bluuebunny/crossref_metadata_2025 huggingface dataset:
RF35 | PSAT304 A Case of COVID-19 Infection; COVID-19 mRNA-Based Vaccine Induced Human Anti-Mouse Antibodies (HAMA) Interfering With TSH Testing
Authors: Hoang Thien , Patricia Luceri , Signore Valentina Del
Published: November 2022

A 71-year-old male presented to the endocrine clinic for evaluation of hypothyroidism which has recently been difficult for his primary care physician to control. He initially developed hypothyroidism in 1990 after neck radiation for squamous cell carcinoma of his sternocleidomastoid muscle. He was previously controlled for many years on levothyroxine 150mcg daily with TSH readings in the normal reference range. Patient was infected with COVID-19 in 2020 and was hospitalized for 10 days. He was treated with 5 days of Remdesivir and 10 days of Decadron. 6 months after the infection he received mRNA COVID-19 vaccination. Upon his first visit to the endocrine clinic post COVID-19 infection and vaccination, his TSH was elevated at 90 uIU/mL with a free thyroxine that was elevated at 1.8 ng/dL even after multiple attempts by his primary care physician to increase his Levothyroxine which was up to 225 mcg daily before he was referred to endocrinology. He is compliant with his levothyroxine and takes it on an empty stomach first thing in the morning without any of his other medications. He is not taking iron supplements, biotin or any other supplements or new medications. TSH values had been normal 1 month prior to his COVID-19 infection and was first noted to be abnormal 8 months after his COVID-19 infection and 2 months after his mRNA COVID-19 vaccine. There was no TSH drawn between when he had COVID-19 and when he received his vaccine. It was suspected that he may have a factitious elevation in his TSH due to antibody interference. Labs were drawn for a TSH with human anti-mouse antibodies (HAMA) treatment which resulted with a markedly suppressed TSH at 0.007 uIU/mL with an elevated free thyroxine of 1.94 ng/dL. HAMA antibodies came back elevated at 552 ng/mL.

Reference

Klee, G., 2000. Human Anti-Mouse Antibodies. Archives of Pathology & Laboratory Medicine, 124(6), pp.921-923.

Koshida, S., Asanuma, K., Kuribayashi, K., Goto, M., Tsuji, N., Kobayashi, D., Tanaka, M. and Watanabe, N., 2010. Prevalence of human anti-mouse antibodies (HAMAs) in routine examinations. Clinica Chimica Acta, 411(5-6), pp.391-394.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 1:00 p.m. - 1:05 p.m.
LBODP067 Primary Amenorrhea - A Common Referral With An Uncommon Cause
Authors: Shaikh Sheeba , Kapoor Ashutosh , Lewis Alexander
Published: November 2022

Introduction

Primary amenorrhea is a commonly encountered referral in the endocrine setting. Thorough history and clinical examination are integral in assessment to identify the cause. Although rare, congenital absence of the uterus and vagina constitutes the second most common cause after primary ovarian insufficiency. Once endocrine causes are excluded, anatomical causes must be explored.

Case

We present the case of a 17-year-old who was referred to our Endocrine unit by primary care with primary amenorrhea. Medical history was significant for acute myeloid leukaemia which was treated with chemotherapy and cranial radiotherapy at the age of 2 years. There was no family history of endocrinopathy. Physical examination revealed no significant abnormalities with a height of 154cm and Tanner staging of 5 in all areas. The patient and her parents were concerned about delayed puberty or hypogonadotropic hypogonadism due to previous oncology treatments. Biochemistry showed normal oestradiol 262 pmol/L, Prolactin 258 mU/L, LH 11.8IU/L, FSH 6.6IU/L, Testosterone 1.1 nmol/L, IGF-1 211 ug/L, TSH 1.7mu/L, T4 12.7 pmol/L, AMH 23.5 pmol/L. Bone age was 17 years 5 months, in keeping with chronological age. Considering normal endocrine investigations and development, anatomical causes of primary amenorrhoea were investigated with ultrasound and then subsequently MRI imaging. This demonstrated the absence of the uterus and upper two thirds of the vagina. Both ovaries were present, and she also had a single pelvic kidney. Results are in keeping with Mullerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome type 2). The patient was counselled on the impact this would have on fertility and sexual functioning and offered psychological support with this diagnosis.

Conclusion

Mayer-Rokitansky-Küster-Hauser (MRKH) is a rare disorder with prevalence of 1 in 4500 and is usually diagnosed in adolescents with primary amenorrhea as first presentation. Genetic origins have been suggested and further research is required as this could impact fertility choices for patient moving forward. This case highlights many of the differential diagnoses at presentation and the need for cross sectional imaging to fully appreciate anatomical and therefore clinical consequences.

Presentation: No date and time listed
LBODP106 Multi-omics Analyses Of MEN1 Missense Mutations Identify Disruption Of Menin-MLL And Menin-JunD Interactions As Critical Requirements For Molecular Pathogenicity
Authors: Dreijerink Koen Marie Anton , Ozyerli-Goknar Ezgi , Koidl Stefanie , Van der Lelij Ewoud , Van den Heuvel Priscilla , Kooijman Jeffrey , Biniossek Martin , Rodenburg Kees , Nizamuddin Sheikh , Timmers Marc
Published: November 2022

Loss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 endocrine tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors. After in silico screening of 253 disease-related MEN1 missense mutations, we selected a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/2 and JunD complexes. Interestingly, we identified three missense mutations, R52G, E255K and E359K, which predominantly reduce the interaction with MLL1 compared to JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites. These findings support the general importance of the menin-MLL1 and menin-JunD interactions in MEN1 gene-associated pathogenic conditions.

