bluuebunny/crossref_metadata_2025 huggingface dataset:
Severe Thyrotoxicosis Following Topical Iodine Application
Authors: Coyne Kasey , Papagiannis Ioannis G
Published: May 2021

Background: Exposure to iodine can lead to iodine-induced hyperthyroidism in patients with underlying thyroid disease. Clinical Case: A 67 year-old woman with a history of nontoxic multinodular goiter and atrial fibrillation presented with fatigue, palpitations, weight loss, and tremor. Laboratory evaluation demonstrated new-onset profound biochemical hyperthyroidism (FT4 > 7.77 ng/dL, n 0.8 – 1.8 ng/dL; FT3 >27.0 pg/mL, n 2.0-4.4 pg/mL). She was treated with beta-blocker, high doses of methimazole, and cholestyramine while further evaluation was pursued. She declined SSKI due to reported iodine allergy and steroids due to concerns about impact on wound healing following recent hip arthroplasty. TSI and TRAb were negative, and thyroid ultrasound showed stable nodules at 1.7cm. Pelvic ultrasound and MRI were obtained due to concern for non-thyroidal etiology, and revealed a 3.7cm septated cystic ovarian lesion, raising suspicion for struma ovarii. Whole body scan to localize site of thyroid hormone production could not be obtained due to high risk of clinical deterioration off methimazole, as she had persistent clinical and biochemical thyrotoxicosis on high doses (up to 90mg/day). She ultimately required 3 sessions of plasma exchange to lower her thyroid hormone levels, and then underwent bilateral salpingo-oophorectomy. Final pathology revealed mucinous cystadenoma without ectopic thyroid tissue. Post-operatively, her thyroid hormone levels were persistently elevated but improved compared to pre-operative levels, allowing for brief cessation of methimazole and completion of whole body scan. Imaging demonstrated a single focus of radioactive iodine uptake in the lower right thyroid lobe, correlating with the dominant 1.7 cm nodule on prior ultrasound, consistent with a toxic adenoma. Additionally, she was found to have an elevated urine iodine level (1200 mcg/24 hours, n 75 – 851 mcg/24 hours). Patient endorsed low iodine diet due to allergy history, and denied recent contrasted imaging study, dietary supplements, or amiodarone use. Upon further inquiry, she recalled using povidone-iodine solution to care for her surgical site post-arthroplasty, approximately a week before the onset of her initial symptoms. Her clinical presentation was ultimately attributed to toxic adenoma, with severe thyrotoxicosis exacerbated by iodine load. She underwent total thyroidectomy and is doing well on levothyroxine post-operatively. Conclusions: Topical iodine administration can contribute to iodine-induced hyperthyroidism in patients with underlying thyroid disease, and its use should be carefully considered in these patients. When evaluating a patient with new thyrotoxicosis, a detailed history of oral, IV, and topical iodine use should be obtained.
Stress Cardiomyopathy Due to Exogenous Thyrotoxicosis From T3 Supplementation
Authors: Shaw Kirsten E , Jamrozy Anya
Published: May 2021

Background: Wilson’s Temperature Syndrome (WTS) refers to a constellation of nonspecific symptoms, some of which include a low-normal body temperature, headaches, and fatigue. WTS was rejected by the American Thyroid Association as a valid medical diagnosis in 2005. Originally proposed in 1990 by Dr. E Denis Wilson, the etiology was theorized to be an impaired ability to convert T4 to T3, although this was not corroborated in thyroid lab abnormalities. Despite being publicly rebuffed as a true medical diagnosis, WTS has continued to gain traction amongst certain alternative medical groups and is treated with T3 supplementation. The development of a stress cardiomyopathy due to T3 supplementation is rare. Extrapolating from endogenous thyroid mediated stress cardiomyopathy and T4 supplementation induced stress cardiomyopathy, the pathophysiologic mechanism is likely excessive sympathetic activation.

Clinical Case: A 58-year old female with no prior cardiac history presented to the emergency department with chest pain. Physical exam revealed a euvolemic appearing women, with intact and symmetric distal pulses, and a normal cardiac exam without murmurs or other abnormal heart sounds. There were no abnormal lung sounds. Her O2 sats were normal on room air. EKG and CXR were unremarkable. Her troponin was elevated (3.7 ng/mL, n< 0.034 ng/mL) and her BNP was elevated (4,568 pg/mL, n< 150 pg/mL). The patient was given aspirin and started on therapeutic heparin given concern for NSTEMI. Echocardiogram revealed an ejection fraction of 30% with hypokinesis of the entire apex and mid ventricle, raising concern for a stress cardiomyopathy.

Coronary angiogram was performed which demonstrated no coronary artery disease. The patient underwent a cardiac MRI which confirmed a stress cardiomyopathy. Meanwhile, her laboratory workup was completed which revealed an undetectable TSH, a low T4 (0.53 ng/dL, n 0.7-1.8 ng/dL), and an elevated T3 (6.37 pg/mL, n 1.71-3.71 pg/mL). Patient endorsed taking oral liothyronine (T3) at doses of 5-40 mcg BID over the past 6 weeks per her alternative medicine provider for treatment of WTS. Her stress cardiomyopathy was presumed to be due to her exogenous thyrotoxicosis from T3 supplementation. She was counseled on the importance of cessation of T3 supplementation, and was started on heart failure medications. On hospital day 3, her T3 normalized to 2.73 pg/mL, and T4 remained low (0.4 pg/mL). Follow-up echocardiogram four months later demonstrated an ejection fraction that had improved to 45%.

