bluuebunny/crossref_metadata_2025_split huggingface dataset:
Taking Advantage of the TGFB1 Biology in Differentiated Thyroid Cancer to Stimulate Sodium Iodide Symporter (NIS)-Mediated Iodide Uptake in Engineered Mesenchymal Stem Cells
Authors: Han Yang , Koehler Viktoria F , Schwenk Nathalie , Schmohl Kathrin A , Spellerberg Rebekka , Kitzberger Carolin , Nelson Peter J , Spitzweg Christine 
Published: May 2021

Abstract
The sodium iodide symporter (NIS) mediates the active transport of iodide into thyroid follicular cells, providing the basis for the use of radioiodide for diagnostic imaging and therapy of differentiated thyroid cancer and also non-thyroidal tumors after tumor-selective NIS gene transfer. Based on their excellent tumor-homing capacity, mesenchymal stem cells (MSCs) can be employed as tumor-selective NIS gene delivery vehicles. Transgenic expression of NIS in genetically engineered MSCs allows noninvasive imaging of functional NIS expression as well as therapeutic application of 131I. The use of promoters activated by tumor micromilieu-derived signals to drive NIS expression enhances selectivity and effectiveness, while limiting potential off-target effects. In this study we aimed to exploit the central role of transforming growth factor B1 (TGFB1) in tumor milieu-associated signaling using a TGFB1-inducible synthetic SMAD-responsive promoter to selectively drive NIS-transgene expression in engineered MSCs (SMAD-NIS-MSC) in the context of differentiated thyroid cancer based on the critical role of TGFB1 in the pathogenesis of radioiodine refractory differentiated thyroid cancer. To evaluate the TGFB1 expression in thyroid cancer cell lines, the TGFB1 concentration in conditioned medium (CM) from an array of established human papillary thyroid cancer (PTC) cell lines (BCPAP and K1) was measured by ELISA. BCPAP-CM showed a higher concentration of TGFB1, while a lower concentration was measured in K1-CM. Stimulation of SMAD-NIS-MSCs with PTC-CM showed a significant increase of NIS-mediated radioiodide-125 uptake in these MSCs in vitro. In addition, iodide uptake in SMAD-NIS-MSCs was significantly stimulated by co-culture with thyroid cancer cells. Cell migration assay was performed to validate the effect of PTC-CM in MSC recruitment. MSCs subjected to a gradient between tumor CM and serum free medium showed a directed chemotaxis towards CM with increased forward migration index (FMI) and center of mass (CoM). In a next step, based on the in vitro studies, SMAD-NIS-MSCs will be systemically applied via the tail vein to mice harboring subcutaneous PTC tumors and tumoral iodide uptake will be monitored by 123I-scintigraphy. Taken together, these data indicate the feasibility of commandeering TGF-β/SMAD signaling in the TGFB1-rich tumor environments of radioiodine refractory differentiated thyroid carcinomas to re-establish functional NIS expression using engineered mesenchymal stem cells as therapy vehicles.