Presentation: No date and time listed
ODP539 AIPB is a Biomarker for ER+/PR+/Her2- Breast Cancers
Authors: Cubbedge Chandler , Perkins Edward , Burak William , Bose Himangshu
Published: November 2022

Aromatase, the rate-limiting enzyme in estrogen synthesis, is expressed in the ovaries of premenopausal, the placentas of pregnant women, and adipose tissue and skin cells in postmenopausal women, although to a lesser extent than in the ovaries. The direct mechanism of controlling breast cancer is to reduce estrogen synthesis by interfering with its production, via ovarian ablation in premenopausal women and use of aromatase inhibitors or inactivators. However, the latter results in drug resistance, making them ineffective for future treatment. In our laboratory, we identified a 22-kDa protein from human breast tissue, Aromatase Interacting Partner in Breast (AIPB), that interacts with aromatase. Western Blotting of the unaffected (nontumorigenic MCF-12A) and tumorigenic (MCF-7 ER+/PR+/Her2-) breast tissues as well as PCR amplification with the AIPB specific primers of the nontumorigenic and tumorigenic cells showed AIPB expression is maximum with the unaffected breast tissue but reduced in ER+/PR+/Her2- tumors. To confirm AIPB's regulatory role, we developed a conditional expression of AIPB by stably selecting with puromycin from MCF-7 cells and thus regulating AIPB expression under a tetracycline promoter. On addition of doxycycline followed by PCR amplification, the AIPB expression was enormously higher than the uninduced cells under identical condition. The estrogenic effect of the stable cells was reduced significantly compared to MCF-7 cells. In summary, our preliminary results suggest AIPB to be a potential biomarker with a potential for cell therapy-mediated decrease of estradiol in ER+/PR+/Her2- tumorigenic breast tissues.

Presentation: No date and time listed
ODP540 Aromatase interacting partner in Breast (AIPB) regulates estradiol in human breast
Authors: Moffitt Alyssa M , Bose Himangshu S
Published: November 2022

Aromatase (estrogen synthetase) catalyzes testosterone to estradiol. It is central in reproduction, reproductive diseases, and a target for inhibitor therapy in estrogen-sensitive diseases. The level of estradiol synthesis is 20-fold or more, during menopause and in breast tumorigenesis. Unfortunately, the mechanism of increased synthesis of estradiol in these affected women is still unknown. Our laboratory has identified aromatase interacting partner (AIPB) from unaffected human breast tissue. Biochemical characterization showed that AIPB is a 22-kDa protein, present in the Endoplasmic Reticulum (ER)along with aromatase. AIPB is stimulated by estrogen but not cAMP or inactivated cycloheximide. The expression of AIPB in unaffected breast tissue and wild-type MCF-12A breast cells showed similar level of AIPB expression. Western blot with tumorigenic human breast tissues showed decrease in expression in AIPB expression in ER+/PR+/Her2- tumors. We further identified that conditional overexpression of AIPB synthesized 3.52 pg/mL of estradiol in comparison to unaffected breast tissue and wild-type MCF-12A breast cells with 9.5 pg/mL and 11.56 pg/mL, respectively. Further incubation of AIPB stable cells with estrogen stimulator, zeranol, reduced estradiol with the increase in AIPB expression confirming that aromatase activity is directly regulated by AIPB. Therefore, AIPB is crucial in understanding the pathophysiology of breast tumor development and in maintaining proper estradiol levels post-menopause and at the start of tumorigenesis. We concluded that there is potential for future advancements in the early prediction of breast cancer with the identification of AIPB expression from breast tissue.

Presentation: No date and time listed
ODP544 Cumulative exposure of metabolic syndrome components and the risk of end-stage renal disease in the general population: a nationwide cohort study
Authors: Yoo Soon Jib , Kwon Prof Hyuk-Sang , Koh Eun Sil , Han Kyung D
Published: November 2022

Aims

Status of metabolic syndrome (MetS) and its components can changes over time. However, few studies have investigated the cumulative burden of MetS and its components on clinical renal outcomes in the general population.

Methods

Using nationally representative data from the Korean National Health Insurance System, 2,664,270 subjects who underwent health examinations for four consecutive years and were free from end-stage renal disease (ESRD) from 2009 to 2013. We used exposure-weighted scores in two ways: (1) cumulative number of MetS diagnosis at each health examination (MetS exposure score, range: 0 to 4); (2) the composite of its five components (MetS component exposure score, 0 to a maximum of 20). Hazard ratio and 95% confidence interval (CI) values for ESRD were analysed using the Cox proportional-hazard model.

Results

Overall, 63.4%, 14. 0%, 8.2%, 6.2% and 8. 0% met the MetS diagnostic criteria 0 to 4, respectively. After a median follow up of 5.3 years, 2,303 incident ESRD cases were identified. In the multivariate adjusted model, the hazard ratio (HR) and 95% confidence interval (CI) for the development of ESRD showed a gradual increase with increasing exposure score of MetS and its components, which was independent of age, sex, and baseline estimated glomerular filtration rate (each p for trend < 0. 0001). The HR of ESRD was 6.48 (95% CI, 4.12 to 10.20) in subjects with a MetS component exposure score of 20 compared with those with a score of 0.