Conclusion: This case highlights the importance of physician awareness of alternative medicine diagnoses and treatment regimens that affect thyroid hormones and may cause harm to patients. This case is an important reminder of the effect thyroid hormones have on coronary vasculature, myocytes and myocardial function.
The Thionamide Paradox: Thyrotoxicosis With Neutropenia as Initial Presentation of Grave’s Disease
Authors: Celis Valentina , Manzano Alex
Published: May 2021

Hyperthyroidism typically presents with symptoms such as tremors, palpitations, weight loss, heat intolerance and anxiety. Although rare, anemia, leukopenia or thrombocytopenia may develop as an unusual manifestation of thyrotoxicosis. Hematologic derangements have been reported as a side effect of antithyroid drugs (ATD) as well, and while ATD associated agranulocytosis is uncommon, it is a life-threatening condition.

A 49-year-old Hispanic female with history of iron deficiency anemia came to the emergency department (ED) with a chief complaint of palpitations. Also reported fatigue, myalgias, headache and anxiety of 1 week duration. Upon​ arrival to the ED she was tachycardic, appeared anxious and diaphoretic. Physical examination revealed a very discrete, non-tender goiter. Bloodwork showed hemoglobin 9.1 g/dL (12.0-16.0), WBC 2.30 c/µ​L (4.8-10.8),​ ANC 1.04 c/µ​L​ (1.80-7.20), ALC 0.88 c/µ​L​ (1.20-4.0), PLT 209 c/µ​L​ (150-450). TFTs were pertinent for TSH 0.007 UIU/mL (0.35-3.74), free T4 5.11 ng/dL (0.76-1.46) and total T3 555 ng/dL (60-181). She received initial treatment with hydrocortisone 300 mg and PTU 300 mg. She was admitted and started on propranolol 40 mg TID and prednisone 20 mg daily, but further doses of ATD were initially held due to concerns for her marked leukopenia. She subsequently became acutely psychotic with psychomotor agitation, visual and auditory hallucinations. CT of the brain revealed no acute abnormalities. She was started on olanzapine 2.5 mg daily for hyperthyroidism induced psychosis, along with methimazole 20 mg daily, KI (Lugol solution) 0.35 mL BID and cholestyramine 4g BID. Further workup of leukopenia showed no dysplastic​ cells on​ peripheral smear, normal vitamin B12 and folate levels, and negative HIV. She displayed marked improvement, denied ongoing hallucinations after 72 hours of initiating ATD, and WBC subsequently normalized. Thyroid workup was diagnostic for GD with positive TRAB and TSI. She was discharged in stable condition on methimazole 40 mg daily.

Agranulocytosis is a rare side effect of ATD (prevalence ~0.5%) and average time of onset is usually within 2-3 months after starting therapy. Although the majority of cases of hematologic alterations in GD are seen as a complication of ATD, our patient presented with the peculiarity that leukopenia (with both neutropenia and lymphopenia) was associated to untreated hyperthyroidism. This case illustrates the fact that in patients presenting with hyperthyroidism and leukopenia, treatment with ATD has proven to result in achievement of euthyroid state along with a sustained improvement in blood cell levels. Despite its rarity, agranulocytosis has become essentially ingrained to ATD amongst medical professionals. Clinicians should be aware that neutropenia is an uncommon feature of uncontrolled hyperthyroidism and feel confident with initiating ATD in this setting.
Thyroid Abscess After FNA Biopsy: A Case Report
Authors: Purdy Nicholas , Jodie Reider , Kevin Stavrides
Published: May 2021

Introduction: FNA biopsy of thyroid nodules is a common bedside procedure that rarely causes serious complications. Thyroid abscess is a rare complication of FNA that requires prompt diagnosis and treatment. We present a case of a thyroid abscess occurring 4 weeks after FNA in a 46 year old female, treated successfully with surgery.

Clinical Case: A 46 year old woman with history of acne presented with dysphagia, right sided neck pain and swelling 4 weeks after FNA of a 4.8cm right thyroid nodule with benign cytology. On physical examination, the right thyroid lobe appeared larger and was tender to palpation. The patient was afebrile. Laboratory evaluation was significant for acutely low TSH 0.06 uIU/mL [0.50 - 6.00 uIU/mL], thrombocytosis 547 K/uL [140 - 400 K/uL] and marked elevated sedimentation rate 98 mm/hr [0 - 20mm/hr]. Interestingly, she had a normal leukocyte count of 9.8 K/uL [4.00 - 10.80 K/uL]. US imaging showed acute increase in size of the right thyroid nodule to 7.6cm. CT neck confirmed a large, partially cystic right thyroid mass and further showed mass effect on surrounding structures and mild stranding in the subcutaneous fat. The patient elected for surgical treatment rather than repeat FNA with drainage of fluid components. Right thyroid lobectomy was planned but converted to surgical abscess drainage with subtotal thyroidectomy due to intense inflammatory changes in the neck. A large amount of purulent material was drained and sent for cultures, which grew multiple Staphylococcus species and Propionibacterium acnes. Surgical pathology showed granulation and connective tissue including skeletal muscle tissue with marked active chronic inflammation, micro abscess formation, few multinucleated giant cells, and fibrosis. Following surgery, TSH normalized, and the patient reported immediate improvement in symptoms of neck fullness, pain, and dysphagia. She was discharged home on post operative day one with a two week course of oral Augmentin 875mg twice daily. 6 weeks post operatively the patient remains symptom free in her usual state of health.

