bluuebunny/crossref_metadata_2025_split huggingface dataset:
8790 A Case Of Ectopic Cushing’s Syndrome Secondary To Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH)
Authors: Goettemoeller T , Fanas R Lopez , Cedeno K , Manavalan A 
Published: October 2024

Abstract
Disclosure: T. Goettemoeller: None. R. Lopez Fanas: None. K. Cedeno: None. A. Manavalan: None.
Introduction: Ectopic Cushing’s syndrome is a rare disease accounting for &lt;20% of cases of endogenous Cushing’s syndrome. DIPNECH is a poorly understood lung disease characterized by abnormal proliferation of neuroendocrine cells in the bronchial mucosa. It can be a precursor to pulmonary carcinoid tumors and has rarely been associated with ACTH production. Clinical Case: A 70-year-old female with intellectual disability and hypertension presented with diffuse edema and weakness. Examination was notable for hypertension, anasarca, and hirsutism. In addition to hypokalemia and metabolic alkalosis, hypercortisolism was observed: random serum cortisol - 50.1 ug/dL, late-night salivary cortisol - 1.72 mcg/dL (normal &lt; 0.09 mcg/dL) and 24-hour urine free cortisol - 1,845.9 mcg (normal: 4.0 – 50.0 mcg/24h). Cortisol level remained &gt; 25 ug/dL after high-dose dexamethasone suppression test. Ketoconazole was initiated and titrated to achieve normal 24-hour urine free cortisol levels and spironolactone was added to manage hypokalemia. An MRI of the sella and pituitary was unremarkable while an abdomen and chest CT identified a 2.5 cm well-circumscribed right middle lobe pulmonary nodule and mild thickening of the bilateral adrenal glands. A gallium-DOTATATE scan revealed a 2.1 cm right middle lobe pulmonary nodule with mildly increased uptake. A transbronchial biopsy of the right middle lobe nodule confirmed a carcinoid tumor. Immunohistochemistry (IHC) staining was positive for CHR, SYN, CD56, and AE1/3. Ki-67 stain showed a low proliferative index. A right middle lobectomy was performed with pathology revealing two typical carcinoid tumors measuring 2.8 and 0.7 cm each, with multiple carcinoid tumorlets and foci of neuroendocrine cell hyperplasia consistent with DIPNECH. IHC staining for ACTH was positive in the carcinoid tumors and tumorlets. Four days after surgery, AM cortisol was 8.1 ug/dL and potassium levels and blood pressure normalized off ketoconazole and spironolactone. The patient was discharged, but was readmitted a month later for anasarca, lethargy, hypokalemia, and metabolic alkalosis. A recurrence of Cushing’s syndrome was confirmed, and medical therapy was resumed. A chest CT revealed post-surgical changes. Her course was complicated by an aspiration event, septic shock, PEA arrest, resuscitation, and intubation. The patient’s care was ultimately transitioned to hospice. Conclusion: Florid Cushing’s syndrome due to ectopic ACTH production associated with DIPNECH is an exceedingly rare condition. Early recognition and treatment are crucial to prevent the numerous complications that may arise, and close follow-up after tumor removal is critical to ensure continued remission has been achieved.
Presentation: 6/1/2024
8338 A Case Series Of 3 Patients With Unusual Miliary Lung Metastases In Paraganglioma: Diagnostic Workup, Treatment Challenges And Outcomes
Authors: Charles K M , Nazari M A , Jha A , Derkyi A , Talvacchio S , Kuo M J , Patel M , Prodanov T , Alzahrani A S , Chen A , Glod J , Del Rivero J , Gharib A M , Pacak K 
Published: October 2024

Abstract
Disclosure: K.M. Charles: None. M.A. Nazari: None. A. Jha: None. A. Derkyi: None. S. Talvacchio: None. M.J. Kuo: None. M. Patel: None. T. Prodanov: None. A.S. Alzahrani: None. A. Chen: None. J. Glod: None. J. Del Rivero: None. A.M. Gharib: None. K. Pacak: None.
Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs, together PPGLs) are uncommon neuroendocrine tumors originating from adrenal medulla chromaffin cells and sympathetic/parasympathetic ganglia. Metastatic disease occurs in a subset of PPGLs, ranging from 5% to 30% depending on the underlying genetic factors. Metastases are typically found in the bone, lung, lymph nodes, or liver. Historically, there have been no reported cases of PPGL with miliary pattern of pulmonary metastases. Methods: Three patients were identified with pulmonary metastases. All patients were evaluated between 2016 and 2023, and all developed extensive pulmonary metastatic disease. The evaluation process involved reviewing their medical history, laboratory results, and potential therapeutic approaches. Each patient underwent surgical intervention for the primary tumor and received systemic therapies once metastatic spread was detected. Results: We present three patients with either germline succinate dehydrogenase subunit D (SDHD) or von Hippel-Lindau (VHL) pathogenic variants who developed this rare condition. Patient 1: a 14-year-old female with right PCC and a recurrent left neck PGL carrying VHL type 2 pathogenic variant: VHL c.250G&gt;T (p.Val84Leu) and received various chemotherapies with an unfavorable response. Patient 2: a 23-year-old female with a left jugular PGL carrying SDHD pathogenic variant: SDHD c.124_127delinsA TA (p.Glu42Ilefs*44). Patient 3: a 26-year-old female with a right PCC carrying a germline VHL type 2 pathogenic variant: VHL c.439C&gt;G (p.Leu147Val). The latter two patients experienced disease stabilization through chemotherapy and systemic targeted radiotherapy, respectively. Discussion/Conclusion: This case series is unique as it highlights the rare occurrence of miliary spread of pulmonary metastases resulting from PCC or PGL. It also provides insight into prospective treatments options and outcomes for clinicians administering care within this population of patients. Though it is not clear at this time, this case series may represent a new subset of PPGL that have different genomic features and require a different therapeutic approach.
Presentation: 6/1/2024
8464 A Unique SERM Reveals An Estrogen Receptor-Dependent Secretion Of DKK1 In Breast Cancer Cells
Authors: Young K S , Hancock G , Kregel S , Fanning S W 
Published: October 2024

Abstract
Disclosure: K.S. Young: None. G. Hancock: None. S. Kregel: None. S.W. Fanning: Grant Recipient; Self; Olema Oncology.
Although Estrogen Receptor positive (ER+) breast cancer has been successfully targeted in primary tumors, the critical limitations of hormone therapies are ultimately revealed as many women often experience disease recurrence. A subset of these patients harbor a distinctive tyrosine to serine missense mutation at position 537 (Y537S) in ER leading to allele-specific transcriptional programs that enhance metastasis. ER is a ligand-dependent master transcriptional regulator. Probing unique ER structural features can reveal new transcriptional activities. We developed a structurally unconventional Selective Estrogen Receptor Modulator (SERM), T6I-29, to better understand these structure-transcriptional relationships. T6I-29 shows effective anti-tumoral activities in Y537S ESR1 breast cancer cells. To examine the anti-tumoral mechanism of T6I-29 action, we performed RNA-sequencing on ESR1 Y537S mutant breast cancer cells. Compared to other clinically relevant compounds, our drug uniquely and significantly downregulated DKK1, a tumor secreted protein known to modulate the Wnt/β-Catenin and PI3K/Akt pathways. Upregulation of DKK1 correlates with metastatic burden across multiple cancers but has not been evaluated in ESR1 mutant breast cancers. We find that DKK1 levels are significantly elevated in the plasma of 108 ER+ breast cancer patients compared to 100 matched healthy donors. Furthermore, in wild-type (WT) PIK3CA breast cancer cell lines, those with Y537S ESR1 mutation show constitutive expression and secretion of DKK1, while DKK1 expression and secretion is estrogen-dependent in WT breast cancer cells. Intriguingly, WT cells show significant surface bound DKK1, which is secreted into the media upon hormone stimulation and blocked by T6I-29. Understanding the ER-dependence and functional importance of DKK1 secretion offers a novel approach to potentially reduce breast cancer metastatic burden.