Conclusions

This provides evidence supporting the strategy of reducing MetS exposure to prevent the development of ESRD in the general population.

Presentation: No date and time listed
ODP559 The prognostic role of IL-17A-neutrophils crosstalk in triple-negative breast cancer
Authors: Khalid Freeha , Takagi Kiyoshi , Guestini Fouzia , Miki Yasuhiro , Miyashita Minoru , Hirakawa Hisashi , Ohi Yasuyo , Rai Yoshiaki , Sagara Yasuaki , Suzuki Takashi , Sasano Hironobu
Published: November 2022

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is characterized by extensive intratumoral heterogeneity. At this juncture, TNBCs are treated with conventional chemotherapy and have few targeted therapies. Due to the presence of increased tumor-infiltrating lymphocytes and immune-checkpoint molecules, TNBCs are considered highly immunogenic. This provides an opportunity to explore various immunotherapeutic options. The immune cells such as Th17 cells or neutrophils (tumor-associated neutrophils; TANs) can secrete a pro-inflammatory cytokine called IL-17A, which is known to be associated with poor outcomes in several cancers. TANs are related to tumor progression and are influenced by certain chemokines. Meanwhile, IL-17A can also regulate chemokine (C-X-C motif) ligand 1 (CXCL1), which is a strong chemoattractant for TANs and can lead to the growth of tumors in breast cancer. However, the significance of IL-17A and its interaction with TANs and CXCL1 has yet not been clearly understood in TNBC. For this purpose, formalin-fixed paraffin-embedded biopsy tissue specimens of 109 Japanese TNBC patients were included in this study. Immunohistochemistry was performed to assess the status of IL-17A, CXCL1, and CD66b (a neutrophil marker) and to understand their correlation among each other, with clinical parameters, and with the outcomes of patients. Also, in vitro studies were performed to evaluate the effect of recombinant IL-17A on TNBC cell lines proliferation, migration, and CXCL1 expression. Clinical results revealed that IL-17A was significantly correlated with CXCL1 and CD66b, which suggested potential crosstalk between them. On the other hand, CXCL1 significantly and CD66b tended to be correlated with tumor size. Also, CD66b was significantly correlated with the Ki-67 labeling index, showing that TANs may have a role in tumor cell proliferation. Kaplan-Meier survival curves showed that high IL-17A was significantly associated with poor disease-free and overall survival, indicating the poor outcome of the TNBC patients. To our great interest, in vitro results revealed that no difference was observed for proliferation or migration of TNBC cell lines (was only observed in the MDA-MB-231 cell line) after treatment with recombinant IL-17A. However, CXCL1 was highly up-regulated in a dose and time-dependent manner after exposure to IL-17A, indicating that IL-17A might be involved in the recruitment of neutrophils through up-regulation of CXCL1. Therefore, we concluded that IL-17A was a poor prognostic factor for TNBC patients, enhancing the chemokine-neutrophil recruitment to the tumor site, leading to tumor progression and aggression. In the future, we intend to explore different pathways for understanding the mechanism of CXCL1 up-regulation by IL-17A.

Presentation: No date and time listed
ODP635 A rare case of metastatic papillary thyroid carcinoma on NTRK inhibitor with thyrotoxicosis
Authors: Fazeli Sasan , Zhao Diana
Published: November 2022

We present a case of 26-year-old Hispanic female with neck enlargement and worsening dyspnea. She was noted to have enlarged thyroid nodules; biopsy revealed papillary thyroid carcinoma (PTC) with ETV6-NTRK fusion by next-generation sequencing (NGS). Further work up revealed extensive bilateral milliary pulmonary metastases and Graves’ disease with elevated thyrotropin receptor antibodies and thyroid-stimulating immunoglobulin titers. Tuberculosis work up was negative and bronchoalveolar lavage revealed metastatic PTC. The patient was initiated on larotrectinib (100mg administered twice daily) as well as block-and-replace regimen with levothyroxine and methimazole. Her dyspnea improved and she successfully underwent total thyroidectomy as well as bilateral neck dissections; methimazole and thyroid hormones were discontinued thereafter. Interestingly, patient developed thyrotoxicosis post-surgery even without being on levothyroxine with elevated free T3 at 18 pg/mL (normal range 2.3–4.2), compared to 5.8 pg/mL prior to surgery. Despite discontinuation of levothyroxine, patient continued to be biochemically and clinically hyperthyroid. She was treated with methimazole for 4 months after surgery, and subsequently underwent radioactive iodine (RAI) ablation with 30 mCi of I-131 of sodium iodide. After RAI, thyroid function started to improve, prompting re-initiation of very low dose levothyroxine about 5 months after surgery. Since then, she has remained clinically stable.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
OR30-2 Targeting Succinate Metabolism in Endocrine Therapy Resistant, ER Positive, Breast Cancer Cells
Authors: Andrade de Oliveira Karla , Clarke Robert , Jin Lu , Sengupta Surojeet
Published: November 2022