Conclusion: Thyroid abscess following FNA is a rare occurrence with few reported cases in the literature. Because of its rarity, diagnosis and treatment may be delayed, resulting in a life-threatening emergency. Both repeat needle aspirations and surgical management, combined with culture directed antibiotics, are acceptable methods for treatment. Immunocompromise, not present in our patient, is the main risk factor reported for thyroid abscess. Propionibacterium and Staphylococcus commonly cause acne, which may have increased our patient’s risk of infection. Our case highlights the importance of maintaining a high level of clinical suspicion for abscess in patients who develop neck pain and swelling following FNA, even in the absence of significant risk factors, in order to facilitate prompt diagnosis and treatment.
Transient Thyrotoxicosis in Molar Pregnancy
Authors: Jancuska Ashley , Hendrickson Chase Dean , Rhee Chanhaeng
Published: May 2021

Introduction: Thyroid function abnormalities commonly occur in pregnancy. Due to the structural homology between beta-human chorionic gonadotropin (beta-hCG) and thyrotropin (TSH), some of these changes may be physiologic, while others can be from pathologic causes. Molar pregnancies represent a unique etiology, as beta-hCG levels are often markedly elevated due to trophoblastic hyperplasia and can cause hyperthyroidism. Case Description: A 20-year-old pregnant female presented at 18 weeks estimated gestational age for persistent nausea and vomiting, which had worsened over the past one to two weeks. She also noted palpitations and heat intolerance. On initial presentation, her heart rate was 145 beats per minute, blood pressure was 135/86 mmHg, oxygen saturation was 98% on room air, and temperature was 98.3 F. Exam was notable for sinus tachycardia; no thyromegaly, palpable thyroid nodules, lower extremity edema, or tremors were appreciated. Transvaginal ultrasound was performed, and an approximately 17-week fetus with no cardiac activity was identified; an enlarged and hydropic placenta and bilateral theca lutein cysts were also seen on imaging, concerning for a partial molar pregnancy. Laboratory data revealed plasma beta-hCG >1,000,000 mIU/mL. Due to her symptoms and tachycardia that were refractory to intravenous hydration, thyroid function tests (TFTs) were assessed: TSH of 0.01 uIU/mL and free T4 (FT4) 6.85 ng/dL. She was started on methimazole and beta blockade in the pre-operative period. She received mifepristone and underwent dilatation and evacuation. Histopathology was consistent with a partial mole, given the presence of fetal somatic differentiation. Beta-hCG and FT4 levels rapidly trended down in the post-operative setting, and methimazole was discontinued. Levels were monitored closely after discharge. Atenolol was stopped when her TFTs normalized. Approximately six weeks after surgery, her TSH was 0.523 uIU/mL and FT4 was 0.70 ng/dL. Three months after surgery, the beta-hCG level had decreased to 4 mIU/mL. Discussion: In North America, the incidence of hydatidiform moles is approximately 100 per 100,000 pregnancies. Hydatidiform moles compromise two distinct entities: complete moles and partial moles, which are distinguishable based on karyotype and histopathological features. In molar pregnancies, the trophoblastic tissues, which produce hCG, are hyperplastic; thus, markedly elevated hCG levels can be seen. Due to its structural similarity to TSH, beta-hCG can activate TSH receptors and drive production of thyroid hormone, which can subsequently result in a thyrotoxic state. Surgical management of the mole is key, as the hyperthyroidism usually resolves with uterine evacuation, though hCG levels must be monitored closely afterwards to ensure gestational trophoblastic neoplasia does not develop.
The Prevalence of Tertiary Adrenal Insufficiency in Patients Receiving Topical Glucocorticoid Treatment for Oral Lichen Planus
Authors: Einarsdottir Margret J , Bankvall Maria , Robledo-Sierra Jairo , Rödström Per-Olof , Trimpou Penelope , Johannsson Gudmundur , Hasséus Bengt , Ragnarsson Oskar
Published: May 2021

Objective: Glucocorticoid (GC) treatment suppress the hypothalamic-pituitary-adrenal axis, which may lead to tertiary adrenal insufficiency. This study aimed to investigate the prevalence of tertiary adrenal insufficiency among patients with oral lichen planus treated with topical GC (clobetasol propionate) in the oral cavity, a standard treatment option for this condition.

Methods: In this cross-sectional study, we included 24 patients with oral lichen planus receiving long-term (> 6 weeks) clobetasol propionate treatment. Adrenal function was assessed by measuring serum cortisol between 8–9 AM, after a withdrawal of treatment for 48 hours. For patients with serum cortisol concentrations below 280 nmol/L (10 µg/dL), a 250 µg corticotropin stimulation test was performed.

Results: Twenty patients had normal serum cortisol concentrations (range 280–621 nmol/L), whereas four patients had low serum cortisol concentrations (13, 45, 63, and 229 nmol/L, respectively). A corticotropin stimulation test revealed partial adrenal insufficiency in two patients (serum cortisol peak level 350 nmol/L and 360 nmol/L) and severe adrenal insufficiency in another two patients (serum cortisol peak level 150 nmol/L and 210 nmol/L).

