bluuebunny/crossref_metadata_2025_split huggingface dataset:
Never Forget the Family History: MEN2A Syndrome Presenting as Metastatic Medullary Thyroid Cancer and Bilateral Pheochromocytoma
Authors: Rodriguez Lisette Patricia , Perez Jesus B , Wiese-Rometsch Wilhelmine 
Published: May 2021

Abstract
Introduction: MEN 2A is an autosomal dominant hereditary syndrome considered part of the medullary thyroid carcinoma (MTC) syndromes. This is characterized by MTC, pheochromocytoma, and parathyroid hyperplasia or adenomas causing primary hyperparathyroidism (PHPT).
Clinical Case: A 34 year old female was referred to our clinic for multi-nodular goiter diagnosed during routine gynecologic evaluation. A thyroid ultrasound revealed a heterogeneous right thyroid lobe with a hypoechoic 2.5 cm nodule, associated macro calcifications and increased vascularity; and a left nodule measuring 2.3 cm with the same characteristics. Bilateral thyroid nodule biopsies were performed, resulting in MTC confirmed by positive calcitonin staining. Pre-operative studies revealed serum calcitonin and carcinoembryonic antigen (CEA), both of which are considered serologic markers of MTC activity, at 4,340 pg/ml (n &lt;= 5) and 276.2 ng/mL (n &lt;= 2.5 in non-smokers) respectively. The patient reported father with history of unspecified thyroid cancer, and paternal uncle with history of pheochromocytoma with a p.Cys634Trp mutation in RET proto-oncogene. Due to her family history, pre-operative screening for primary hyperparathyroidism (PHPT) resulted in a calcium 10 mg/dL (n 8.6-10.2), PTH 34 pg/mL (n 14-64). Additionally, screening for pheocromocytoma revealed an elevated 24 hour urine metanephrines of 2,276 (n &lt;= 49-290) ug/24h, plasma metanephrines, including fractionated metanephrine (MN) at 163 (n &lt;= 57) pg/ml, fractionated nor-metanephrine (NMN) at 182 (n &lt;= 148) pg/ml, and total, Free (MN+NMN) metanephrines at 345 (n &lt;= 205) pg/ml. CT abdomen revealed bilateral adrenal nodules, right measuring 1.4 x 3.3 cm and left 2.4 x 3.3 cm. The patient underwent posterior retroperitoneoscopic adrenalectomy with cortex sparing prior to thyroidectomy. Adrenal pathology resulted in bilateral pheochromocytoma with peri-adrenal adipose tissue microscopic involvement, and positive synaptophysin and S-100 stain. Subsequently, she underwent total thyroidectomy with extensive cervical lymph node resection, with pathology resulting in MTC with lymph node metastasis, involving 5/18 cervical lymph nodes. Post-operative labs revealed serum calcitonin &lt;= 2 pg/ml, CEA 26.8 ng/mL, MN &lt; 25 pg/ml, NMN 102 pg/ml, and MN+NMN of 102 pg/ml, which suggested initial surgical success. Post-operative genetic test evaluation revealed abnormal RET oncogene testing compatible with MEN 2A, variant 1: c.1902C&gt;G (p.Cys634Trp).
Conclusion: This case illustrates that patients presenting with MTC and reporting family history of thyroid cancer should be screened for familial MTC syndrome. Patients with RET mutation should be screened for pheochromocytoma prior to surgery for MTC to prevent life-threatening hypertensive crisis.