Estrogen receptor positive (ER+) breast cancer is the most common subtype among all breast cancers and is responsible for most breast cancer related deaths. Endocrine therapies, such as selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI), often given in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, are initially effective but the majority of advanced ER+ breast cancers eventually become refractory to endocrine therapies. Therefore, understanding the underlying molecular mechanisms that enable or promote resistance to endocrine therapies may lead to novel therapeutic targets.Cancer cells have a high energy demand and as a result consume greater quantities of glucose to meet their energy and anabolic demands to support cell growth and proliferation. In this study, we used breast cancer cell models that are endocrine therapy sensitive and resistant and investigated the metabolic flux of glucose by growing the cells in the presence of the stable glucose isotope, UC13-Glucose. We measured the C13-labelled metabolites of glycolysis and the TCA cycle. Glucose consumption was higher in endocrine therapy resistant MCF7/LCC9 (LCC9) cells compared with parental MCF7 (MCF7) and estrogen independent, endocrine therapy sensitive MCF7/LCC1 (LCC1) cells. Notably, in LCC9 cells the m+4 and m+6 isotopomer of C-13 labelled citrate was absent. Further, in LCC9 cells, C-13 labelled fumarate was very low while the succinate: fumarate ratio was markedly higher. These results suggest that the TCA cycle is impaired in LCC9 cells and the conversion of succinate to fumarate is dysregulated. Succinate dehydrogenase (SDH) enzyme is responsible for catalytic conversion of succinate to fumarate. SDH is a multimeric protein comprised of four different subunits and SDH assembly factor 2 (SDHAF2), which is a tumor suppressor gene. Our study further showed that SDHAF2 protein was under expressed in LCC9 cells compared with LCC1 cells, likely contributing to lower SDH activity. Intriguingly, when SDH activity was inhibited using dimethylmalonate, the LCC9 were re-sensitized to both Fulvestrant and 4-hydroxytamoxifen. Data analysis of clinical samples shows that poor relapse free survival in ER+ breast cancer patients is correlated with lower expression levels of SDHAF2. Overall, this study suggests that targeting succinate metabolism may help to restore sensitivity to Fulvestrant and tamoxifen in endocrine therapy resistance in ER+ breast cancer cells.

Presentation: Tuesday, June 14, 2022 10:00 a.m. - 10:15 a.m.
PSUN363 GCM2 variants in Parathyroid Carcinoma
Authors: Costa-Guda Jessica , Arnold Andrew
Published: November 2022

Germline, in vitro activating GCM2 variants are notably overrepresented in patients with primary hyperparathyroidism (PHPT), in both the familial and sporadic settings. While increased compared with the general population, most individuals with such variants in the population have a very low risk of developing PHPT. However, for those individuals who do develop PHPT, the degree to which harboring such a variant might impact the disease severity remains unclear. An increased likelihood of multigland involvement and a lower rate of biochemical cure has been reported in GCM2variant-positive patients as compared with variant-negative patients. In the context of familial isolated primary hyperparathyroidism, one individual with a GCM2 Y394S variant was reported to have developed parathyroid carcinoma (Guan, 2016) and another developed parathyromatosis (Koh, 2021). In another family, carrying I383M, parathyroid carcinoma was seen in one individual and atypical adenoma in another (Canaff, 2022). No GCM2 variants were noted in two other kindreds which included at least one individual with parathyroid carcinoma, for which other known causes of FIHP had already been ruled out (Cetani, 2019). Rare GCM2 variants were reported in three patients with sporadic parathyroid carcinoma: two with K388E (Song, 2020) and one with V382M (Canaff, 2022). V382M was also observed in a patient with atypical adenoma (Song, 2020). No GCM2 variants have been reported in whole exome sequencing (WES) studies of parathyroid carcinoma. However, in 45% of reported cases subjected to WES, germline variants were specifically filtered out during data analysis. In the remaining reported cases for which germline DNA was unavailable, filtering would have excluded common variants, such as Y282D, but rare GCM2 variants may have been detectable. We sought to determine the frequency of GCM2 germline variants of interest in a series of 15 sporadic parathyroid carcinomas by direct DNA sequencing. No sequence variants were identified within the C-terminal conserved inhibitory domain (CCID) of GCM2, nor was the PHPT-associated Y282D variant found in any of our samples. Across all studies to date, GCM2 CCID variants have been detected in 3 of 48 (6.25%) sporadic parathyroid carcinomas and Y282D in 4 of 56 (7.14%) of cases. Our results demonstrating a dearth of GCM2 variants in individuals with parathyroid carcinoma, combined with the absence of malignancy in the overwhelming majority of patients harboring PHPT-associated GCM2 variants, suggest individuals in the general population with such variants are at exceedingly low risk of developing parathyroid carcinoma. However, some very rare variants, such as I383M, might be show higher penetrance. Given the potential implications for surveillance/monitoring approaches and/or surgical decision making, the hypothesis that in certain genetic and/or environmental contexts GCM2 variants may be associated with more severe clinical phenotypes merits further investigation.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF05 | PSUN354 Associations between immune-related thyroid dysfunction and efficacy of immune checkpoint inhibitors – A systematic review and meta-analysis
Authors: Cheung Yee-Ming Melody , Wang Wei , McGregor Bradley , Hamnvik Ole-Petter
Published: November 2022

Background

There is growing evidence suggesting that the occurrence of immune-related adverse events (irAEs) may be a predictor of immune checkpoint inhibitor (ICI) efficacy. Whether this association extends to all irAEs or just those within particular organs/systems is yet to be resolved. As immune-related thyroid dysfunction (thyroid irAE) is one of the most commonly reported irAEs, this study aims to summarize the available data and determine if thyroid irAE is a surrogate marker for improved cancer outcomes during ICI therapy.