Conclusion: In this small study, approximately 20% of patients receiving chronic topical GCs treatment for oral lichen planus had tertiary adrenal insufficiency. It is essential to be aware of this potential risk and to inform patients about the need for GC stress-doses during an intercurrent illness episode.
Urine Proteomic Analysis of Differences Between Patients With Hyperthyroidism Before and After Carbimazole Treatment
Authors: Masood Afshan
Published: May 2021

Background: Hyperthyroidism, characterised by increased circulating thyroid hormone (TH) levels, alters the body’s metabolic and systemic haemodynamic balance and directly influences renal function However, the underlying mechanisms and metabolic implications of these changes are not well understood. Objective: In the present study we aimed to study the changes occurring in the urinary proteome of patients with hyperthyroidism before and after treatment. The levels of the excreted proteins in the urine were studied using an untargeted 2D DIGE MALDI TOF proteomic approach with network analysis. Methods: The study included 9 age matched patients with mean age 38.6 ± 12.1 years with newly diagnosed hyperthyroidism. The patients were evaluated at baseline and after receiving treatment with carbimazole. Urine samples were obtained from the same patient at baseline (hyperthyroid state) with serum FT4 levels of 35.4 + 9.9 pmol/L and TSH 0.014 + 0.014 mIU/L (mean + SD), and post treatment with anti-thyroid drugs (euthyroid state) with levels of FT4 17.0 + 2.8 pmol/L and TSH 0.6 + 0.5 mIU/L (mean + SD).

Results: Alterations in the abundance of urinary proteins, analyzed by Progenesis software, revealed statistically significant differential abundance in a total of 40 spots corresponding to 33 proteins, 26 up and 7 down (≥1.5-fold change, ANOVA, p ≤ 0.05). The proteins identified in the study are known to regulate processes related to cellular metabolism, transport, acute phase response. The urinary proteins upregulated with hyperthyroidism included serotransferrin, transthyretin, serum albumin, ceruloplasmin, α1B glycoprotein, syntenin-1, nesprin, and glutamilnyl peptide cyclotransferase while the 3 notable down regulated proteins were plasma kallikrein, protein glutamine gamma-glutamyl transferase and serpin B3. Bioinformatic analysis using Ingenuity Pathway Analysis (IPA) identified dysregulation of pathways related to cellular compromise, inflammatory response, cellular assembly and organization and identified the involvement of the APP and AKT signaling pathways via their interactions with interleukins as the central nodes. Conclusion: The urine proteomic profiling between the hyperthyroid and euthyroid states demonstrates alteration in the protein levels involved in acute phase response and in maintaining an individual’s haemodynamic state.
A Case of Renal Cell Carcinoma and Pheochromocytoma Due to Germline Inactivating Mutation in Fumarate Hydratase (FH)
Authors: Reda Sarah Alicia , Japp Emily A , Si Qiusheng , Badani Ketan , Levine Alice C
Published: May 2021

A 60-year-old female with a history of well-controlled hypertension, prediabetes, status post hysterectomy for fibroids, presented for evaluation of hematuria and unintentional weight loss. She denied palpitations, headaches, tremors, and diaphoresis. Initial CT demonstrated a right renal mass suspicious for renal cell carcinoma and an adrenal mass. Magnetic resonance imaging (MRI) confirmed a hypervascular, right adrenal mass (6.7 x 6 x 5 cm) without loss of signal.

Laboratory Testing: elevated 24-hour urine vanillylmandelic acid (VMA) 17.5 mg/24 h (<6), and urine normetanephrines 2276 ug/24 h (122-676) with normal urine metanephrines 158 ug/24 h (90-315). 24-hour urine free cortisol was normal. The patient underwent a right adrenalectomy and partial nephrectomy. Pathology confirmed a low-grade renal cell carcinoma (RCC) and a 6.8 cm pheochromocytoma (PCC). Genetic analysis revealed an inherited mutation in the fumarate hydratase (FH) gene, which is diagnostic of hereditary leiomyomatosis and renal cell cancer (HLRCC). Wildtype FH codes for an enzyme that converts fumarate to malate in the mitochondrial Krebs cycle. Inactivating mutations in FH trigger the hypoxia pathway by activating hypoxia-inducible factor (HIF) thereby promoting tumor growth and angiogenesis.

In PCC, 30-40% are hereditary and another 40-50% are found to have somatic mutations in 1 of 20 PCC susceptibility genes. Several autosomal dominant heritable syndromes, including Neurofibromatosis type 1 (NF-1), von Hippel-Lindau (VHL), Multiple Endocrine Neoplasia Type 2 (MEN 2), and Paraganglioma Syndromes Types 1–5, have an increased incidence of PCC, most of which modulate hypoxia pathways. FH mutations are similarly inherited in an autosomal dominant fashion and cause HLRCC.

HLRCC is associated with 75-80% risk for cutaneous and uterine leiomyomas, and a 10-16% risk for type II papillary renal cell carcinoma. The risk of RCC in patients with FH mutations is much greater than in the general population, where the prevalence is ~2% in those who lack the mutation. In one study, FH deficiencies attribute between 19-41% of all RCC cases. Rare families with PGL/PCC have also been found to carry this germline FH mutation. This FH mutation is associated with increased risk of metastasis in patients with PGL/PCC by a similar mechanism of carcinogenesis via the hypoxia pathway. Currently, there are no strict guidelines for surveillance in individuals with HLRCC, however, patients should have a yearly abdominal MRI, skin examination every 2 years, and an annual gynecological evaluation for leiomyosarcoma. Each first-degree relative should be offered genetic testing of the FH mutation, as 50% of relatives may carry the gene. This case underscores the importance of genetic workups in patients with PCC, especially if associated with other tumors.
Hypercalcemia in Pheochromocytoma: From MEN to VHL
Authors: Mittal Madhukar , Gupta Parul , Chaudhary Gautam R , Garg Mahendra K
Published: May 2021