VERU-111: An Oral Tubulin Inhibitor That Suppresses Taxane-Sensitive and Taxane-Resistant Breast Cancer
Authors: Deng Shanshan , Krutilina Raisa I , Parke Deanna , Chen Hao , Miller Duane D , Li Wei , Seagroves Tiffany Nicole 
Published: May 2021

Abstract
Triple negative breast cancer (TNBC) patients have poorer overall prognosis relative to patients diagnosed with other molecular subtypes due to rapid onset of drug resistance to conventional chemotherapies and increased risk of visceral metastases. The microtubule inhibitor paclitaxel (Taxol, a taxane) is a frontline therapy for advanced breast cancer. We evaluated in TNBC models the preclinical safety and efficacy of a novel, potent, and orally bioavailable tubulin inhibitor, VERU-111, a tubulin inhibitor targeting the colchicine binding site. VERU-111 showed potent anti-proliferative and anti-migratory activity against several taxane-sensitive and taxane-resistant TNBC breast cancer cell lines. Based on these observations, taxane-resistant HER2+ cell lines were generated, and were also found to be responsive to VERU-111 treatment. In vivo, orally administered VERU-111 inhibited MDA-MB-231 tumor growth in a dose-dependent manner with antitumor potency similar to paclitaxel, and repressed metastases originating from the mammary fat pad or following tail vein injection. In contrast, in a MDA-MB-231 paclitaxel-resistant (TxR) subline, tumor growth was refractory to paclitaxel whereas VERU-111 significantly inhibited primary tumor growth and reduced lung and liver metastases. VERU-111 was then tested in a luciferase-labeled, multidrug resistant patient-derived xenograft (PDX) TNBC model. VERU-111 significantly inhibited HCI-10 PDX tumor growth and suppressed the expansion of axillary lymph node metastases present prior to initiation of therapy while suppressing lung, liver, bone and kidney metastases at study endpoint. Moreover, in contrast to paclitaxel, VERU-111 therapy did not cause a significant decrease in mouse body weight during treatment. Evaluation of efficacy of VERU-111 in taxane-sensitive and -resistant HER2+ xenograft models is in progress. Overall, we conclude that VERU-111 is a new generation orally bioavailable tubulin inhibitor that potently inhibits the growth of taxane-sensitive and taxane-resistant breast cancers with reduced adverse side effects relative to paclitaxel. Importantly, VERU-111 is well-tolerated in patients as evaluated in phase I/II clinical trials for advanced prostate cancer patients (NCT03752099). We propose that VERU-111 will be an effective second line therapy for patients with advanced breast cancer who progress on taxane-based therapeutic regimens.
Double the Battle: Two Cases of Irreversible Endocrinopathies in Patients Already Fighting Metastatic Cancer
Authors: Petrenko Olesya , Stucky Nicholas 
Published: May 2021

Abstract
Immune Checkpoint Inhibitors (ICI) have been approved since 2011 to treat patients with advanced solid and hematological malignancies and have had remarkable results. However, case reports of endocrine adverse events are becoming increasingly reported and can be fatal if not recognized early. Here we present two unique cases of rare endocrinopathies after the use of ICIs. A 47 year old male with metastatic melanoma presented with nausea, vomiting, polyuria, polydipsia of 5 days. Three weeks prior, he was started on nivolumab and ipilimumab. On presentation, he was tachycardic and tachypneic. Lab work was remarkable for a glucose of 676, Na 129, K 6.2, CO2 6, Cr 2.43 (baseline of 1.1) and beta-hydroxybutyrate of 11.7 with elevated HgA1c of 7.1%. DKA was diagnosed and fluids and insulin drip were started. Further work up revealed a normal cortisol level, TFTs and C-peptide &lt;1 consistent with new-onset type I diabetes mellitus in the setting of two ICI agents. Patient was started on insulin regimen. An 81 year old female with metastatic bladder cancer on Pembrolizumab was admitted with 2 weeks of fatigue, positional dizziness and dyspnea. She recently presented with hyperkalemia attributed to dehydration. On admission, she was hypotensive with a blood pressure of 81/59 with normal heart rate and no fever. She had dry mucous membranes on exam but no abnormal skin. Further work up revealed an AM cortisol of &lt;1, ACTH of 458 and positive Cosyntropin stim test, consistent with primary adrenal insufficiency. CT-Abdomen Pelvis did not reveal any acute adrenal masses. She was started on hydrocortisone at discharge with fludrocortisone due to hypotension. ICIs are categorized as target programmed death-1 receptor inhibitors (PD-1) nivolumab, pembrolizumab, cemiplimab, programmed death-ligand 1 inhibitors (PDL1) atezolizumab, avelumab, durvalumab and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) iplimumab. Immune checkpoint proteins are T-cell surface receptors that cause inhibition when they bind to their ligands to limit the immune response. Tumors manipulate these inhibitory pathways to evade rejection. ICIs no longer halt the immune response and result in effective cancer treatment. However, a robust immune response can go on to attack healthy tissue resulting in endocrinopathies such as hypophysitis, hypo-or hyperthyroidism, diabetes mellitus or adrenal insufficiency. Acute hypocortisolemia or thyroid storm can be fatal if not identified acutely. Current guidelines recommend baseline screening with TFTs, morning cortisol and ACTH and screening monthly thereafter in patients on ICIs. In this report, we present two unique cases of irreversible endocrinopathies in patients treated with ICI who developed type I diabetes and primary adrenal insufficiency. These cases warn physicians to be vigilant with patients on ICI and consider the possibility of life-threatening endocrinopathies.