Presentation: 6/3/2024
7409 Estrogen Receptor a (ERa) Signaling Mediates Pro-Tumor Neutrophil Activation In The Setting of Lymphangioleiomyomatosis (LAM)
Authors: Elisabeth O'Leary Katherine , Gibbons Erin , Minor Briaunna M N , Henson Thomas , Hammes Stephen R 
Published: October 2024

Abstract
Disclosure: K.E. O'Leary: None. E. Gibbons: None. B.M. Minor: None. T. Henson: None. S.R. Hammes: None.
Lymphangioleiomyomatosis (LAM), is a rare disease marked by the irregular proliferation of smooth muscle-like cells containing tuberous sclerosis (TSC) gene mutations. The resultant tumor growth causes cyst formation in the lung parenchyma which leads to decline in respiratory function. Notably, LAM almost exclusively affects biological females and appears to be estrogen sensitive. Prior studies have suggested that LAM tumor cells may originate from the uterus, thus explaining the female sexual dimorphism and the estrogen sensitivity. However, recent work from our laboratory suggests that estradiol not only stimulates TSC2-null smooth muscle cells, but also promotes neutrophil production via estrogen receptor α (ERα) signaling in the bone marrow, which in turn stimulates TSC2-null tumor progression. The precise mechanism by which ERα signaling promotes neutrophil production is unknown, nor are the direct effects of ERα signaling in neutrophils well understood; therefore, here we investigated the role of ERα signaling in tumor associated neutrophil activation. We hypothesized that estradiol, in concert with tumor-derived factors, may augment pro-tumorigenic and immunosuppressive functions of neutrophils. To address our hypothesis, Ly6G+ neutrophils were isolated from the harvested bone marrow of both C57BL/6 control and ERα knockout mice. Tumor conditioned media (TCM) containing potential tumor-derived stimulating factors was generated from LTM3 myometrial cells derived from uterine-specific TSC2-null mice (a mouse model for LAM tumors). Isolated neutrophils were then cultured in either fresh cell culture media or TCM for 24 hours. mRNA was collected and real-time quantitative PCR performed to investigate changes in mRNA expression of several known neutrophil activation markers. Our results show ERα was required for full expression of neutrophil elastase (Elane), nitric oxide synthase 2 (Nos2), and programmed death-ligand 1 (Pdl1/Cd274), all markers of neutrophils activated to support tumor progression. In addition, capacity for ERα signaling led to suppression of the chemokine receptor Cxcr2 mRNA. Our results indicate that, in addition to stimulating neutrophil production in bone marrow, estradiol signaling through ERα receptors on neutrophils may have significant influence on the quality of tumor exposed neutrophil activation, promoting a pro-tumorigenic immunosuppressive phenotype.
Presentation: 6/3/2024
12452 Unraveling An Intriguing Clinical Sequence: Thyrotoxicosis Antecedent To Stiff Person Syndrome
Authors: Jain Ashali , Natasha Rayan Melanie 
Published: October 2024

Abstract
Disclosure: A. Jain: None. M.N. Rayan: None.