Background: Co-occurrence of phaeochromocytoma and primary hyperparathyroidism is usually seen in patients of Multiple Endocrine neoplasia 2A(MEN2A) and is rare in Von Hippel Lindau disease (VHL). Parathyroid adenoma with pheochromocytoma in a genetically confirmed VHL has been reported only once till date (1). Clinical Case: A 30-year male was admitted for evaluation of hypertension and incidentally diagnosed adrenal mass on ultrasound. 9-years back, he was diagnosed as a case of VHL (right renal clear cell carcinoma, pancreatic cystadenoma, spinal hemangioblastoma and epididymal cysts). Right nephrectomy and pancreatic cyst excision had been done and past work-up for pheochromocytoma was normal. He also had been operated twice for recurrent renal calculi. Family history revealed surgery in mother for pancreatic mass. Current imaging revealed right adrenal mass (4.7*4.6 cm) with left renal cysts and calculi, pancreatic cysts and spinal- medullary hemangioblastoma and epididymal cysts. Fundus examination was normal. 24-hours urinary fractionated normetanephrines were elevated (2062 mcg/24 hours) and I131MIBG scan showed 4.7*4.6cm concentrating lesion in right renal fossa suggestive of right adrenal pheochromocytoma. However his biochemical evaluation revealed hypercalcemia (12.1 mg/dl), low phosphorus (3.2 mg/dl), low 25(OH) D (24.84 nmol/l), and raised PTH (121pg/ml). Ultrasound neck and Tc99m-Sestamibi localized left inferior parathyroid adenoma. DEXA scan showed severe osteoporosis. Genetic analysis confirmed VHL mutation in exon-1. Calcitonin and RET mutation were normal (ruled out MEN2A). Therapeutic approach was surgical excision of adrenal pheochromocytoma followed by parathyroidectomy. We report a case of pheochromocytoma with primary hyperparathyroidism (cause: left inferior parathyroid adenoma) in a patient of VHL (Renal clear cell carcinoma, pancreatic cystadenoma, epidydymal cysts and medullary and spinal hemangioblastoma). Hypercalcemia seen in patients of VHL is either due to bone metastasis/PTHrP/IL-6 secretion from RCC or due to PTHrP/PTH/calcitonin secretion from pheochromocytoma and rarely due to associated parathyroid adenoma. Literature search revealed four case reports of parathyroid adenoma with VHL. In only one of these, VHL had pheochromocytoma associated with parathyroid adenoma (1). Conclusion: Ours is the 2nd such case reported in literature of primary hyperparathyroidism in a genetically confirmed case of VHL with pheochromocytoma. This case highlights the overlap of tumorigenesis in two rare genetically divergent syndromes and importance of long-term follow-up for sequential development of new tumors. Reference: Arao T, Okada Yet al. A case of VHL disease with bilateral pheochromocytoma, renal cell carcinoma, pelvic tumor, spinal hemangioblastoma and primary hyperparathyroidism. Endocr J. 2002 Apr;49(2):181–8.
Metastatic Insulinoma Presenting After Bariatric Surgery in a Patient Subsequently Diagnosed With MEN 1
Authors: Poku Caroline A , Samarasinghe Shanika Prajani
Published: May 2021

Background: Hypoglycemia is a recognized complication of bariatric procedures due to changes in the gut hormonal milieu. Possible causes of hypoglycemia include dumping syndrome, nesidioblastosis and rarely insulinoma. MEN1 is a heritable disorder characterized by the occurrence of parathyroid, anterior pituitary and pancreatic islet cell tumors. Clinical Case: A 48 yo female with HTN, depression, PCOS, primary hyperparathyroidism s/p 3.5 gland parathyroidectomy 2008, facial angiofibroma 2011, obesity s/p gastric sleeve 2018, and a history of DMT2 presented with frequent episodes of hypoglycemia. DMT2 was diagnosed in 2003, but all DM drugs were withdrawn shortly after sleeve gastrectomy. One year after surgery, she started to develop primarily fasting hypoglycemia in the 40-50 mg/dl range confirmed on CGM. Symptoms included perioral numbness, diaphoresis and confusion which resolved with glucose tablets. She reported a 7 kg weight regain due to eating every 2 hours to minimize episodes but symptoms progressed. Family history was significant for HTN and DM. A 72 hour fast confirmed hyperinsulinemia with symptomatic hypoglycemia at a serum glucose of 37 mg/dl, a suppressed ß-hydroxybutyrate of 0.6 mmol/L, elevated proinsulin 7.7 ρmol/L and inappropriate normal c-peptide 0.8 ng/mL. The oral hypoglycemic panel was negative. A pancreatic protocol CT revealed a 1.2 cm heterogeneous arterial enhancing lesion in the body of pancreas, a 0.6 cm focus in the tail of pancreas, a 1.6 cm enhancing lesion in the liver and a 1.4 cm abdominal wall mass. Genetic testing was positive for MEN-1 and additional biochemical evaluation including VIP, gastrin and glucagon was negative. A pituitary MRI was unremarkable. She underwent an ex-lap, partial hepatectomy, distal pancreatectomy, splenectomy, and resection of the duodenal mass. The pancreas had multiple NETs, largest was 1.6 cm and stained positive for insulin. The liver mass demonstrated a metastatic well differentiated NET. The 1.7 cm duodenal mass was consistent with a leiomyoma. All surgical margins were negative, but focal lymphovascular and perineural invasion was identified with negative lymph nodes (0/27). She was diagnosed with a metastatic insulinoma with histopathology revealing a well differentiated neuroendocrine tumor G1, <1mitosis/2mm2, Ki-67 less than 3%, stage pT1N0M1. Hypoglycemia resolved post-operatively. Conclusion: Hypoglycemia predominantly in the fasting state, worsening shortly after bariatric surgery, or refractory to dietary or medical management should be further evaluated to exclude insulinoma. Given her medical history, there was concern for MEN-1, thus prompting genetic testing. Unlike with sporadic cases, there is a higher rate of recurrence with MEN-1 associated insulinoma. Highly unusual is also the finding of metastatic disease, occurring only in 4- 14% of all insulinoma cases.
Use Of Temozolomide In Parathyroid Carcinoma With Negative Mgmt Promoter Methylation
Authors: Reddy Niyoti , Dima Danai , Kuri Danica Maria Vodopivec , McAneny David , Kulke Matthew , Lee Stephanie L
Published: May 2021