Methods

PubMed, EMBASE and Cochrane Library were searched up to July 1st 2021 for studies assessing the relationship between thyroid irAE development during ICI therapy and cancer outcomes. Outcome measures of interest include overall survival (OS) and progression free survival (PFS). Sub-group analyses based on cancer type and adjustment for immortal time bias (ITB) were also performed.

Results

Forty-seven studies were included in the systematic review. Twenty-one studies were included in the OS meta-analysis whilst 15 were included in the PFS meta-analysis. Development of thyroid irAE during ICI therapy was associated with improved OS and PFS (OS: HR 0.52, CI 0.43-0.62, p<0.001; PFS: HR 0.58, CI 0.50-0.67, p<0.001). Sub-group analyses involving non-small cell lung cancer populations and studies where ITB was accounted for, observed similar results (HR 0.37, CI 0.24-0.57, p<0.001) and (HR 0.51, CI 0.39-0.69, p<0.001), respectively.

Conclusion

Despite the heterogeneity and biases identified, the evidence does suggest that the development of thyroid irAE is associated with anti-tumor effects of ICIs and therefore, can be used as a surrogate marker for clinical response.

Presentation: No date and time listed
RF07 | PSAT233 The First Case Report of a de-novo Purely Prostatic Large Cell Neuroendocrine Carcinoma with Thyroid and Adrenal Metastases
Authors: Paparodis Rodis , Karvounis Evangelos , Zoupas Ioannis , Bantouna Dimitra , Efthymiadou Roxani , Ioakeimidou Christina , Kelgiorgou Dionysia , Panopoulos Christos
Published: November 2022

Background

Large Cell Neuroendocrine Carcinoma (LCNEC) is the rarest neuroendocrine prostatic malignancy. It usually arises after androgen-deprivation therapy (ADT), while de novo cases are even more infrequent with only 6 cases described to date.

Case presentation

A 78-year-old man with no history of ADT presented with cervical lymphadenopathy. Diagnostic approach included PET/CT, MRI, and CT scans, U/S, biopsies, cytological and immunohistochemical evaluations. CT revealed a non-enriching region on the right lobe of the thyroid gland. An 18F-FDG PET-CT found increased uptake in the thyroid gland and both adrenal glands. Neck ultrasound identified a right thyroid lobe nodule. A fine needle aspiration of the nodule was performed and cytology was consistent with poorly differentiated carcinoma. A total thyroidectomy with central and bilateral lymph node dissection was performed and the pathology report diagnosed a LCNEC metastatic to the thyroid gland. Additional metastases were identified in both adrenal glands. Despite appropriate treatment, the patient succumbed to his disease.

We report the first patient with a de novo purely prostatic LCNEC, metastasizing to the thyroid and the adrenal glands.

Conclusions

De novo LCNECs of the prostate are very rare, highly aggressive tumors with poor prognosis. They are resistant to most therapeutic agents, have high metastatic potential and are usually diagnosed at an advanced stage. Further studies are needed to characterize these tumors.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:24 p.m. - 1:29 p.m.
RF07 | PSUN356 Synergistic Combination of HSP90 and PI3K inhibitors in Adrenocortical Cancer
Authors: Mishra Prachi , Shen Min , Hall Matthew , Zhang Ya-Qin , Nilubol Naris
Published: November 2022

Adrenocortical cancer (ACC) is a rare and aggressive cancer (0.5-2 cases/ million/ year) with a poor 5-year survival (<40%). Most patients inevitably succumb to the wide-spread metastasis because of the lack of effective systemic treatment options or to complications from uncontrolled hypercortisolism. Therefore, it is critically important to identify new effective treatments that can be readily used in a clinical trial. In this direction, we identified a potent synergistic combination of Heat Shock Protein 90 (HSP90) and PI3K inhibitors via quantitative high-throughput drug screening (qHTS) for ACC, using a pharmaceutical library comprised of ∼5000 drugs (FDA approved or investigational), and evaluation of drug synergy by a computerized drug combination matrix analysis. The synergistic efficacy of HSP90 inhibitor STA9090 and PI3K inhibitor, PIK75 was validated in vitro, in ACC cell lines H295R and SW13, by proliferation assay, which also determined the most efficacious doses of individual and combinatorial drugs. The drug combination significantly induced apoptosis and disintegrated the 3D-ACC spheroids as compared to the individual drugs, with a simultaneous upregulation of apoptotic protein markers (cleaved-Caspase3, cleaved-PARP), inhibition of the phosphorylation of PI3K pathway members (AKT1, mTOR, S6K, 4EB1 and GSK3α/β), and alteration in the G2/M phase of the cell cycle, in ACC cells. The synergetic effect of the drug combination was also effective in reducing the metastatic potential as revealed by invasion/migration assay, which was confirmed by the downregulation of the mesenchymal protein (Vimentin, N-cadherin, SNAIL and Zeb1) markers. Consistent with our data, observations from the gene expression data from The Cancer Genome Analysis (TCGA) & Gene Expression Omnibus (GEO) databases, revealed significant mRNA overexpression of HSP90AA1, HSP90AB1 HSP90B1 and its clients AKT2, CDK1, CDK4, NR3C1 indicating both HSP90 and PI3K/AKT pathways are highly activated in ACC cohorts. Overexpression and a positive correlation of mesenchymal markers TWIST1, ZEB1, VIM with HSP90AB1 and PI3KCA, in GEO and TCGA respectively, was consistent with the invasive potential of the ACC cells. In conclusion, our studies on the combination of HSP90 and PI3K inhibitors demonstrated a promising preliminary synergistic efficacy by inhibiting proliferation and epithelial-to-mesenchymal transition of ACC. Our findings can lead to development of an efficient mechanism-specific novel combination therapy that can be expedited to clinical trial in advanced ACC patients.