Background: Stiff Person Syndrome (SPS) is an autoimmune phenomenon resulting in the progressive rigidity of limbs and trunk muscles. It is associated with GAD-positive antibodies in the CSF and serum and is linked to Type 1 Diabetes, Celiac disease, and other autoimmune diseases. Clinical Case: A 34-year-old female with no past medical history was brought into the ED by family for paranoia, suicidal ideations, and visual and auditory hallucinations. She was found to be tachycardic and altered in the ED. Endocrinology was initially consulted for concerns of hyperthyroid pathology due to lab work showing a TSH of &lt;0.008 uIU/mL and free T4 of 4 pg/mL. Thyroid ultrasound revealed heterogeneous, hypervascular thyroid tissue. Further investigation revealed TRAB 4.05 IU/L (n 0-0.9 IU/L) and TSI 3 IU/L (n &lt; 0.577 IU/L). A diagnosis of Graves’ disease was made, and she was started on methimazole 20mg daily and metoprolol 25mg daily. Due to a lack of response to methimazole, other organic causes were investigated including psychiatric and neurological etiology. The patient's symptoms continued to worsen, with new tremors of the upper and lower extremities. Thyroid labs showed improvement, and hence thyrotoxicosis was not thought to be the underlying etiology of her encephalopathy. Neurology was consulted, and EEG and MRI Brain were performed which were unrevealing. Lumbar puncture revealed elevated oligoclonal bands and GAD-65 antibodies, suggesting autoinflammatory encephalitis. High-dose steroids were started, with no improvement. Due to the failure of steroids to treat her symptoms, she was given 5 days of plasmapheresis and a dose of rituximab. Slowly, the patient began to improve and could follow commands and communicate with staff. A formal diagnosis of SPS was made at this time. Upon seeing her in follow-up 1 month after discharge, her TRAB and TSI antibodies were negative, and she was able to be titrated off of methimazole. Conclusion: SPS is strongly associated with autoimmune diseases, with up to 30-40% having T1DM. The association between hyperthyroidism and SPS, however, is exceedingly rare and the etiology remains unclear.
Presentation: 6/1/2024
8464 A Unique SERM Reveals an Estrogen Receptor-Dependent Secretion of DKK1 in Breast Cancer Cells
Authors: Young K S , Hancock G , Kregel S , Fanning S W 
Published: October 2024

Abstract
Disclosure: K.S. Young: None. G. Hancock: None. S. Kregel: None. S.W. Fanning: Grant Recipient; Self; Olema Oncology.
Although Estrogen Receptor positive (ER+) breast cancer has been successfully targeted in primary tumors, the critical limitations of hormone therapies are ultimately revealed as many women often experience disease recurrence. A subset of these patients harbor a distinctive tyrosine to serine missense mutation at position 537 (Y537S) in ER leading to allele-specific transcriptional programs that enhance metastasis. ER is a ligand-dependent master transcriptional regulator. Probing unique ER structural features can reveal new transcriptional activities. We developed a structurally unconventional Selective Estrogen Receptor Modulator (SERM), T6I-29, to better understand these structure-transcriptional relationships. T6I-29 shows effective anti-tumoral activities in Y537S ESR1 breast cancer cells. To examine the anti-tumoral mechanism of T6I-29 action, we performed RNA-sequencing on ESR1 Y537S mutant breast cancer cells. Compared to other clinically relevant compounds, our drug uniquely and significantly downregulated DKK1, a tumor secreted protein known to modulate the Wnt/β-Catenin and PI3K/Akt pathways. Upregulation of DKK1 correlates with metastatic burden across multiple cancers but has not been evaluated in ESR1 mutant breast cancers. We find that DKK1 levels are significantly elevated in the plasma of 108 ER+ breast cancer patients compared to 100 matched healthy donors. Furthermore, in wild-type (WT) PIK3CA breast cancer cell lines, those with Y537S ESR1 mutation show constitutive expression and secretion of DKK1, while DKK1 expression and secretion is estrogen-dependent in WT breast cancer cells. Intriguingly, WT cells show significant surface bound DKK1, which is secreted into the media upon hormone stimulation and blocked by T6I-29. Understanding the ER-dependence and functional importance of DKK1 secretion offers a novel approach to potentially reduce breast cancer metastatic burden.