Adrenal Crisis in Long Term Use of Exogenous Steroid With Inappropriate Tapering off Process
Authors: Oktavia Nani , Pratiwi Chici , Nasaruddin Jerry , Mokoagow Muhammad Ikhsan , Epriliawati Marina , Kshanti Ida Ayu 
Published: May 2021

Abstract
Background: Adrenal crisis is an emergency condition in endocrinology that commonly found in primary adrenal insufficiency but also occur in chronic adrenal insufficiency triggered by various conditions such as sepsis, infection, trauma, burns, surgery, and myocardial infarction. In chronic adrenal insufficiency, adrenal crisis can be induced by excessive reductions or inadequate discontinuation of steroid treatment.
Case Illustration: A 40-year old-man admitted with chief complaint abdominal pain since seven days before admission. He felt pain in the umbilical area and slowly radiated to all the part of abdomen. Other than that, he also felt nausea, had vomitus, fever, and constipation for five days. He was immobilized for four months, with muscles weakness and atrophy. He was diagnosed with Focal Segmented Glomerulosclerosis and had a high dose of methylprednisolone (48 mg) for 6 months, 40 mg for the next 2 months and methylprednisolone 12 mg for the last 2 months. The last two month, he began to have severe general weakness and hypotension. On physical examination we found hypotension, fever (38.1o C), pale conjunctiva, moon face, buffalo hump, slightly distended and tenderness of abdomen, normal bowel sound, and purple striae all over the abdomen and extremities. On laboratory examination, Hb was 8.2 (n 11.7 – 15.5 g/dl), leukocytes 10,400 (5.00 – 10.00 x 103/μL), Na 123 (n 135 – 147 mmol/L), random blood glucose 74 (n 70 – 140 mg/dL). On abdominal X ray, there was prominent faecal material and no signs of ileus. No sign of infection found in urinalysis. He had sodium correction, packed red cell transfusion, symptomatic therapy including laxative, methylprednisolone 12 mg, but no improvement of signs and symptoms beside be able to defecate. The abdominal ultrasound gave a normal result. The morning cortisol level was then examined, with the result 14.4 (n 3.7–19.4). The patient was then diagnosed with adrenal crisis based on the clinical manifestations and had hydrocortisone therapy 100 mg a day for 2 consecutive days. After hydrocortisone administration, the symptoms improved, no fever and abdominal pain, he had normotension, increased sodium level 132 (n 135 – 147 mmol/L) and blood glucose level 118 (n 70 – 140 mg/dL). On the third day the patient discharged with oral hydrocortisone 15 mg in the morning and 10 mg in the afternoon.
Conclusion: Adrenal crisis was generally found in primary adrenal insufficiency but could also occur in secondary adrenal insufficiency due to inappropriate tapering off process of long term glucocorticoid use.
Adrenal Insufficiency Presenting as Hypoglycemia & Hyponatremia in a Patient With Liver Cirrhosis; Hepatoadrenal Syndrome
Authors: Farrukh Hina , Mehrab Amina , Khan Abeera 
Published: May 2021

Abstract
Hepatoadrenal syndrome is described as a progressive impairment in the adrenocortical reserve in advanced liver disease resulting in relative adrenal insufficiency (AI). This can present as critical hypoglycemia and hyponatremia as in the case described.