Presentation: Saturday, June 11, 2022 1:12 p.m. - 1:17 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF19 | PSUN353 Liquid Biopsies - Detecting and Tracking Circulating Cell Free Tumor Derived DNA in Patients with Neuroendocrine Neoplasms
Authors: Gohil Shailesh , Page Karen , Rob Hastings , Iwuji Chinenye , Richards Cathy , Reddy Narendra , Shaw Jacqui , Levy Miles
Published: November 2022

Introduction

There is a clinical need to develop novel and better biomarkers to monitor patients with neuroendocrine neoplasms (NENs). Circulating cell free tumor derived DNA (ctDNA), a form of liquid biopsy, is finding clinical utility in an ever increasing number of malignancies however has not been widely tested in patients with NENs.

Aims

Our aim was to identify and track plasma ctDNA in a cohort of patients with NENs using a personalized, patient specific approach.

Materials and methods

A total of 35 serial plasma samples were collected from 9 patients with metastatic, well differentiated NENs (6 small intestinal and 1 lung, 1 ovarian and 1 pelvic; range 2-5 plasma samples per patient) over the space of 2-25 months. For each patient, NEN specific somatic mutations (single nucleotide variants and insertions/deletions) were identified through whole exome sequencing of paired tumor-leucocyte DNA and were used to design a bespoke multi-variant Ampliseq™ HD ctDNA panel (5-20 variants per patient) for targeted next generation sequencing. Imaging and treatment were provided as per usual clinical care.

Results

ctDNA was detectable in 6/9 patients and in 19/35 plasma samples. A rise in the number of ctDNA target variants and/or variant allele frequency was seen in 4/6 patients who experienced disease progression. Two of these patients received peptide receptor radionuclide therapy after which ctDNA disappeared in one patient and substantially reduced in the other, which correlated with treatment response. The 3 patients who did not have detectable ctDNA at any time point all had grade 1 small intestinal NENs with stable disease during the observation period.

Discussion

Our data provide exciting evidence for the feasibility of using ctDNA as a biomarker in NENs. By targeting multiple individualized variants using next generation sequencing, we have demonstrated that ctDNA can track changes in disease burden and can monitor response to treatment in patients. Of equal importance, ctDNA was not detectable in patients with quiescent disease. This could help identify patients who do not need intensive monitoring. Targeting bespoke, multiple variants per patient is a novel and powerful approach for NENs, especially given their heterogenous genetic landscape. This study provides important early evidence that ctDNA may be a clinically useful biomarker for detection and surveillance of NENs.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:06 p.m. - 1:11 p.m.
RF19 | PSUN383 Potential Role of Activin A During Pancreatic Acinar-to-Ductal Metaplasia of Orthotopic Pancreatic Tumor Mice
Authors: Elesh Ibrahim F , Kim So-Youn , Luan Yi , Oupicky David , Tang Siyuan , Yu Seok-Yeong
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) comprises more than 90% of pancreatic cancer cases and commonly harbors mutations in KRAS and TP53. PDAC is the third leading cause of cancer-related deaths in the US with approximately 10% 5-year relative survival rate. The poor survival rate largely pertains to aggressive growth following metastasis and limited understanding of prognostic factors. Accumulated evidence indicates that PDAC survival rates are inversely correlated with the pancreatic gene expression of INHBA, which encodes inhibin βA, and circulating levels of activin A (a dimer of inhibin βA), which is overexpressed in pancreatic cancer cells. However, potential mechanisms supporting the correlations have remained unclear. PDAC is etiologically related to sustained metaplasia of acinar cells to ductal-like cells (ADM). Therefore, in this study, we tested the hypothesis that activin A plays a tumor-promoting role via ADM. We implanted mouse PDAC KPC (KrasG12D and Tp53R172H) cells into the pancreata of C57BL/6 male mice and divided them into four groups; sham and three groups of orthotopic mice intraperitoneally (IP) injected with either no (TO), scramble (sc) or inhba siRNA (inhba) packaged with CPX nanoparticles, which previously exhibited tumor-targeted delivery, starting on postoperative day 4. On day 16, blood and tissues were harvested for analyses of tumor-related prognostic blood markers and tumor histology. Implanted KPC cells significantly elevated serum activin A levels and induced tumors as demonstrated by the accumulation of SOX9-positive ADM and a-SMA-positive fibroblasts when compared to sham group. Also, metastases occurred to the liver, spleen, kidney, and intestine. No differences were observed between TO and sc groups. However, when compared to sc group, inhba group had significantly suppressed serum activin A levels and reduced tumor size. Statistically, inhba group had fewer metastases and longer survival rates. Histologically, inhba group exhibited more amylase-positive acini conserved and less accumulation of a-SMA-positive cells in the pancreas. Further, the expression of activin A receptor type 2B (ACVR2B) was greatly induced on the acinar cells undergoing ADM transition in sc group, whereas such expression was subdued in inhba group. Collectively, our data indicate that inhba suppression impedes ADM mediated by KPC cells in mice and suggests activin A as one of tumor-initiating factors. It warrants further investigations in human PDAC models and clinical settings to test the potential therapeutic roles of targeting tumor INHBA in early PDAC development.