Presentation: 6/3/2024
9354 Combination Of Novel Ruthenium-based Small Molecule Bold-100 And Capecitabine Is Effective In Inhibiting Growth Of Estrogen Receptor Positive Metastatic Breast Cancer
Authors: Scheidemann Erin R , Demas Diane M , Ashai Nadia , Shajahan-Haq Ayesha N 
Published: October 2024

Abstract
Disclosure: E.R. Scheidemann: None. D.M. Demas: None. N. Ashai: None. A.N. Shajahan-Haq: None.
The most common breast cancer subtype in both women and men is estrogen receptor alpha positive (ER+). In the adjuvant setting, ER+ tumors are initially treated with endocrine therapy that includes antiestrogens. Mechanistically, estrogen triggers a mitogenic signaling cascade through the ER, which activates the cyclin D1-cyclin-dependent kinase 4 and 6 (CDK4/6) complex to promote cell growth. ER+ tumors that progress on antiestrogens are subsequently treated with a combination of antiestrogens and CDK4/6 inhibitors (palbociclib, ribociclib or abemaciclib). However, 20% of ER+ tumors never respond to CDK4/6i due to intrinsic resistance and the tumors that initially respond will develop acquired resistance. In the absence of driver mutations, resistant tumors are treated with standard chemotherapies, including capecitabine, which interferes with DNA synthesis. However, treatment with capecitabine show meager success and accompany adverse side effects. BOLD-100 is a ruthenium-based novel small molecule drug that demonstrated antitumor activity as a monotherapy in a phase I clinical trial with a manageable safety profile at the maximum tolerated dose. BOLD-100 has recently been investigated in a multicenter global Phase 1B/2A trial (NCT04421820) of gastrointestinal cancer patients in combination with chemotherapy FOLFOX, which includes fluorouracil, the active form of capecitabine. Previously, we have shown that in breast cancer cells, treatment with BOLD-100 disrupted proteins involved in DNA repair pathway, stimulated reactive oxygen species (ROS) and induced cell death via interrupting autophagy and inducing apoptosis. In this study, we show that combination of BOLD-100 and capecitabine synergistically inhibits growth of breast cancer cells and tumors that are resistant to CDK4/6 inhibitors. Cells treated with combination of capecitabine and BOLD-100 shows increase in apoptosis and DNA damage compared with cells treated with monotherapies or control. Therefore, capecitabine and BOLD-100 is a potential novel combination therapy for breast cancer that has progressed on standard of care treatment.
Presentation: 6/2/2024
5113 Investigation And Management Of Primary Aldosteronism With Adrenal Vein Sampling At The CHU De Québec-Université Laval
Authors: Boisvert Amélie , Coll Julie-Catherine , Gagnon Nadia , Lamarre Andre 
Published: October 2024

Abstract
Disclosure: A. Boisvert: None. J. Coll: None. N. Gagnon: None. A. Lamarre: None.
Background: Adrenal vein sampling (AVS) is the gold-standard test to assess for lateralization in primary aldosteronism (PA). In case of unsuccessful right adrenal vein (RAV) cannulation, our tertiary care centre (CHU de Québec-UL) uses a multinomial regression model to extrapolate the RAV cannulation results. Objectives: 1) To determine the proportion of successful RAV cannulation during AVS at the CHU de Québec-UL; 2) To evaluate the management and clinical evolution of patients with PA who underwent AVS at the CHU de Québec-UL, including those who were treated based on the multinomial regression model results. Methods: This retrospective cohort study included patients aged ≥18 years with a diagnosis of PA who underwent AVS between January 2017 and September 2022 at the CHU de Québec-UL. Epidemiological data at diagnosis were collected, as well as data on AVS cannulation, AVS complications and PA clinical evolution. Successful RAV cannulation was determined by the interventional radiologist and by cortisol ratios. Results are presented as percentage or mean±SD. Results: 39 patients were included (33,3% women; mean age 51,1±11,5 years; 89,7% with hypertension treated with a mean of 2,5±1,1 antihypertensive drugs; 74,4% with hypokalemia), for a total of 40 AVS procedures. 3 procedures (7,5%) selectively cannulated both adrenal veins. 3 procedures (7,5%) led to complications (subcutaneous hematoma). Of the 33 incomplete AVS procedures, the clinical management after 6 of these procedures was unavailable due to follow-up in other hospital centres. Among the remaining 27 patients, 5 (18,5%) had a second complete AVS in another tertiary care center, 12 (44,4%) were medically treated, 1 (3,7%) had an adrenalectomy and 11 (40,7%) were treated according to the multinomial regression model results. The model lateralized aldosterone secretion in 5 patients, who then all had adrenalectomy, after which 4 were diagnosed adrenal adenomas and one was diagnosed adrenal hyperplasia on pathology. The 8 complete AVS procedures led to 6 diagnoses of unilateral disease and 2 diagnoses of bilateral disease. Applying the multinominal regression model to the initial AVS procedure of these 8 cases would have correctly predict aldosterone lateralization in 7 cases (87,5%). Conclusion: AVS success rate in our tertiary care centre was low. The multinominal regression model appeared to adequately detect unilateral disease in our small sample. It is necessary to reevaluate our AVS technical protocol to increase our AVS successful cannulation rate.