54 year old male with past medical history of hypothyroidism, pericardial effusion, liver cirrhosis and prior alcohol use disorder presented to the hospital with altered mental status. He felt lethargic and complained of recurrent diarrhea for a month. His blood sugar was 30 mg/dl (n=70–140 mg/dl) for which he received dextrose and his mentation improved. He was hypothermic with stable vitals otherwise. There was no skin hyperpigmentation. Labs demonstrated sodium of 123 mmol/L (n=136–145 mmol/L) and pancytopenia. TSH, ammonia, renal and hepatic functions were within normal limits except mildly elevated AST and total bilirubin. Total protein, albumin, HDL, Insulin and cortisol levels were low. Hepatitis panel was negative. CT Chest, abdomen and pelvis revealed massive abdominopelvic ascites, hepatic cirrhosis and splenomegaly. Adrenal glands appeared normal. Urine studies were consistent with salt-wasting nephropathy. Patient was started on intravenous fluids as well as dexamethasone. Diagnostic and therapeutic paracentesis was performed. Cosyntropin stimulation test revealed a baseline AM cortisol of 2.0 ug/dl (n=4.3–22.4 ug/dl), 30 min value of 4.0 ug/dl and 60 min value of 5.8 ug/dl (n=18-22ug/dl). Delta cortisol level was also low. Treatment with hydrocortisone was initiated until ACTH levels became available. To rule out sarcoidosis, ACE levels were obtained, which were normal. Dihydroxy 1,25 Vitamin D levels were low. ACTH returned as 21.7 pg/ml (n=7.2–63.3 pg/ml). 21 hydroxylase antibody was negative. MRI brain with IV contrast demonstrated no pituitary mass or abnormality. Blood cultures, body fluid cultures, AMA and ASMA were negative. Anti- tTG and Anti Gliadin antibodies were positive confirming celiac disease. Patient was started on gluten free diet which resolved his diarrhea. He responded well to steroids however, he remained intermittently confused which was thought to be related to hypoglycemic brain injury. Patient was converted to hydrocortisone PO 20 mg in AM and 10 mg in PM and advised to follow up outpatient with endocrinologist and gastroenterologist.
Hepatoadrenal syndrome is an important differential to consider in patients with liver disease presenting with hypoglycemia and hyponatremia. It is a potentially life-threatening condition requiring immediate treatment and appropriate work up. The condition improves with corticosteroid replacement therapy.
Reference: Anastasiadis SN, Giouleme OI, Germanidis GS, Vasiliadis TG. Relative adrenal insufficiency in cirrhotic patients. Clin Med Insights Gastroenterol. 2015;8:13–17. Published 2015 Mar 2. doi:10.4137/CGast.S18127
Adrenal Mass Hemorrhage Clinically Mimicking a Pheochromocytoma
Authors: Panjawatanan Panadeekarn , Daniyal Muhammad , Delgado Hurtado Juan Jose 
Published: May 2021

Abstract
Background: A pheochromocytoma is diagnosed clinically using correlation of clinical, imaging, and laboratory studies. We report the case of an adrenal mass hemorrhage that presented with significantly elevated urine metanephrines mimicking a pheochromocytoma.
