bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the Octreotide Acetate Pen Injector in a Formative Human Factors Study
Authors: Andre Anthony , Squittieri Nicholas , Patil Satyashodhan
Published: May 2021

Introduction: Subcutaneous injection of octreotide acetate is indicated to treat adults with acromegaly and diarrhea associated with carcinoid tumors or vasoactive intestinal peptide tumors. In this formative human factors study, we evaluated the readability and comprehension of the instructions for use (IFU) and ease of use of the octreotide pen injector. Methods: The study enrolled patients and healthcare practitioners who would be using the pen injector. The IFU contained a stepwise process with illustrations to detail injection administration and safe storage of the octreotide pen injector. Participants read the IFU and familiarized themselves with the device. Participants administered 2 unaided injections into skin-like pads. Injection success was defined as an attempt that delivered the correct dose into the pad. Each injection was evaluated by objective performance and subjective measures. Objective performance measures included assessment of steps necessary to deliver the correct medication dose and ensure user safety. Subjective measures included soliciting participant feedback on perceived success and difficulties administering a dose with the octreotide pen injector, as well as suggestions for improvements. Additional goals included evaluation of the IFU and octreotide pen injector usability aspects. Results: A total of 8 patients and 3 healthcare practitioners enrolled in the study. All (n = 11) participants successfully administered both injections, leading to an overall injection success rate of 100% across twenty-two injections. Subtask errors included participants priming the pen injector with the incorrect dose (n = 1) and not holding the injection button for 10 seconds after the injection (n = 2), but neither error resulted in dosing failure. Participant suggestions for improving the IFU included changes to the illustration of the plunger, reordering statements to clarify the priming process, and detailing how long to let the pen injector come to room temperature. Conclusion: Overall, participants felt the octreotide pen injector was easy to use and the instructions were clearly written and illustrated. Participant feedback and observations by moderators of the study led to recommendations for improvements to the clarity of the IFU.
Halting Retrograde Transport Excludes ErbB-2 From the Nucleus Abrogating Tumor Growth in Triple Negative Breast Cancer
Authors: Madera Santiago , Izzo Franco , Chervo María Florencia , Dupont Agustina , Chiauzzi Violeta Alicia , Montero Diego , Deamicis Agustina Roldán , Proietti Cecilia Jazmín , Schillaci Roxana , Elizalde Patricia Virginia , Russo Rosalia Ines Cordo
Published: May 2021

Triple negative breast cancer (TNBC) refers to a subtype of tumors with poor prognosis, devoid of hormone receptors and of membrane overexpression or gene amplification of ErbB-2. Due to its molecular heterogeneity, TNBC represents a major clinical challenge. In this regard, clinical biomarkers and targeted therapies remain elusive, and chemotherapy has been the standard of care for early and metastatic TNBC. ErbB-2, a member of the ErbB family of tyrosine kinase receptors, is a major player in the BC scenario. While it is a cell membrane-bound receptor, it migrates to the nucleus (NErbB-2) where it acts as a transcription factor or coactivator. We recently found that both the canonical (wild-type, WT) ErbB-2 and the alternative isoform c are located in the nucleus of TNBC, a scenario with an aggressive oncogenic potential. The route of intracellular transport from the plasma membrane to the trans Golgi network (TGN) and the endoplasmic reticulum (ER) is termed retrograde trafficking, and constitutes the pathway by which ErbB-2 migrates to the nucleus. The retrograde transport route is also hijacked by toxins and viruses to access the ER and exert their deleterious effects. Retro-2, a small molecule inhibitor, was shown to protect cells from toxin and virus effects by blocking their retrograde trafficking. Given the high levels of NErbB-2 in TNBC cells, we explored whether treatment with Retro-2 modulates localization of ErbB-2 and proliferation in TNBC.

We found that Retro-2 treatment decreased the levels of both WT ErbB-2 and isoform c in the nucleus of TNBC cells demonstrating that Retro-2 effects are not limited to a particular ErbB-2 isoform. Indeed, immunofluorescence assays revealed accumulation of ErbB-2 in the Golgi after Retro-2 treatment further preventing its sorting to the ER. We previously demonstrated that growth factors induce ErbB-2 migration into the nucleus in ErbB-2-positive BC cells. Consistently, we observed that Retro-2 prevents growth factor-induced NErbB-2 in ErbB-2-positive BC cells. Retro-2 treatment resulted in a dose-dependent decrease in cell proliferation in a panel of TNBC cells, whilst did not inhibit cell proliferation in the ErbB-2-negative MCF10A normal breast cell line. Moreover, disruption of retrograde transport by Retro-2 decreased the expression of cell cycle related NErbB-2 target genes (i.e. Erk5 and cyclin D1) therefore inducing cell cycle arrest at the G0/G1 phase. Most importantly, Retro-2 excluded ErbB-2 from the nucleus and abrogated tumor growth in preclinical models of TNBC.