Reversible Catecholamine Induced Cardiomyopathy
Authors: Tofil Kathrin Sandra , Mushref Malek 
Published: May 2021

Abstract
Background: Pheochromocytomas and paragangliomas (PPGL) are rare neuro-endocrine tumors associated with a myriad of poor outcomes as a result of long-term exposure to catecholamines. Although paragangliomas are less commonly associated with increased catecholamine production than adrenal pheochromocytomas, there have been a few reports of catecholamine-induced cardiomyopathy in patients diagnosed with PPGL. We report a case of a PPGL associated with hypercoagulability and cardiomyopathy. Clinical Case: 42-year-old man with uncontrolled hypertension presented to the emergency department with abdominal pain. On CT imaging, he was found to have hepatic lesions, aortocaval lymph node concerning for metastatic disease, left renal infarct, and a left ventricular thrombus. Soon after his admission, he developed acute ataxia, gaze palsies and left hemiparalysis. CTA of the head showed a basilar artery thrombus [FJ1] which was treated with emergent thrombectomy. In addition patient had absent distal pulse of the right foot[FJ2], and found to have thrombus of the popliteal artery, which was treated with thrombectomy. Further workup with abdominal MRI showed retroperitoneal mass[FJ3] and multiple hepatic lesions concerning for metastatic extra-adrenal neuroendocrine tumor. Plasma normetanephrine was 4.5 nmol/L (ULN 0.89), plasma metanephrine 0.3 nmol/L (ULN 0.49) Chromogranin A was 387 ng/ml (ULN 160). Ga-68 DOTATE scan was consistent with an extra adrenal paraganglioma with less prominent radiotracer activity in hepatic lesion concerning for dedifferentiated metastatic disease. In addition, echocardiogram showed reduced LV ejection fraction of 24% with global hypokinesis, and confirmed the LV thrombus. Cardiac MRI showed infiltrative nonischemic cardiomyopathy and mild dilation of left ventricle, as well as patchy delayed enhancement in the basal and inferoseptal walls suggestive of myocarditis. Treatment included rivaroxaban[FJ4], lisinopril, doxazosin, furosemide, and carvedilol. Several months after discharge, his EF improved to 48%. Hepatic lesions concerning for dediffertiated tumor vs unrelated malignancy was biopsied[FJ5] and consistent with neuroendocrine tumor. Future plan for his PPGL include revaluation for resection of retroperitoneal mass or DOTA Lutathera therapy. Conclusions: This case highlights a young man who was incidentally found to have metastatic paraganglioma with catecholamine-induced cardiomyopathy. The patient was asymptomatic until he developed significant heart failure. Cardiomyopathy in this setting is thought to be secondary to uncontrolled hypertension, as well as sympathetic overdrive from overstimulation of norepinephrine. We present the case to highlight the management challenges in a patient with PPGL with significant cardiovascular compromise and limited therapeutic options.
Simultaneous Occurrence of Germline Pathogenic Allele Variants of TMEM127 and TP53 in a Brazilian Family With Li-Fraumeni Syndrome
Authors: Lima Jose Viana , Scalissi Nilza Maria , Ricardo Gustavo Piech , Piech Mr Gustavo , Biscolla Rosa Paula Mello , Chiamolera Maria Izabel , Olivati Caroline , Baratela Wagner , Ferreira Elisa Napolitano , Kater Claudio E 
Published: May 2021

Abstract
Background: We will describe a Brazilian family whose index case had pheochromocytoma and in the evaluation of the genetic panel by Next Generation Sequence (NGS), the germline pathogenic variants in the TMEM127 and TP53 genes were identified. Clinical Case: A 32-year-old female patient with a clinical picture of paroxysms and difficult to control arterial hypertension, with a personal history of stroke and acute myocardial infarction. She had a 6.5 cm tumor in the right adrenal and urine metanephrine levels of 5.5 mg / g creatinine (VR &lt;1 mg / g creatinine) compatible with pheochromocytoma. She underwent laparoscopic right adrenalectomy. There was a reversal of arterial hypertension and paroxysms. 10 years after adrenalectomy, she was diagnosed with bilateral breast cancer, she underwent radical total mastectomy and 2 years ago there was a recurrence of breast cancer and currently undergoing chemotherapy. Germinative genetic panel carried out by NGS had identified pathogenic variants c.1010G&gt; A, p. (Arg337His) in heterozygosity in the TP53 gene and c.117_120del p. (Ile41Argfs * 39) in heterozygosis in the TMEM127 gene. Her 28-year-old daughter diagnosed bilateral breast cancer and meningeoma in the central nervous system and she had the same pathogenic variants germlines. Thus far, there is no clinical, laboratory or radiological picture of pheochromocytoma. Her 11-year-old granddaughter has only the pathogenic allele variant c.117_120del p. (Ile41Argfs * 39) in heterozygosity in the TMEM127 gene and thus far she has no clinical, laboratory and radiological picture of pheochromocytoma. Conclusion: This is the first case report of the simultaneous occurrence of pathogenic germline variants in the TMEM127 and TP53 genes. Reference: 11) Toledo RA et al Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary pheocromocytomas and paragangliomas. Nature Reviews Endocrinology 13, 233-247 (2017).
Development of a PTHrP Chemiluminescent Immunoassay to Assess Humoral Hypercalcemia of Malignancy
Authors: Ashrafzadeh-Kian Susan Louise , Bornhorst Joshua , Algeciras-Schimnich Alicia 
Published: May 2021

Abstract
Background: Measurement of parathyroid hormone related peptide (PTHrP) is helpful in the diagnosis and clinical management of patients suspected of humoral hypercalcemia of malignancy (HHM). In these patients uncontrolled release of PTHrP by tumor cells is responsible for the hypercalcemia and PTH concentrations are typically suppressed.