Presentation: Sunday, June 12, 2022 12:30 p.m. - 12:35 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF27 | LBSUN342 Ar-targeted Linked-read Sequencing Reveals Complex Ar Structural Variants In Castration Resistant Prostate Cancer Models
Authors: Zivanovic Andrej , Munro Sarah A , Miller Jeffrey T , Li Yingming , Passow Courtney N , Dehm Scott
Published: November 2022

Androgen deprivation therapies are employed for the treatment of advanced prostate cancer to suppress the transcriptional activity of the androgen receptor (AR). However, over the course of therapy, AR transcriptional activity re-emerges, and the disease progresses to castration resistant prostate cancer (CRPC). During CRPC progression, AR becomes heavily altered by genomic aberrations that include amplification, missense mutations, and structural variants (SVs). AR SVs are heterogeneous across CRPC specimens, with variability noted in SV class, breakpoint locations, and co-occurrence with amplification. Further variability has been observed for sub-clonal enrichment of AR SVs within tumors. A barrier to understanding the clinical significance of AR SVs is the challenge of deciphering this high degree of variability from short-read DNA-sequencing data. To address this challenge, we performed AR-targeted linked-read DNA-sequencing of CRPC cell line and patient-derived xenograft (PDX) models with the goal of resolving sub-clonal and complex AR SVs. We benchmarked this approach using prostate cancer cell lines and LuCaP86.2 PDX tissue harboring known AR SVs. Using this benchmarking approach, we identified linked AR SVs that co-occurred on single DNA molecules in LuCaP35CR and LuCaP105CR PDX models. We also identified a novel AR SV in the LuCaP77 PDX model and a castration-resistant derivative, LuCaP77CR. These results have revealed heterogeneous trajectories of AR SVs in CRPC and define a new class of complex AR SVs where multiple rearrangements co-occur on single DNA molecules to yield highly rearranged AR gene structures.

Presentation: Monday, June 13, 2022 1:05 p.m. - 1:10 p.m.
PSAT014 Pheochromocytoma in a Pregnant Woman with VHL leading to First Trimester Fetal Demise
Authors: Gorbonos Allen , Kamat Arnav , Williams Belinda , Rodriguez Giovanna , Bahtiyar Gul
Published: November 2022

Introduction

Pheochromocytomas (PCCs) are rare neuroendocrine tumors that secrete catecholamines. They may be associated with familial syndromes such as Multiple Endocrine Neoplasia type 2 (MEN 2), von Hippel-Lindau disease (VHL), and Neurofibromatosis type 1 (NF 1). PCCs are a common cause of malignant hypertension in pregnancy and can lead to adverse maternal and fetal outcomes if left undiagnosed or untreated.

Case Description

A 39-year-old Latin American primigravid woman at 8 weeks 4 days gestation was referred to the endocrinology clinic for labile blood pressure (160/90 mmHg at recent ER visit) and a lab finding of elevated catecholamines (plasma norepinephrine 4720 pg/ml; normal 0-874 pg/ml). She reported chronic headaches and 2-lb unintentional weight loss during pregnancy. Past medical history was significant for right adrenal PCC diagnosed at age 13 (currently status post adrenalectomy), and a cerebrovascular accident at age 29. Family history was relevant for PCC in the patient's sister and mother. The patient's home medications were nifedipine 30 mg daily and prenatal vitamins. On physical exam, her blood pressure was 126/76 mm Hg, heart rate was 67/min and a scar of previous right adrenalectomy was noted. Doxazosin 1 mg daily was added to her regimen and nifedipine was discontinued. The patient was initially planned for an elective cesarean section at term. However, at 10 weeks 5 days of gestation, she had a missed abortion. Further genetic testing of syndromic PCC revealed a heterozygous mutation in the VHL gene. Abdominal MRI showed a left adrenal mass (3.6×2.6×3.6 cm3) and retroperitoneal lymphadenopathy. The patient underwent left adrenalectomy and is currently hemodynamically stable on maintenance hydrocortisone and fludrocortisone.

Discussion

We report a case of PCC complicating pregnancy in a 39-year-old primigravida who had a family history of PCC. In females of reproductive age with a known PCC diagnosis, we suggest early genetic testing as it can further advise family planning, antepartum monitoring, and management. Medically, these patients can be managed with α-adrenergic blockers and calcium-channel blockers, followed by β-blockers. This can improve maternal and fetal outcomes primarily by minimizing paroxysmal elevations in catecholamines. Definitive treatment of PCC is surgical excision, usually performed during the second trimester or postpartum. Management of patients with VHL requires lifelong clinical, laboratory, and imaging surveillance for other manifestations of the disease.

References

Bancos, Irina et al. Maternal and fetal outcomes in phaeochromocytoma and pregnancy: a multicentre retrospective cohort study and systematic review of literature. Lancet Diabetes Endocrinol 2021; 9: 13–21

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
PSAT023 Not Every Pain Is a Gain! A Rare Case of Adrenal Leiomyosarcoma.
Authors: Syeda Javeria Nasir , Zafar Rafia , Rajamani Krishnakumar , Azim Salman
Published: November 2022

Introduction

Adrenal leiomyosarcoma (AL) is a rare malignant tumor, representing only 0.1% to 0.2% of all retroperitoneal soft tissue sarcomas in adults (1). A young male's acute abdominal and back pain led to an unusual diagnosis of AL.