Collectively, our findings reveal Retro-2, a non-toxic inhibitor of the retrograde transport route, as a candidate novel therapeutic agent for TNBC based on its ability to evict ErbB-2 from the nucleus and to abrogate TNBC growth.
Osteoblast-Induced Prostate Cancer Cell Migration and Invasion Is Mediated Through TGF-β1/SMAD2 Signal Pathway and Blocked by 17α-Estradiol
Authors: Shi Jian , Zhao Lian , Duncan Brittany , Su Jie , Manzo Jale , Liu He , Zhu Yuan-Shan
Published: May 2021

Prostate cancer (PCa) is curable if it is diagnosed and treated in localized and regional stage. However, PCa outcome is poor once it has distant metastasis. Approximately 70% to 100% of PCa deaths have bone metastasis, which may be associated with a specific bone microenvironment. In this study, we investigated the effect and molecular mechanism of osteoblast cells on stimulation of PCa cell migration and invasion and examined the effectiveness of 17α-estradiol on blocking osteoblast-induced PCa cell migration and invasion using in vitro cell analysis. PCa cells (PC3, LNCaP and DU145), osteoblast hFOB, kidney CV-1, breast tumor MCF-7 and liver cancer Huh-7 cells (ATCC) were cultured in RMPI-1640 or DMEM media supplemented with or without fetal bovine serum (FBS) at 37 oC in a 5% CO2-humidified incubator. hFOB condition media (HCM) without FBS were collected at different times of hFOB cell culture. Transwell and wound-healing experiments were used to determine PCa cell migration and invasion. Cell migration and invasion in PC3, DU-145 and LNCaP PCa cells were markedly promoted by co-culturing hFOB osteoblast cells or HCM, but not by cells or condition media originated from kidney (CV-1), liver (Huh-7) and breast (MCF-7). Compared to other non-osteoblast cell conditioned media, HCM had much higher levels of several cytokines and chemokines including tumor growth factor (TGF) β1. Both HCM and TGF-β1 produced a dose- and time-dependent induction of PCa cell migration and invasion as well as SMAD2 phosphorylation without altering cell proliferation. These HCM and TGF-β1 effects were inhibited by a specific TGFβ receptor inhibitor, LY2157299, as well as by 17α-estradiol in a dose-dependent manner. Most intriguing, 17α-estradiol significantly inhibited the HCM and TGF-β1-induced PCa cell migration and invasion at very low nanomolar concentrations, presumably mediated through estrogen receptor β. These findings suggest that TGF-β1 is a major factor in mediating hFOB cell stimulation of PCa cell migration and invasion, and 17α-estradiol is a potential agent to block PCa cell bone metastasis, probably through inhibition of TGF-β1/SMAD2 signal pathway.
Protein Signatures of Parathyroid Carcinomas Using Proteomic Analyses
Authors: Kong Sung Hye , Kim Jung Hee , Han Do-Hyun Han , Bae Jeong Mo , Hong Namki , Lee Joon-Hyop , Park So Young , Choi Yong Jun , Lee Sihoon , Rhee Yumie , Kim Sang Wan , Shin Chan Soo
Published: May 2021