Objective: Develop a sensitive and specific assay for quantitation of PTHrP in plasma.
Method: Calibrators (PTHrP 1-86) and samples (50uL) were incubated with an anti-PTHrP goat polyclonal acridinium ester labeled antibody. Complexes were transferred and incubated in a microplate coated with an anti-PTHrP polyclonal rabbit antibody. After washing, the acridinium ester generated signal, which is directly proportional to the amount of PTHrP in sample, was quantified.
Results: In this assay PTHrp was stable for 24 hours ambient, 3 days refrigerated, 34 days frozen and through 3 freeze/thaws. Intra and inter-assay imprecision in EDTA plasma (~0.16-35.0 pmol/L) ranged from 2.2-8.6% and 5-15%, respectively. The limit of detection was 0.04 pmol/L and the limit of quantitation was 0.16 pmol/L (15% CV). The analytical measuring range was 0.39-50.5 pmol/L (slope of 1.07 and r2 of 0.99). Average spike recovery was 98% (range 85-108%). The assay was not affected by hemoglobin of ≤500 mg/dL, triglycerides of ≤2000 mg/dL, or bilirubin of ≤50mg/dL. No hook effect was noted up to 500 pmol/L. PTH (1-84) did not cross-react in the assay. C-terminal PTHrP(107-139), and N-terminal PTHrP(1-36) had no significant cross-reactivity (≤1.1%). Mid-PTHrP(38-94) had 8.3% cross-reactivity. Comparison with an in-house PTHrP assay (n=267) showed an r2 of 0.96, and slope of 2.25 by Passing-Bablok regression fit. The 97.5% reference interval for PTHrP (n=114) was ≤0.7 pmol/L, however a higher concentration (≤4.2 pmol/L) was identified as a more specific clinical cut-off. A retrospective clinical validation study showed that using ≤4.2 pmol/L resulted in a 91% clinical sensitivity and a 98% clinical specificity.
Conclusion: We have developed an analytically and clinically sensitive and specific PTHrP immunoassay. A cutoff of ≤4.2 pmol/L is clinically useful in the evaluation of patients suspected of hypercalcemia of malignancy.
Growth Hormone Receptor Inhibition Sensitizes Human Pancreatic Cancer to Chemotherapy Treatments
Authors: Basu Reetobrata , Kopchick John Joseph , Ortiz Silvana Duran , Qian Yanrong , Kulkarni Prateek 
Published: May 2021

Abstract
Human growth hormone (GH) and its cognate growth hormone receptor (GHR) have been established to have a distinct role in promoting the progression of several types of human cancers. We had earlier described a newfound role of the GH-GHR axis in driving chemoresistance in melanoma by upregulating drug efflux by ABC multidrug transporter expression and a phenotype switch by induction of epithelial-to-mesenchymal transition (EMT). Here we present an in-depth analysis of this role of GH-GHR in the highly therapy resistant human pancreatic cancer which has a 5-year survival rate of only 10% in 2020. Using human and mouse pancreatic cancer cells and RNA and protein expression analyses by RT-qPCR, ELISA, and western-blot, we identified that (i) GH upregulates specific ABC-transporter expressions in a drug-context specific manner, (ii) GH upregulates EMT transcription factors, (iii) GH activates specific oncogenic signaling pathways, and (iii) GH action increases cytochrome P450 members involved in hepatic drug metabolism. The GH antagonist, Pegvisomant, significantly inhibited these effects. Additionally, we confirmed the effects of these molecular changes by specific assays. For example, GH increases basement membrane invasion, viability of circulating tumor cells, and drug efflux; while inhibition of GHR by pegvisomant in pancreatic cancer cells reversed this aggressive tumor phenotype and sensitized the tumor cells to chemotherapy. Cell viability assays confirmed a decreased IC50 of gemcitabine, doxorubicin, and erlotinib in pancreatic cancer cells treated with pegvisomant and an increase in IC50 cells treated with GH. We further verified our results using in silico analyses of TCGA datasets for pancreatic cancer - which provided robust confirmation of our experimental findings. Presently we are validating our observation in nude mice with human pancreatic cancer cell xenografts. In conclusion, our in vitro results confirm that GHR antagonism can drastically sensitize human pancreatic cancer cells by blocking mechanisms of drug resistance, thus providing a valuable window for improved efficacy of available chemo- and targeted therapy.