Introduction: Parathyroid carcinoma (PC) is a rare malignancy with a high rate of recurrence and metastasis. Case: A 63-year-old man with a 13-year history of recurrent PC requiring 5 operations, including parathyroidectomies, thyroidectomy, and neck dissections presented with polyuria, polydipsia, and worsening rib pain. He had been recently treated with 6 monthly octreotide injections and maximal dose cinacalcet for gradually rising Ca/PTH levels. Tests revealed serum Ca 13.1mg/dL (8-10.5mg/dL), PTH 1750pg/mL (11-90 pg/mL), and serum Cr 3.34mg/dL (0.5-1.3mg/dL). Imaging identified tumor in the right 6th rib (3.6cm lytic lesion), and soft tissue lesions in the left thyroid bed (3 masses, the largest 1.6cm) and the suprasternal notch (1.1cm). He underwent rib resection (metastasectomy) and PTH declined from 2334pg/mL to 671pg/mL. Although metastasectomy improved the PTH level, Ca levels began to rise from the residual tumor. A multidisciplinary team deemed the risk of complications from repeat neck surgery to be prohibitively high. Temozolomide (TEM) (150-200mg/m2/d x 5d, q28d) was instituted 3 months after the rib resection. 13 months later, PTH has stably ranged from 600-800 pg/mL with a normal serum Ca of 9.8mg/dL. Recent imaging shows stable disease in the neck, without distant disease. Discussion: The mainstay of therapy for initial and recurrent/metastatic PC is surgery. Inoperable disease has a poor prognosis because of lack of effective systemic therapies. Radiation and chemotherapy have not shown much efficacy. Results of treatment with octreotide have not been encouraging. Anti-PTH immunotherapy and Lutathera are promising but require further investigation. Usually, no targetable mutation is found. Anti-angiogenic TKI’s (sorafenib, lenvatinib) have been used with varying success. An exciting therapy used in this patient is TEM, an alkylating agent used for CNS tumors, neuroendocrine tumors (NET) and aggressive pituitary tumors. A previous report described successful use of TEM in a case of metastatic PC, whose tumor harbored high O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, a known predictor of positive response in CNS tumors. Promoter methylation is an epigenetic alteration that leads to low MGMT enzyme activity & enhances the cytotoxicity of TEM. Some studies in NET demonstrated tumor response irrespective of MGMT status. This leads to the question of whether the same is true in PC. Our patient has radiographic/biochemical stable disease on TEM, and a surprising retrospective discovery was that the MGMT promoter was unmethylated. This is a unique case of PC which seems to be responding to TEM despite absent promoter methylation. Further studies are warranted, as the incidence of PC is rising over the past decades. In the interim, clinicians could consider using TEM for in-operable PC irrespective of MGMT methylation status.
Well-Differentiated Malignant Neuroendocrine Cell Tumor Originating From the Jejunum With Excessive Insulin Secretion
Authors: Ahmed Haris , Vu Alan , Alam Junaid , Ogar Bonny , Lines Barbara
Published: May 2021

Background: Insulinomas are rare, well-differentiated insulin-secreting neuroendocrine tumors of the pancreas. Insulin-secreting, extra-pancreatic tumors have rarely been reported in the literature. We present a case of a well-differentiated neuroendocrine tumor with clinical, laboratory, and immunohistochemical tumor findings supportive of ectopic insulin production in a non-pancreatic neuroendocrine tumor of the small bowel.

Clinical Case: A 70 year-old female with past medical history of end stage renal disease, Type II diabetes mellitus, and hypertension presented to our facility with multiple episodes of dizziness and syncope due to hypoglycemia. She had initially managed her diabetes with metformin but stopped taking the medication due to increasingly frequent episodes of hypoglycemia. Significant labs during the hospitalization include blood glucose <20 mg/dL, insulin 75.9 IU/mL (2.6-21.9 IU/mL) and C-peptide 57.7 ng/mL (1.1-4.4 ng/mL). Her symptoms persisted despite dextrose supplementation. Abdominal and Pelvic CT showed proximal small bowel obstruction and sclerosing mesenteritis with a calcified lymph node but no pancreatic mass. A diagnostic laparoscopy was performed, showing 18 inches of small bowel with malignant appearing masses that were adherent to the mesentery. A 21.0 cm segment of jejunum was resected. There were at least 30, variably sized masses throughout the bowel, involving the mucosa, submucosa, muscularis propria and subserosal fat; along with lymphatic, venous, and perineural space tumor permeation, and metastases involving multiple regional lymph nodes. The tumors ranged in size from 0.5 up to 1.5 cm. They showed well-differentiated nuclear morphology, a mitotic count of 0 per 80 high power fields, and a Ki-67 proliferation index of 1%, indicative of a G1 NET. Immunohistochemical stains confirmed neuroendocrine differentiation with positive staining for chromogranin, synaptophysin, and INSM1 (insulinoma-associated protein 1) transcription factor, while insulin staining was negative. The patient was diagnosed with a pT3N1, G1, ectopic insulin-secreting neuroendocrine tumor of small bowel origin. She was started on diazoxide with significant improvement in her hypoglycemia.