Parathyroid carcinomas are rare endocrine tumors derived from the parathyroid glands with poor prognosis. Moreover, parathyroid carcinomas are resistant to radiation or drug therapy, and surgical resection is the only treatment option. Understanding the molecular pathogenesis of parathyroid carcinomas may pave the way for early diagnostic biomarkers and therapeutic targets. Therefore, we aimed to elucidate the protein signatures for parathyroid carcinomas through quantitative proteomic analyses. We performed liquid chromatography with tandem mass spectrometry (LC-MS/MS) technique with formalin-fixed paraffin-embedded (FFPE) samples and reached a quantitative depth of more than 5,000 proteins per sample. For the analyses, 23 parathyroid carcinoma and 15 adenoma samples were collected from five tertiary hospitals in Korea. Patients’ mean age was 52 years, and 24 (63%) were female. Patients with parathyroid carcinoma had higher parathyroid hormone (PTH) and serum calcium level than adenomas (PTH, 1077.6 ± 760.7, 181.8 ± 139.8 pg/mL; calcium 13.0 ± 2.8, 11.3 ± 1.0 mg/dL, respectively). From the proteomic expression profiling, there were 137 differentially expressed proteins with the cutoff of both p <0.05 and fold change > 1.5. Using the Ingenuity Pathway Analysis (IPA), top enriched canonical pathways in parathyroid carcinomas included glycoprotein-6 signaling related to the coagulation pathway, acute phase response, mTOR, and clathrin-/caveolar-mediated endocytosis signaling. In transcription factor analysis, TGFβ and TP53 were activated in carcinoma, and these factors were up-regulators of CD44 antigen and Annexin A2 (ANXA2) proteins. In network analysis, α-1-acid glycoprotein 1 (ORM1), laminin subunit β-2 (LAMB2), and Serpin family (SERPIN) proteins were derived as essential proteins and correlated to the AKT complex. Also, with the support vector machine (SVM)-based classification method, we derived a set of proteins that can discriminate carcinomas from adenomas, which consists of Carbonic anhydrase 4 (CA4), α/β hydrolase domain-containing protein 14B (ABHD14B), CD44, LAMB2, phosphatidylinositol transfer protein β isoform (PITPNB), and ORM1, with the lowest error rate of 11.1%. In conclusion, from the proteomics analyses of parathyroid neoplasms, newly recognized pathways - signaling related to coagulation, acute phase response, and endocytosis - were enriched in parathyroid carcinoma in addition to the known mTOR signaling pathway. The proteins such as α-1-acid glycoprotein and laminin subunit β-2 from SVM classification and network analyses could be the distinctive signature of carcinoma and may provide insights into the therapeutic target.
A Rare Case of Resistant Pigmentation
Authors: Sheth Kaushal Vinaykumar
Published: May 2021

Introduction: Familial glucocorticoid deficiency (FGD) is characterised by ACTH resistance & isolated glucocorticoid deficiency, with typical biochemical findings of low serum cortisol & high plasma ACTH. Patients present with hyperpigmentation (due to stimulation of MC1R by POMC products) & hypoglycemia. Clinical presentation includes failure to thrive & susceptibility to infections.

Case Report: A 14 year old girl presented to us with generalised hyperpigmentation of the skin and oral mucosa- it started when she was 4 years of age. There was history of recurrent respiratory infections around the same time the hyperpigmentation appeared - the patient required multiple hospitalisations for the same (she was admitted 3 times in 6 months). Her random serum cortisol was measured – it came out to be 8.27nmol/L. Her serum Na+ was 140 mEq/L & K+ was 3.5 mEq/L. She was also diagnosed with subclinical hypothyroidism at that time (TSH- 7.3 mIU/L, anti TPO antibodies positive). There was no history of alacrimia or achalasia. Her 17-OHP was 2.20 nmol/L. A probable diagnosis of autoimmune polyendocrine syndrome was made & oral hydrocortisone (@ 12 mg/m2) & levothyroxine (@25 mcg) was started. The patient was compliant with the treatment, but the mother complained that her hyperpigmentation improved only by 20–30 % despite continued treatment. There was no history of salt wasting crises or hospitalisations after the initiation of treatment. Her serum ACTH values were checked 2 times (2011 & 2015) and were > 2000 pg/ml on both the occasions. The hydrocortisone dose was increased to 20mg/m2 for 1 year in between, without any improvement in hyperpigmentation. Patient presented to us with persistent hyperpigmentation in 2019. She was a product of consanguineous marriage. Non-compliance was ruled out. She had attained menarche at the age of 12 years. There was history of delayed pubarche (started @ age of 13 years) & axillary hair was absent. Again, her serum ACTH was > 2000 pg/ml and electrolytes and BP were normal. In view of normal electrolytes with low cortisol at the time of diagnosis & persistent hyperpigmentation even on supraphysiological doses of hydrocortisone, Familial Glucocorticoid Deficiency was considered. Genetic analysis showed mutation in Thioredoxin Reductase (TXNRD2) Gene. This gene mutation has recently been reported in FGD. (Prasad R et al, JCEM Aug 2014.) Conclusion: In cases of primary adrenal insufficiency with normal electrolytes & resistant hyperpigmentation, familial glucocorticoid deficiency should be thought of. Treatment with standard glucocorticoid therapy should be given. Serum ACTH values should not be chased. The hyperpigmentation may not resolve completely. TXNRD2 deficiency leads to impaired redox homeostasis, highlights the important redox pathway in addition to defective ACTH signaling, giving us new insights in regard to steroidogenesis.
Steroid Receptor Co-Activators Regulate Metabolic Kinases to Drive Therapy Resistant ER+ Breast Cancer
Authors: Truong Thu Ha , Benner Elizabeth A , Hagen Kyla M , Temiz Nuri A , Kerkvliet Carlos Perez , Wang Ying , Cortes-Sanchez Emilio , Yang Chieh-Hsiang , Pengo Thomas , Guillen Katrin P , Welm Bryan E , Telang Sucheta , Lange Carol A , Ostrander Julie Hanson
Published: May 2021