A Case of Paraneoplastic Hypoglycemia From Squamous Cell Carcinoma of Undetermined Primary
Authors: Murati Jonila , Reddy Niyoti , Knapp Philip E , Alexanian Sara 
Published: May 2021

Abstract
Case: A 57 year old man with squamous cell carcinoma (SCC) of the tongue with complete response to chemoradiation was found unresponsive with a reading of “low” by a POC glucometer. He was treated with an IV dextrose bolus but had recurrent hypoglycemia requiring a continuous dextrose infusion. He was diagnosed with COVID-19 pneumonia, acute hepatitis (elevated liver enzymes), and acute kidney injury (elevated serum creatinine 1.2 mg/dL). Other labs: elevated TSH 8.44 uIU/mL, normal AM cortisol 16.4 ug/dl. A 5.1 cm mass was discovered in the left lung with bilateral nodules, biopsi revealed SCC of unclear origin (either lung or metastatic disease from prior tongue cancer). He was malnourished from prior cancer related dysphagia and nutritional supplements were added. Despite this and improvement in liver and kidney function, he had persistent hypoglycemia. He became hypoglycemic within 4-hrs while performing a 72-hr fast with labs: serum glucose 45 mg/dL, insulin &lt 2 uU/mL, c-peptide &lt 0.1 ng/mL, proinsulin &lt 4 pmol/L, beta hydroxybutyrate 0.17 mmol/L, IGF1 &lt 16 ng/mL (ref: 50 - 317), IGF2 147 ng/mL (ref: 267-616), negative hypoglycemia panel and insulin antibody. This was consistent with a paraneoplastic hypoglycemia known as non-islet cell tumor hypoglycemia (NICTH). To discontinue the dextrose infusion, he was started on prednisone 20 mg daily titrated up to 60 mg daily, intermittent tube feeds and palliative chemotherapy. With this, hypoglycemia improved, and the dextrose infusion was discontinued. Unfortunately, he had ischemic bowel perforation leading to cardiac arrest and death. Discussion: Our patient had NICTH as suggested by the 72-hr fast (non-insulin mediated hypoglycemia, IGF2/IG1 ratio &gt 10) and the presence of a tumor. It is mediated by tumor-produced IGF-2 causing increased glucose utilization, decreased gluconeogenesis, glycogenolysis and ketogenesis. Curiously, IGF-2 may not be elevated if the tumor produces a partially processed “big IGF-2” for which there is no commercial assay. Instead, an IGF2/IGF1 ratio close to or more 10 is indicative of NICTH. Mesenchymal and hepatic tumors are the most common cause of this rare entity with an incidence of one per million people years. A literature search showed very few reports of SCC-mediated-NICTH, with one case of esophageal SCC. Our patients’ primary tumor was undetermined (lung vs tongue) - but in either case this could be a novel association. A multidisciplinary approach is required centered around the tumor (surgery, chemotherapy, or radiation). High dose prednisone 30 to 60 mg daily can be used in the interim as it decreases IGF-2 but is not always successful. Recombinant hGH and glucagon are alternatives or can be combined with steroids. In summary IGF2/IGF1 ratio should be calculated, palliative tumor directed therapy should be initiated with prednisone and supplemental nutrition as adjuncts.
ACTH Producing Mediastinal Tumor - Multidisciplinary Approach
Authors: do Amaral Camila Lopes , Veras Victor Rezende , Araújo Jéssica Silveira , Amancio Samuel Aguiar , Da Rocha Duilio Reis , Alves Newton de Albuquerque , Alencar Renata Carvalho , Quidute Ana Rosa 
Published: May 2021

Abstract
Introduction: Ectopic ACTH syndrome is rare but is frequently a severe condition because of the intensity of the hypercortisolism. Patient management is complex and demands both strategies: the diagnosis and treatment of Cushing syndrome, and the specific management of neuroendocrine tumors. Therefore, management should be performed ideally by experienced endocrinology teams in collaboration with surgeons, oncologists, nuclear medicine, specialized hormonal laboratory and modern imaging platforms.