Conclusion: Insulin production by non-pancreatic tumors is extremely rare. Clinical, laboratory, and immunohistochemical tumor findings in this case support ectopic insulin production by a well-differentiated neuroendocrine tumor of small bowel origin.
Effect of Conventional Chemotherapy in Patients With Neuroendocrine Tumours: A Systematic Review
Authors: Divanovic Anida , Druce Maralyn Rose
Published: May 2021

Background: Neuroendocrine tumours (NETs) are a wide-ranging group of neoplasms originating from neuroendocrine cells. In 2014 NETs incidence was 7 per 100000 people annually. The purpose of this systematic review is to evaluate the safety and efficacy of various types of chemotherapeutic agents on gastroenteropancreatic NETs (GEP NETs) and to determine which type of chemotherapy is the most effective for different tumour types, with minimum adverse events. To our knowledge, this study is the first systematic review that compares several types of chemotherapy and evaluates their safety and efficacy on GEP NETs. Methods: The study followed recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines on reporting systematic reviews. The literature search for this systematic review was conducted using the following databases and search engines: Cochrane library, EMBASE, Google Scholar, PubMed, and Web of Science, from 1963 to 2020. Results: The review comprised 26 observational studies, and 5 randomized controlled trials (RCTs). The total number of subjects included in this study was 1783. Our study showed that the most effective treatment for Grade 3 NETs and Grade 3 neuroendocrine carcinomas was cisplatin/etoposide. Furthermore, capecitabin/temozolomide therapy has been shown to be most effective in Grade 1 and Grade 2 NETs. Conclusion: Therapy with two chemotherapeutic agents has been shown to be more effective than monotherapy and therapy with three chemotherapeutic agents. Unfortunately, our study has limitations and we urgently need RCTs or larger observational studies that will contain all the necessary efficacy and safety tools, and thus provide answers to our clinical questions.
Effects of Growth Hormone in Human Melanoma Drug Resistance
Authors: Arora Pranay , Basu Reetobrata , Kopchick John Joseph
Published: May 2021

Melanoma, an extremely drug resistant form of cancer, displays elevated levels of growth hormone (GH) and growth hormone receptor (GHR) expression. We have described a GH dependent mechanism of chemoresistance in melanoma through a series of earlier studies. In GHR overexpressing human melanoma, GH action drives active drug efflux and phenotype switching by upregulating ATP-binding cassette transporters (ABC-transporters) and epithelial-to-mesenchymal transition (EMT) markers. Inhibition of GHR activation reverses these effects, increases drug retention, and sensitizes the melanoma cells to chemotherapy. GH action in melanoma also appears to drive drug sequestration in melanosomes as we present here. GH action was found to modulate the levels of melanocyte-inducing transcription factor (MITF), the master regulator of melanosome synthesis and melanoma. Additionally, MITF target gene levels and drug sequestering ABC transporter expression were also elevated by GH treatment in vitro and in vivo in mouse tumor xenografts. This was corroborated by in silico analyses of tumor databases. Furthermore, we observed a dose dependent increase in tyrosinase activity and melanogenesis in human melanoma cells with GH, in the presence of chemotherapy, which was suppressed by siRNA mediated GHR inhibition. Thus, we describe an array of molecular mechanisms by which GH drives chemoresistance in melanoma. Therefore, GHR inhibition combined with chemotherapy should lead to better tumor clearance and improve overall survival.
Effects of Growth Hormone on Pancreatic Cancer Derived Exosomes
Authors: Kulkarni Prateek , Basu Reetobrata , Kopchick John J
Published: May 2021

In 2020, the National Cancer Institute (NCI) estimates 57,600 new cases and 47,050 deaths in the US due to pancreatic ductal adenocarcinoma (PDAC). A dismal 10% five-year overall survival rate in PDAC is attributed to late diagnosis, limited treatment options, a remarkably high metastasis rate, and resistance of this cancer to available therapies. Therefore, a better understanding of the mechanisms of how PDAC tumors acquire drug resistance and spread to distal parts of the body are necessary for developing novel therapeutic approaches. Exosomes, microscopic vesicles released from most cells (both tumor and non-tumor) have been recently established to play a significant role in cell to cell communication. Exosomes modulate their target cell responses systematically depending on the nature of exosomal cargoes (nucleic acids, proteins, and lipids). PDAC derived exosomes have been implicated to promote metastasis via forming a pre-metastatic niche of cells as well as enhancing drug resistance. Growth hormone (GH) secreted primarily by the pituitary gland promotes metastasis and drug resistance as shown by plethora of studies. No study has directly assessed the effect of GH on exosomal cargoes in terms of promoting metastases and drug resistance. In this report, we show that GH modulates various pancreatic cancer cell exosomal cargoes which in turn potentially amplifies tumor invasion and metastases. Our data shows that GH treatment on human and mouse PDAC cells increases the exosomal protein levels of TGFβ - a critical inducer of epithelial-to-mesenchymal transition (EMT, a process leading to metastasis). In addition, GH treatment also increases extracellular matrix-degrading enzymes, MMP2 and 9, as well as multi-drug efflux pump ABCC1, ABCB1, and ABCG2 in PDAC cells. These results strongly implicate GH action in driving EMT and chemoresistance via exosomes in pancreatic cancer. Exosomes have a crucial impact especially in the areas of diagnostics and therapeutics. This report is the first to show that GH modulates the effects of exosomes secreted by pancreatic cancer cells. Acknowledgement: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Student Enhancement Award and Edison Biotechnology Institute.
High Expression of Nucleobindin-2 Is Associated With Poor Prognosis in Gastric Cancer
Authors: Okada Junichi , Yamada Eijiro , Saito Tsugumichi , Nakajima Yasuyo , Ozawa Atsushi , Okada Kazuya , Pessin Jeffrey E , Okada Shuichi , Yamada Masanobu
Published: May 2021