Case Presentation

A 38-year-old male patient with no past medical history presented with a history of right sided abdominal pain of several months duration radiating to the back and significant weight loss. His vital signs were stable; however, he appeared mildly distressed and had tenderness on deep palpation in the right mid-upper quadrant. An abdominal sonogram showed a hypoechoic mass between the liver and the right kidney with no evidence of acute cholecystitis. A CT scan of the abdomen with IV contrast showed a lobulated mass invading the right adrenal gland, measuring 5.4×4.3×5.1 cm, with a post-contrast density measurement of 30 Hounsfield units. Laboratory tests showed plasma renin of 1.8 (upper limit of normal ULN 4.3 ng/ml/h), aldosterone of 8.6 (ULN 21 ng/dl), plasma metanephrine of <0.2 (ULN 0.50 nmol/l), and plasma normetanephrine of 0.49 (ULN 0.90 nmol/l). Additionally, his cortisol level after dexamethasone suppression was 0.9 (ULN 22.4 ug/dl). He underwent a right-sided laparoscopic adrenalectomy. The histopathological testing returned as a high-grade undifferentiated malignant neoplasm consistent with leiomyosarcoma. The IHC stains showed positive staining for SMA, CD10, and GATA3. He underwent whole-body PET/CT that showed multiple hypermetabolic abnormalities, including the right adrenalectomy bed, with a possible tumor invading the right upper renal pole. Systemic chemotherapy with doxorubicin and dacarbazine was initiated. Foundation panel testing showed NF1 loss on exons 2-3, CDKN2A/B CDKN2A rearrangement on exon 2, and TP53 loss on exons 1-4. He has received two rounds of chemotherapy, with no evidence of disease progression.

Discussion

Adrenal leiomyosarcoma usually originates from the smooth muscle cells of the adrenal or adjacent vascular structures. The tumor is asymptomatic until it enlarges and compresses the surrounding structures. Currently, there are about 50 reported valid cases (2) with no reports of NF-1 exon loss to our knowledge. The primary treatment is radical surgery with or without adjuvant chemotherapy and radiotherapy. Foundation panel testing showing NF-1 and TP53 exon loss may guide future targeted therapy.

References

1-Fatema Jabarkhel, Henri Puttonen, Lina Hansson, Andreas Muth, Oskar Ragnarsson, Primary Adrenal Leiomyosarcoma: Clinical, Radiological, and Histopathological Characteristics, Journal of the Endocrine Society, Volume 4, Issue 6, June 2020. 2-Bahador Oshidari, Amir Zamani, Hooman Bahrami-Motlagh, Elena Jamali, Setareh Mahmoodi, Manoochehr Ebrahimian, Primary leiomyosarcoma of the adrenal; a case report, International Journal of Surgery Case Reports, Volume 90, 2022, 106707.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
OR20-4 Expression of the Neuropeptide Substance P and the NK1 Receptor in Aldosterone-Producing Adenomas
Authors: Amar Laurence , Cornu Erika Cornu , Defortescu Guillaume , Duparc Céline , Fernandes-Rosa Fabio L , Lefebvre Hervé , Louiset Estelle , Manceau Gilles , Meatchi Tchao , Renouf Sylvie , Sabourin Jean-Christophe , Zennaro Maria-Christina , Lopez Antoine-Guy
Published: November 2022

Background

Aldosterone-producing adenoma (APA) is a major cause of primary aldosteronism (PA) which is the most frequent form of secondary hypertension (1-2). The pathophysiology of PA is quite complex and still incompletely understood. Substance P (SP) encoded by the TAC1 gene belongs to a family of bioactive peptides named tachykinins. A recently published study indicated that SP, released by subcapsular nerve fibres, stimulates aldosterone production through activation of the neurokinin type 1 receptor (NK1R) in the human adrenal gland (3). The aim of our work was to investigate the presence of SP fibres and the NK1 receptor in a large series of APA in order to assess the potential role of this peptide in the pathophysiology of PA.

Methods

APA tissues were studied by molecular and histological approaches. Expression of SP and NK1 receptor was searched for in a series of 51 APA by RT-Q-PCR and immunohistochemistry.

Results

Quantitative RT-PCR data indicated that adenomas strongly express TAC1 mRNA. Immunohistochemistry showed the presence of SP-positive nerve fibres in APAs tissues. SP was also detected in a subpopulation of adenomatous cells. Adenomas strongly express mRNA encoding the NK1 receptor. The distribution of the NK1 receptor within APAs is similar to that of aldosterone synthase (CYP11B2), suggesting that SP may regulate aldosterone secretion by APAs.

Conclusion

These results suggest that SP and its NK1 receptor may be involved in the pathophysiology of aldosterone hypersecretion by APAs. References: 1. Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, et al. Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice. J Am Coll Cardiol. 2017;69(14): 1811-20. 2. Buffolo F, Monticone S, Tetti M, Mulatero P. Primary aldosteronism in the primary care setting. Curr Opin Endocrinol Diabetes Obes. 2018;25(3): 155-9. 3. Wils J, Duparc C, Cailleux A-F, Lopez A-G, Guiheneuf C, Boutelet I, et al. The neuropeptide substance P regulates aldosterone secretion in human adrenals. Nat Commun. 2020;11(1): 2673.

Presentation: Monday, June 13, 2022 11:45 a.m. - 12:00 p.m.