Recurrence of metastatic breast cancer stemming from acquired endocrine and chemotherapy resistance remains a health burden for women with luminal (ER+) breast cancer. Disseminated ER+ tumor cells can remain viable but quiescent for years to decades. Contributing factors to metastatic spread include the maintenance and expansion of breast cancer stem cells (CSCs). Breast CSCs are poorly proliferative and frequently exist as a minority population in therapy resistant tumors. Our objective is to define novel signaling pathways that govern therapy resistance in ER+ breast cancer. In this study, we show that cytoplasmic complexes composed of steroid receptor (SR) co-activators, PELP1 and SRC-3, modulate breast CSC expansion through upregulation of the HIF-activated metabolic target genes PFKFB3 and PFKFB4. Seahorse metabolic assays demonstrated that cytoplasmic PELP1 influences cellular metabolism by increasing both glycolysis and mitochondrial respiration. PELP1 interacts with PFKFB3 and PFKFB4 proteins, and inhibition of PFKFB3 and PFKFB4 kinase activity blocks PELP1-induced tumorspheres and protein-protein interactions with SRC-3. PFKFB4 knockdown inhibited in vivo emergence of circulating tumor cell (CTC) populations in ER+ mammary intraductal (MIND) xenografts. Application of PFKFB inhibitors in combination with ER targeted therapies blocked tumorsphere formation in multiple models of advanced breast cancer, including tamoxifen (TamR) and paclitaxel (TaxR) resistant models and ER+ patient-derived organoids (PDxO). Together, our data suggest that PELP1, SRC-3, and PFKFBs cooperate to drive ER+ tumor cells that include CSCs and CTCs. Identifying non-ER pharmacological targets offers a useful approach to blocking metastatic escape from standard of care ER/estrogen (E2)-targeted strategies to overcome endocrine and chemotherapy resistance in ER+ breast cancer.
Stress-Induced Differential miR-4633-5p Expression in Thyroid Cancer Health Disparities
Authors: Mancao Jonathan , Lee Jin , Rood Kristiana , Davis Ryan , Perez Mia , Simental Alfred , Khan Salma
Published: May 2021

Filipino Americans (FA) are known to have higher rates of thyroid cancer incidence and disease recurrence compared to European Americans (EA). FA are also known to be two times more likely to die of thyroid cancer compared to EA. Epidemiological studies in California have shown that thyroid cancer is the second most common cancer among FA women. Currently, there are no studies that demonstrate the mechanism behind these discrepancies. Evidence shows a strong correlation between obesity and more aggressive forms of thyroid cancer; obesity has an increased frequency in FA populations. The exact connection between the mechanisms of obesity and cancer is poorly understood. This epigenetic phenomenon may be due to microRNAs (miRNAs), which post-transcriptionally regulate gene expression. Dysregulated miRNA profiles have been associated with various diseases including obesity and cancer. MiRNAs are linked to different types of cancer; tumor suppressor genes and oncogenes are subject to modulation by dysregulated miRNAs. No study elucidates the association of miRNAs to tumor staging or prognosis in thyroid cancer health disparities. In this study, we determined miRNA expression profiles and found significant differences in the miRNA profiles between FA and EA thyroid cancer patients. Our pilot study showed several dysregulated miRNAs, from which we chose to assay dysregulated miR-4633-5p segments that are known to be associated with thyroid cancer signaling. We used QIAGEN’s miRNA extraction kit to obtain high-quality miRNA from paraffin-embedded thyroid tissues. We performed next-generation miRNA sequencing using equal number of FA and EA samples and identified the top ten significantly up- and down-regulated miRNAs from the pool of differentially expressed miRNAs by qPCR assays. Our investigation demonstrated a 1.5-2-fold higher expression of an upregulated miR-4633-5p in FA versus EA miRNA samples (n=70) after normalized to controls. In contrast, miR-323b-3p showed no difference between FA and EA after normalized to controls. For our future work, we plan to analyze multiple up- and down-regulated miRNAs by qPCR, determine whether the miRNA signatures are consistent between samples from FA versus EA, and explore the use of these miRNA signature differentials for affordable and rapid thyroid cancer screening and prognosis.
Multifocal Multisystem Langerhans Cell Histiocytosis in an Adult Female Atypically Presenting With Multiple Abdominopelvic Abscesses
Authors: Khong Brian , Hyon Maximiliano
Published: May 2021

Introduction: Langerhans Cell Histiocytosis (LCH) is a condition of malignant clonal proliferation of myeloid bone marrow cells that more commonly affects children than adults. Furthermore, its presentation remains variable ranging from single organ to multisystem involvement including bone, skin, lymph, liver, spleen, lung, and central nervous system. We report an unusual case of multisystem LCH in an adult female presenting with multiple soft tissue abscesses.