Nucleobindin-2 (NUCB2) is a 396-amino acid protein, cleaved into the N-terminal nesfatin-11-82, nesfatin-285-163 and the C-terminal nesfatin-3166-396. NUCB2 contains a signal peptide, a leucine zipper structure, two Ca2+ binding EF-hand domains, and has a wide variety of basic cellular functions. NUCB2 is also a precursor protein of nesfatin-1, which was originally identified in hypothalamic nuclei, and which is a regulatory factor involved in the central control of food intake and energy balance. There are several reports indicating that NUCB2 is also expressed in various human peripheral tissues. Moreover, recent studies have reported that high levels of NUCB2 mRNA and protein are a potent prognostic factor for prostate cancer, endometrial carcinoma, and breast cancer. NUCB2 was also identified as a potential tumor antigen eliciting autoantibody responses in 5.4% of gastric cancer patients but not in the healthy individuals. However, theclinicopathological significance of NUCB2 expression in gastric cancer has still not been elucidated. Therefore, we examined NUCB2 expression in a large number of gastric cancer patients, using immunohistochemistry, to explore its clinicopathological significance. To explore this, we aimed to investigate the NUCB2 expression in gastric cancer tissues and adjacent non-tumor tissues and its potential relevance to clinicopathological factors and prognosis using immunohistochemistry analysis. In our study, NUCB2 level in gastric cancer tissues was higher than in non-tumor tissues. A high expression of NUCB2 is significantly associated with tumor depth, lymph node metastasis, lymphatic invasion, venous invasion and clinical stage. Furthermore, the expression level of NUCB2 protein was independent predictor of progression-free survival. In summary, NUCB2 might play a crucial role in gastric cancer development and could serve as an independent predictor of prognosis of gastric cancer patients.
Inhibition of ALDH1A1 Activity in Cisplatin-Resistant Ovarian Cancer Cells Alters Their Cancer Stemness, Cell Cycle Profile and Mitochondrial Respiration Rate
Authors: Ramachandran Ilangovan , Ramadoss Sivakumar , Sen Suvajit , Karuppaiyah Selvendiran , Kumaran R Ileng , Chaudhuri Gautam
Published: May 2021

Introduction: Ovarian cancer is one of the leading cause of morbidity and death among women, with a five-year relative survival rate of only 30% in patients diagnosed with distant metastasis. The ovarian cancer cells initially respond to first-line platinum drug cisplatin [cis-diamminedichloroplatinum(II) (CDDP)] treatment. But, they subsequently develop resistance to CDDP and eventually exhibit chemoresistance. Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) is one of the key functional markers of ovarian cancer stem cells (CSCs) that confers cancer stemness and therapeutic resistance, and is associated with poor prognosis and patient survival. In this study, we have assessed the anticancer effects of the ALDH1A1 inhibitor, A37, in CDDP-resistant ovarian cancer cells in vitro. Experimental Methods: SK-OV-3-CDDP, cisplatin-resistant ovarian cancer cells were treated with different concentrations of the small molecule inhibitor of ALDH1A1, A37. We determined the cell proliferation using water-soluble tetrazolium salt (WST-1) assay at 24 and 48 h. The distribution of cell division phases by cell cycle analysis and oxygen consumption rate (OCR) via seahorse extracellular flux analysis were assessed by flow cytometry and seahorse XFe24 analyzer, respectively. Furthermore, we examined the protein expression of key signaling molecules by western blot analysis and cancer stemness by tumorsphere formation assay. Results: Treatment of SK-OV-3-CDDP cells with A37 significantly reduced the ovarian cancer cell proliferation. Interestingly, A37 induced cell cycle arrest as observed by an increase in G1 phase of the cell cycle. Additionally, A37 reduced the mitochondrial respiration of ovarian cancer cells as observed by the decrease in basal OCR. Moreover, A37 treatment markedly decreased the expression of WW domain containing transcription regulator 1 (WWTR1) protein [also called as transcriptional co-activator with PDZ-binding motif (TAZ)], which is a key downstream effector of mammalian Hippo signaling pathway that promotes cancer stemness, metastasis and chemoresistance. Importantly, A37 reduced the number and size of the tumorspheres. Conclusions: Our study suggests that inhibiting the ALDH1A1 activity using A37 reduced the cell proliferation and induced cell cycle arrest in CDPP-resistant ovarian cancer cells. The mechanism by which A37 elicits its anticancer effects on ovarian cancer cells include impairment in mitochondrial respiration that could alter cancer cell metabolism, and a decrease in WWTR1/TAZ expression and tumorsphere formation that could suppress cancer stemness. Our findings demonstrate that inhibition of ALDH1A1 could effectively eliminate the chemoresistant ovarian cancer cells, and therefore, new strategies targeting ALDH1A1 could lead to the development of novel therapeutics for aggressive chemoresistant ovarian cancer.