Clinical Case: Female patient, born in 2000, at the age of 15 was diagnosed with Cushing’s syndrome secondary to ACTH secretion by mediastinal tumor. At diagnosis, ACTH 1152pg/ml was found (reference value &lt;46pg/ml). Turkish seat resonance was normal, and chest tomography described a 4.5x3.6x3.8cm mediastinal lesion. Underwent a mediastinal surgical approach in 2015, with clinical and laboratory remission of hypercortisolism. The analysis of the lesion revealed a well-differentiated neuroendocrine carcinoma, with Ki67 5%. Progression of the mediastinal lesion was observed, without an exuberant clinic or laboratory, and a new surgery was performed in 2017, with a remaining macroscopic tumor, due to technical difficulties in resection due to contact with vascular structures. The immunohistochemistry of the resected lesion in this approach showed Ki67 30%, which reflects loss of differentiation. Octreoscan was performed, with no uptake. She evolved without exuberant Cushing’s syndrome until May 2019, when the clinical condition decompensated due to hypercortisolism, and was submitted to a new hospitalization. She was assisted by the thoracic surgery and oncology teams. From this moment a follow-up with endocrinology team started. Ketoconazole was introduced and PET-DOTATOC was requested. She underwent chemotherapy with Oxaliplatin and Capecitabine. In March 2020, DOTATOC uptake was checked and a somatostatin analogue was started. She showed considerable clinical and laboratory improvement. The patient remains clinically stable, with control of hypercortisolism using Ketoconazole 600mg daily and Octreotide 30mg every 28 days. The patient remains under clinical and laboratory surveillance. Awaiting PET-FDG. Mediastinal radiotherapy, lutetium, new mediastinal surgical approach, and bilateral adrenalectomy are also considered as possible therapeutic alternatives.
Clinical Lesson: The reported case shows a rare location of an ACTH-producing tumor, emphasizing the severity of the presentation, the evolution of tumor de-differentiation, the different results identified in octreoscan and PET-DOTATOC, and the importance of multidisciplinary management.
A Tale of Two Cities: Do They Have the Same Destination: Asymptomatic Pheochromocytomas: Biochemically Functioning vs Non Functioning
Authors: Paniagua Gabriela Zuniga , Vimarni Samarth , Broutin Dominique , Martinez Suzanne , Suryanarayanan Sowmya K 
Published: May 2021

Abstract
Background: Pheochromocytomas (PHEOs) are enterochromaffin tumors arising from the adrenal gland. Their diagnosis and preoperative preparation is crucial due to high morbidity and mortality rates with unrecognized, undiagnosed PHEOs. Case 1: 62-year-old male with a medical history of HCC, noted to have right adrenal adenoma measuring 1.7 x 1.6 cm. Denied any symptoms and normotensive on exam. A PET scan done showed a hypermetabolic right adrenal nodule concerning for malignancy. Serum metanephrines were 45 pg/ml (nl &lt;57 pg/ml) and total plasma metanephrines were 172 pg/ml (nl &lt;205 pg/ml). A CT guided biopsy was consistent with a PHEO. Other labs included: 24 hour urine metanephrines: 155 mcg (nl 90–315), total metanephrines: 520 (nl 224–832) and vanillylmandelic acid was 3.6 (nl &lt;6.0). 24-hour urine epinephrine: 10 mcg (nl 2–24), norepinephrine:57 mcg (nl 15–100) and dopamine: 421 (normal 52–480). Case 2: 55 year old male with UTI and flank discomfort, noted to have incidental 8cm Right adrenal mass noted concerning for malignancy. Also denied any symptoms and normotensive. Plasma fractionated metanephrines 938 (ref &lt;206), metanephrine 279,Normetanephrine 659(ref &lt;148), 24 hr urine metanephrines=1176mcg/24 hr (90–315), Normetanephrines 1487 (122–676), 24 hr urine total metanephrines 2663 (224–832). He is refusing α and β blockade due to normotension in preparation for surgery. Discussion: It is important to suspect, confirm, localize, treat, and PHEOs for several reasons. Most of these tumors hypersecrete catecholamines, and if untreated, cardiovascular morbidity and mortality are high. Another reason to encourage case detection is that, for familial disease, detection of a tumor in the proband may result in earlier diagnosis and treatment in other family members. Alpha-blockade is usually used prior to resection of Pheochromocytomas. However, the data available in the literature regarding alpha blockade for “truly asymptomatic” functioning or non functioning Pheochromocytomas is scarce. However what is unique to our cases is that they both are normotensive and asymptomatic and refusing preoperative preparation. Conclusion: Asymptomatic PHEO are becoming more common presentation given Pheochromocytomas are rare. Are the genetics and biochemical nature any different than classic pheos? Are we supposed to manage them the same way? Would we rethink current guidelines for managing normotensive or nonfunctioning pheochromocytomas pre operatively? We also would like guidelines on how to prepare such truly asymptomatic patients prior to surgery. We refer to Endocrine Society guidelines for management of such tumors.