Case: We report a case of a 38-year-old female with a past medical history of polysubstance abuse, type 2 diabetes, polycystic ovarian syndrome, and isolated central diabetes insipidus who had multiple hospitalizations for recurrent soft tissue abscesses treated with incision and drainage and antibiotics. Imaging studies revealed multiple osteolytic lesions involving the bilateral iliac crests, acetabulum and femur, as well as an iliopsoas abscess. Given her prior history of isolated central diabetes insipidus, the possibility of LCH as the cause was entertained. Histological evaluation performed on an inguinal soft tissue sample stained positive for CD1a and S100, and a formal diagnosis of Langerhans Cell Histiocytosis (LCH) was made. The patient was treated with chemotherapy with good results.

Conclusion: This report presents a rare and unusual case of adult onset multisystem LCH involving bone, skin, lymph, and central nervous system presenting with recurrent large abdominopelvic abscesses. These abscesses may represent a rare and unrecognized form of soft tissue involvement of LCH.
Tissue Is the Issue - A Case of Malignant Insulinoma
Authors: Arous Tania , Gianfagna Sara , Del Rivero Jaydira , Harbuz-Miller Inga
Published: May 2021

Introduction: Insulinomas are rare, functioning pancreatic neuroendocrine tumors, predominantly benign (90%). Most are sporadic, but they can occur as part of inherited disorders. Large size insulinomas are more likely to be malignant. 68Gallium (Ga)-DOTATATE scan is an essential tool in diagnosis and treatment of pancreatic neuroendocrine tumors. However, tissue diagnosis is the ultimate prognosis predictor and treatment guide.

Clinical Case: An 80-year-old man presented with left ankle fracture after a syncopal episode. In the past several months he reported multiple episodes of lightheadedness. He denied history of diabetes. Past medical and surgical history included prostate cancer, gastroesophageal reflux disease and bilateral orchiectomy for undescended testes. His left ankle appeared swollen, otherwise the exam was unremarkable: he was well-nourished, the abdomen was soft and nontender, there were no palpable masses. He was noted to have several episodes of hypoglycemia. Hypoglycemia work up included negative sulfonylurea screen, plasma glucose 51 mg/dl (60-99 mg/dl), insulin of 31 uIU/ml (3-25 uIU/ml), proinsulin 85.4 pmol/L (<8 pmol/L), C peptide 3.4 ng/ml (1.1-4.4 ng/ml). Abdominal Computed Tomography with contrast showed a 4.7 x 3.1 cm exophytic mass in the body of pancreas, a 5.3 x 5 cm mass in the head of pancreas and multiple ill-defined hepatic lesions concerning for metastatic disease. 68Ga-DOTATATE scan revealed an avid pancreatic mass and multiple avid foci throughout the liver suspicious for metastatic disease. Octreotide and intravenous dextrose were started for the treatment of persistent hypoglycemia. He underwent Whipple procedure and resection of the metastatic liver lesions. Postoperatively hypoglycemia resolved. The pathology revealed large cell pancreatic neuroendocrine carcinoma with areas of well differentiated tumor and multiple liver metastatic neuroendocrine carcinoma, Ki-67 of 50-80% was reported in the primary tumor and metastatic lesions.

Discussion: Metastatic insulinomas carry a significant morbidity and mortality risk. Surgical resection to decrease tumor burden can reduce the risk of hypoglycemia. Histopathology is essential in treatment decision making. Surprisingly our patient’s pathology revealed poorly differentiated neuroendocrine carcinoma, changing the prognosis and treatment. Treatment with platinum-based chemotherapy and etoposide is the standard of care for aggressive neuroendocrine neoplasms. Despite hypoglycemia resolution following surgery and good DOTATATE uptake by the well differentiated neuroendocrine tumor portion, our patient’s prognosis remained poor in view of the high-grade carcinoma. Due to complicated hospital course, and decreased functional status patient was not a candidate for chemotherapy immediately post hospital discharge.
ACTH-Dependent Cushing’s Syndrome in an Elderly Woman with Pituitary, Adrenal, and Intrathoracic Lesions
Authors: Japp Emily A , Levine Alice C
Published: May 2021

A 77-year-old female with rheumatoid arthritis on etanercept, depression on venlafaxine, and treated hypothyroidism presented with easy bruising and muscle weakness. She denied any steroid use. She had normal BP and BMI, but appeared mildly Cushingoid with round facies, and increased dorsocervical and supraclavicular fat.