Clinical Case: A 59-year-old healthy woman presented to the ED with chest pain, left flank and upper quadrant pain associated with diaphoresis and palpitations. Vital signs were significant for a pulse of 92 bpm, and a BP of 213/88 mm Hg. Physical exam revealed tenderness to palpation on the left upper quadrant and left costovertebral angle. Laboratory tests were significant for an elevated D-dimer (2,449 ng/mL, reference range 215–499 ng/mL). CT abdomen with IV contrast showed a 3.5 x 2.9 cm round mass abutting the lateral limb of the left adrenal gland with surrounding fat stranding with suspicion of inflammation or hemorrhage. 24-hour urine metanephrines showed elevated metanephrine (7,227 mcg/24hr; reference range &lt;400 mcg/24 hr) and normetanephrine (1,209 mcg/24hr; reference range 900 mcg/24 hr). In the setting of up trending cardiac enzymes and inferior-lateral ST segment depression, a cardiac catheterization was performed which was unrevealing. She was discharged from the hospital and referred to endocrinology. On that visit, ~ 1 month after the patient was admitted to the hospital, plasma metanephrines were ordered which showed mildly elevated plasma metanephrine (0.83 nmol/L; reference range &lt;0.5 nmol/L) and normetanephrine (1.2 nmol/L; reference ranges &lt;0.9 nmol/L). An MRI abdomen with and without contrast revealed a 2.7 x 2.2 x 1.8 cm nodule arising from the lateral limb, with loss of signal on in-phase images suggestive of blood products. Plasma metanephrines and MRI findings ruled out the diagnosis of a pheochromocytoma.
Conclusion: To our knowledge, few cases of an adrenal mass hemorrhage clinically mimicking a pheochromocytoma have been reported. Although the inpatient clinical presentation of our patient was consistent with this, the outpatient plasma metanephrines and MRI were not. An adrenal adenoma hemorrhage should be considered as a potential differential diagnosis for elevated metanephrines, which can clinically mimick a pheochromocytoma.
References: (1)Sekos K, Short T, Ing SW. Adrenal hemorrhage due to hypercoagulable state mimicking pheochromocytoma. Journal of Clinical and Translational Endocrinology: Case Report. 8. 9–12. 2018.(2)Wordsworth S, Thomas B, Agarwal N, Hoddell K, Davies S. Elevated urinary cathecholamines and adrenal haemorrhage mimicking phaechromocytoma. BMJ Case Reports. 2010.
Aldosterone/Direct Renin Concentration Ratio Versus Aldosterone/Plasma Renin Activity for Diagnosis of Primary Hyperaldosteronism: Case Presentation
Authors: Shanik Michael Howard , Romao Isabela J , Velayati Sara 
Published: May 2021

Abstract
Aldosterone/Direct Renin concentration ratio versus Aldosterone/Plasma renin activity for diagnosis of Primary Hyperaldosteronism: Case presentation.
Introduction: Primary hyperaldosteronism (PA) is the most common cause of secondary hypertension. Endocrine Society guidelines recommend using aldosterone-to-renin ratio (ARR) for screening of PA1. This ratio can be obtained using two different methods. The first is plasma aldosterone concentration (PAC) divided by plasma renin activity. ARR greater than 20 is suggestive of PA. Further testing is required for confirmation. Due to limitations and challenges in obtaining PRA, another method of measurement was developed in which the direct renin concentration (DRC) is measured. There have been inconsistent recommendations regarding what ratio is appropriate using this assay to diagnose hyperaldosteronism. The aim of this case presentation is to review a patient with PA in whom both measurement methods were used and compared for screening.
Case Presentation: A 45-year woman with past medical history of Graves’ disease and hypertension presented with hypokalemia. Blood pressure was well-controlled on amlodopine for 3 years. PAC and DRC were measured. PAC was 21.2 ng/dL and DRC 2.8 pg/ml with ARR 7.6. This was repeated and confirmed (PAC 19.6 ng/dL and DRC 3.9 pg/ml with ARR 5). Plasma Renin Activity (PRA) was measured. PAC was 36.3 ng/dL and PRA was 0.19 ng/ml/hr (ARR 191), suggestive of hyperaldosteronism. Further workup including a CT scan of the abdomen with IV and oral contrast demonstrated an enhancing 1.8 cm nodule in the left adrenal gland. Adrenal vein sampling was performed. Left adrenal vein aldosterone level was 1400 ng/dl and on the right, 33.1 ng/dl. The patient was treated with left laparoscopic adrenalectomy. The pathological evaluation of the specimen demonstrated a 2.5 cm adenoma of benign etiology. Later follow-up showed the patient was normokalemic with PAC of 3.1.