Presentation: 6/1/2024
7409 Estrogen Receptor a (ERa) Signaling Mediates Pro-Tumor Neutrophil Activation in the Setting of Lymphangioleiomyomatosis (LAM)
Authors: Elisabeth O'Leary Katherine , Gibbons Erin , Minor Briaunna M N , Henson Thomas , Hammes Stephen R 
Published: October 2024

Abstract
Disclosure: K.E. O'Leary: None. E. Gibbons: None. B.M. Minor: None. T. Henson: None. S.R. Hammes: None.
Lymphangioleiomyomatosis (LAM), is a rare disease marked by the irregular proliferation of smooth muscle-like cells containing tuberous sclerosis (TSC) gene mutations. The resultant tumor growth causes cyst formation in the lung parenchyma which leads to decline in respiratory function. Notably, LAM almost exclusively affects biological females and appears to be estrogen sensitive. Prior studies have suggested that LAM tumor cells may originate from the uterus, thus explaining the female sexual dimorphism and the estrogen sensitivity. However, recent work from our laboratory suggests that estradiol not only stimulates TSC2-null smooth muscle cells, but also promotes neutrophil production via estrogen receptor α (ERα) signaling in the bone marrow, which in turn stimulates TSC2-null tumor progression. The precise mechanism by which ERα signaling promotes neutrophil production is unknown, nor are the direct effects of ERα signaling in neutrophils well understood; therefore, here we investigated the role of ERα signaling in tumor associated neutrophil activation. We hypothesized that estradiol, in concert with tumor-derived factors, may augment pro-tumorigenic and immunosuppressive functions of neutrophils. To address our hypothesis, Ly6G+ neutrophils were isolated from the harvested bone marrow of both C57BL/6 control and ERα knockout mice. Tumor conditioned media (TCM) containing potential tumor-derived stimulating factors was generated from LTM3 myometrial cells derived from uterine-specific TSC2-null mice (a mouse model for LAM tumors). Isolated neutrophils were then cultured in either fresh cell culture media or TCM for 24 hours. mRNA was collected and real-time quantitative PCR performed to investigate changes in mRNA expression of several known neutrophil activation markers. Our results show ERα was required for full expression of neutrophil elastase (Elane), nitric oxide synthase 2 (Nos2), and programmed death-ligand 1 (Pdl1/Cd274), all markers of neutrophils activated to support tumor progression. In addition, capacity for ERα signaling led to suppression of the chemokine receptor Cxcr2 mRNA. Our results indicate that, in addition to stimulating neutrophil production in bone marrow, estradiol signaling through ERα receptors on neutrophils may have significant influence on the quality of tumor exposed neutrophil activation, promoting a pro-tumorigenic immunosuppressive phenotype.
Presentation: 6/3/2024