Laboratory evaluation showed: ACTH 70.8 pg/mL (< 63.3), cortisol 24.3 ug/dL, 24 h urine free cortisol 223 ug (< 50), salivary cortisol 0.428 ug/dL, DHEA-S 165.7 ug/dL (< 142.8), LH 0.1 mIU/mL, FSH 2.7 mIU/mL, and hgbA1C 6.1 % (< 5.6 %). All other hormonal testing was normal. MRI of the pituitary showed a 4 x 2 x 3 mm hypoenhancing defect of the anterior pituitary. CT of the chest and abdomen showed a 1.1 cm left adrenal nodule, and a 1 cm non-specific right middle lobe lung nodule. Inferior petrosal sinus sampling (IPSS) with CRH did not show a central ACTH step-up. PET/CT with DOTATATE showed mildly increased tracer uptake in the right middle lobe measuring 1 cm with SUV max 3.7, and a 0.6 cm left apical subpleural nodule with SUV max 1.9.

The patient underwent a right middle lobectomy and pathology was positive for typical carcinoid. Post-operatively, she needed hydrocortisone replacement for 9 months. ACTH was 19.7 pg/dL, cortisol 9.5 ug/dL, DHEA-S 31.3 ug/dL, LH 61.8 mIU/mL, and FSH 112.4 mIU/mL. Her Cushingoid features and myopathy resolved.

This case highlights several challenges in the diagnosis and source localization in patients with ACTH-dependent Cushing’s Syndrome (CS). In this slim, elderly female, the typical features of CS were subtle. In addition, dynamic biochemical testing with high dose dexamethasone does not reliably distinguish eutopic from ectopic ACTH-dependent CS, as the sensitivity and specificity range from 60–80%. Thus, the diagnosis largely depends on sophisticated imaging and IPSS.

The patient had pituitary, adrenal, and lung lesions. The pituitary lesion initially pointed towards a central ACTH source, but IPSS was negative. The prevalence of pituitary incidentalomas is high, at 10.6% based on autopsy data, with an increasing proportion being recognized in the elderly. Adrenal incidentalomas are also often noted in older individuals, but that was clearly not the cause of CS in this patient with a non-suppressed DHEA-S and elevated ACTH. PET/CT with DOTATATE has emerged as a sensitive test for the detection of often small tumors producing ectopic ACTH and was positive in the lung lesion. In spite of newer localization techniques, the source of ectopic ACTH often remains unidentified (12.5% in a large retrospective case-record study). False negatives on PET/CT with DOTATATE imaging may be due to cortisol’s suppressive effect on the somatostatin receptor expression in neuroendocrine tumors. Thus, in cases of ACTH-dependent CS with negative IPSS, ectopic ACTH must remain as a likely source, and be re-explored after medical treatment of the hypercortisolism.
Adrenal Cushing’s in Pregnancy, Managed with Metyrapone to Optimize for Adrenalectomy at 27 Weeks Gestation
Authors: Shah Leena , Meislin Rachel , Berkin Jill , Fernandez-Ranvier Gustavo , Skamagas Maria
Published: May 2021