Conclusion: Patients with PA despite controlled hypertension, experience higher rates of cardiovascular events, hence early and accurate diagnosis is essential. PRA measurement has multiple limitations including inter-laboratory variations, higher cost, availability in only advanced laboratories and values influenced by blood pressure medications. Therefore, some institutions have replaced it with direct renin concentration (DRC) which is cheaper and more widely available. DRC has limitations with fewer positive ARR results. When the clinical suspicion is high, PRA is the more precise study to calculate ARR. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. John W. Funder, Robert M. Carey, Franco Mantero, et al. The Journal of Clinical Endocrinology & Metabolism, Volume 101, Issue 5, 1 May 2016, Pages 1889–1916, https://doi.org/10.1210/jc.2015–4061.
Bilateral Pheochromocytoma Due to Von Hippel Lindau With Adrenal-Sparing Adrenalectomy in a Child
Authors: Hilk Kelly , Agrawal Anurag K , Cadenas Nicola , Roman Sanziana , Srivastava Priya S , Yen Kevin , Lodish Maya Beth 
Published: May 2021

Abstract
Background: More than 40% of pediatric pheochromocytoma or paragangliomas have associated underlying genetic germline mutation. (1) Clinical Case: We present an 8-year-old male who arrived the emergency department with hypertension to 170/115. MRI of the abdomen revealed bilateral well demarcated adrenal masses with central necrosis. Urine metanephrines showed elevated normetanephrine of 15244 µg/24 hr (reference range, 58 - 670 µg/24 hr) and normal urine metanephrines. Urinary vanillylmandelic acid was mildly elevated 35 mg/gCr and homovanillic acid was normal. MIBG scan revealed increased radiotracer activity correlating to the bilateral adrenal masses without evidence of metastasis. Diagnosis of bilateral pheochromocytomas was made. Genetic testing revealed a novel, heterozygous, pathogenic variant of VHL tumor suppressor gene, consistent with Von Hippel-Lindau syndrome. Perioperative blockade was achieved with prazosin, amlodipine, and metoprolol. Due to low likelihood of metastasis in pheochromocytomas due to VHL, adrenal sparing bilateral adrenalectomy was attempted and resulted in 15% sparing of left adrenal gland vs radial bilateral adrenalectomy. (2) Clinical Lessons: 1. Endocrine etiologies of hypertension, although rare, are important causes of hypertension in the pediatric population. 2. Genetic testing prior to surgical intervention could determine surgical course and preservation of adrenals. 3. A multidisciplinary approach to care and referral to a center with experienced surgery, oncology, nephrology, endocrinology, anesthesiology, critical care and genetics is crucial to maximizing outcomes with pheochromocytoma. Reference: 1. NGS in PPGL (NGSnPPGL) Study Group, Toledo RA, Burnichon N, Cascon A, Benn DE, Bayley JP, Welander J, Tops CM, Firth H, Dwight T, Ercolino T, Mannelli M, Opocher G, Clifton-Bligh R, Gimm O, Maher ER, Robledo M, Gimenez-Roqueplo AP, Dahia PL. Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nat Rev Endocrinol. 2017 Apr;13(4):233–247. 2. King KS, Prodanov T, Kantorovich V, Fojo T, Hewitt JK, Zacharin M, Wesley R, Lodish M, Raygada M, Gimenez-Roqueplo AP, McCormack S, Eisenhofer G, Milosevic D, Kebebew E, Stratakis CA, Pacak K. Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J Clin Oncol. 2011 Nov 1;29(31):4137–42.