progression of the disease. He was recommended to start pazopanib, a kinase inhibitor. Discussion: Aggressive Prolactinomas present a rare and intricate management challenge, necessitating a multidisciplinary approach. Despite standard therapies, achieving remission can be elusive. While Pembrolizumab showed promise in reported cases, our patient remained refractory. Literature indicates favorable responses to Pazopanib in a small number of refractory cases. A reassessment in a few months will evaluate our patient's response to Pazopanib. This case emphasizes the need for further research to refine refractory prolactinoma management and develop response indicators for investigational agents. Presentation: 6/3/2024