Background: Cushing’s syndrome in pregnancy is associated with increased fetal and maternal morbidity and mortality. Prompt diagnosis and management during pregnancy is critical to improving these outcomes. Clinical Case: Patient is a 28-year-old female who presented to our hospital at 25 weeks of pregnancy with severe striae, high blood pressure, mildly elevated blood sugars and hypokalemia. Striae began in the 6th week of her pregnancy but progressed in the 2nd trimester to encompass multiple sections of skin. Blood pressure on presentation was 146/100 mmHg (on labetalol) and fasting glucose 113 mg/dL (goal <95 mg/dL in pregnancy). Labs were consistent with ACTH-independent Cushing’s Syndrome: AM serum cortisol of 42.3 mcg/dL (n < 22.6 mcg/dL), PM serum cortisol of 46 mcg/dL (n < 11.9 mcg/dL), ACTH of <1 pg/mL (normal 7–63 pg/mL), 24-hour urinary free cortisol of 1388 mcg/day (n <45 mcg/day), and salivary midnight cortisol of 2.2 mcg/dL (n <0.3 mcg/dL). An abdominal MRI scan without contrast showed a 3.2 cm fat-containing right adrenal lesion consistent with an adenoma. The fetus was large for gestational age at 98th percentile. Patient was started on metyrapone 250 mg twice daily, which was titrated up to 250 mg three times daily. Her blood pressure and glucose levels, treated with labetalol and insulin respectively, improved on metyrapone. Surgery, Maternal Fetal Medicine, Endocrine, Anesthesia, and Neonatal physicians reviewed her case at an interdisciplinary meeting. She received metyrapone for 1 week pre-operatively. AM serum cortisol improved to 21.4 mcg/dL and 24-hour urinary free cortisol improved to 139 mcg/day. She underwent laparoscopic right adrenalectomy at 27 weeks of pregnancy. Betamethasone was given 2 days prior to ensure fetal lung maturity in case of preterm labor. Stress dose hydrocortisone 100 mg was given intra-operatively. Fetal heart monitoring was normal throughout the surgery and post-operatively. After surgery, metyrapone was stopped and hydrocortisone was tapered to 20 mg and 10 mg. Five weeks after her adrenalectomy, striae decreased in size and glucoses normalized. Remarkably, fetal size is now appropriate for gestational age in the 62th percentile at 34 weeks. However, blood pressure remains elevated and is being treated with labetalol. She is planned for induction of labor at 37 weeks due to her elevated blood pressures and will be given stress dose steroids intraoperatively. Conclusion: Medical management of adrenal Cushing’s in pregnancy with metyrapone followed by adrenalectomy required a multidisciplinary team approach. Patient underwent successful adrenalectomy without complications of severe hypercortisolism, including infection, thromboembolism, pre-eclampsia, preterm labor and pregnancy loss. After surgery, there was normalization of maternal blood sugars as well as fetal size, and persistent, but improved, elevated blood pressure.
Atypical Adrenaliemmas
Authors: Maradni Ahmad Al , Vinales Karyne Lima , Correa Ricardo Rafael
Published: May 2021

Introduction: Adrenal Incidentalomas (AI) are increasingly found with recent proliferation in imaging techniques. The precise prevalence of AI is not well established but estimated to be about 5%. Such findings require thorough work and follow up plans to assess for hormonal functionality and differentiate between benign or a malignant entity. Adrenocortical carcinoma (AC), schwannoma (SCH), ganglioneuroma (GN), myelolipoma (ML), neuroblastoma (NB), and ganglioneuroblastoma (GNB) are a rare presentation of AIs. In this case series, we present 2 cases of uncommon AIs. Cases Series: Case 1: A 55-year-old man presented to the hospital with episodic dizziness, nausea, vomiting, and diaphoresis. His physical examination and blood workup were unremarkable. He takes multiple antihypertensive medications at home. CT abdomen revealed an incidental 5 cm mass adjacent to the left adrenal gland which was confirmed to be of adrenal origin on MRI. The hormonal workup was negative. and patient. Laparoscopic left adrenalectomy was performed. Histopathological diagnosis pointed to a benign nerve sheath tumor. Tumor cells stained positive for S-100 and negative for CD34 and epithelial membrane antigen. The morphologic features and immunohistochemical profile consistent with adrenal SCH diagnoses, confirmed by two histopathologists. Postoperatively, Blood pressure improved, and the patient has no evidence of recurrence on subsequent follow-ups. Case 2: A 38-year-old female presented to the hospital with severe right groin pain. During the workup, a CT abdomen revealed a homogeneous, lobulated, minimally enhanced, 5.8 cm right adrenal mass with no calcifications. The hormonal workup was negative. FDG-PET scan showed low uptake in the right adrenal mass. Adrenalectomy was performed and histological examination revealed Schwan cells and neurites with occasional ganglion cells compatible with benign GN. Discussion: SCHs originate from Schwann cells in peripheral nerve sheaths. Adrenal SCHs are rare, they represent about 0.5% of all SCHs. Surgical resection is the initial management as imagings are non-diagnostic and appearance does not distinguish benign from malignant lesions. Adrenal GNs originate from neural crest cells in the adrenal medulla and represents between 20–30% of all GNs. They may be primary or evolve from differentiating NB. The majority of them are sporadic. GNs are typically benign and asymptomatic. However, larger GNs are associated with an increased risk of malignancy, a 33% risk for 5 cm compared to 92% for 6 cm. Surgical resection is necessary, especially for larger masses. Conclusion: Besides the common adrenal incidentalomas and their proper work and follow up plans, a clinician should consider atypical adrenal tumors with unusual presentation. Surgical treatment and histological examination are essential for an accurate diagnosis.
Atypical Adrenocortical Incidentaloma Causing Autonomous Cortisol Secretion and Cardiovascular Complications
Authors: Gaballa Salem , Memon Areeka , Roberts Marigny
Published: May 2021

Introduction: Autonomous cortisol secretion (ACS) is found in approximately 10% of patients with an adrenocortical incidentaloma (AI). The majority of these cases are due to non-ACTH-dependent ACS. 2% of patients with AI have adrenocortical cancer. ACS is associated with cardiovascular morbidity, includes arterial stiffness, hypertension, coronary heart disease, and fatal or nonfatal myocardial infarction.

Case presentation: A 62-year-old Caucasian male with a history of hypertension (HTN), hyperlipidemia (HLD) and poorly controlled type-2 diabetes mellitus (T2DM) and a recent myocardial infarction (MI) status post (s/p) coronary artery bypass graft (CABG) who presented to the endocrine clinic for evaluation of left adrenal mass. Family history was significant for adrenal carcinoma of his brother at the age of 60. The patient denied any facial flushing, palpitations, tremors, heat or cold intolerance, abnormal sweating, diarrhea, constipation, abdominal pain, recent weight change. Physical examination was unremarkable except midline sternal scar s/p CABG. Vital signs were remarkable for a blood pressure of 142/90. Labs were unremarkable. CT adrenal revealed a left adrenal mass 4.9 x 3.5 x 2.3 cm with HU -3 to 28 heterogeneous. HbA 1C was 8.2 %. Adrenal incidentaloma workup revealed a normal 24-hour urine cortisol level of 29 mcg, abnormal mid-night salivary cortisol of 0.13 mcg/dL and 0.31 mcg/dL, elevated cortisol after 1 mg dexamethasone suppression test (DST) of 343 mcg/dL, elevated cortisol after 8 mg DST of 90 mcg/dL, normal metanephrines of 10 pg/mL and normal normetanephrine of 49 pg/mL, normal aldosterone of 6.1 ng/dL, normal renin activity of 0.36 ng/ml/hr (Aldo/ PRA ratio 16). ACTH was 4.5 pg/ml. The endocrine surgeon was consulted for left adrenalectomy. The pathology showed atypical adrenal cortical neoplasm which does not clearly fulfill the criteria for adrenal cortical carcinoma confirmed by two pathologists. Upon six months follow-up, a 24-hour urine cortisol level was normal, 1mg overnight DST was normal, and no evidence of left adrenal on adrenal CT.

Discussion: Adrenal incidentaloma (AI) is a common endocrine diagnosis affecting ~2% of the general population. Up to 10% of patients with AI have autonomous secretion of adrenal hormones. Pheochromocytoma and autonomous cortisol secretion should be excluded in every case and aldosteronism in patients with underlying hypertension and/or hypokalemia. ACS in patients AI has been associated with hypertension, insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome, coronary artery disease, and increased mortality. Adrenalectomy is recommended for patients with a functional unilateral adenoma, with clinically significant hormone excess. Metabolic improvement after adrenalectomy, including weight loss, blood pressure lowering, glucose tolerance, lower lipids have been reported.
Biotin Supplementation Creates the Misleading Diagnosis of Secondary Adrenal Insufficiency
Authors: Motahari Hooman , Thumma Soumya , Menon Lakshmi
Published: May 2021

Introduction: Biotin (vitamin B7) is a water-soluble vitamin and an essential cofactor for the metabolism of fatty acids, glucose, and amino acids. Cases of biotin interference with laboratory testing have been described, most of which involve interference with thyroid function tests. Interference with gonadal steroids, adrenal, and pituitary hormones are rare. We report a case of T3 thyrotoxicosis in which biotin supplementation created the appearance of secondary adrenal insufficiency (AI).

Case: A 66-year-old woman was referred for the evaluation of low TSH. She had chronic fatigue, low libido, and dizziness on standing. Vitals were stable with BP 135/64 mmHg and BMI 23.5. No evidence of mucosal or cutaneous hyperpigmentation. Laboratory evaluation revealed low ACTH <5 (7.2–63.3 pg/mL), low morning cortisol 3.8 and high DHEA-S 174 (13–130 ug/dL). TSH was low at 0.32 (0.32–5.60 uIU/mL) with normal prolactin and appropriately elevated FSH and LH. The labs raised concern for secondary AI. Cosyntropin stimulation test (CST) was done with a peak cortisol of 17.4 ug/dL. In the setting of suppressed ACTH and failed CST, she was started on Hydrocortisone therapy. Subsequently, CT of abdomen was obtained due to high DHEA-S which showed normal appearance of both adrenals. Pituitary MRI was normal. A detailed review of the medication list revealed that the patient was taking a Biotin containing multivitamin. Repeat labs 1 week after stopping biotin showed normalization of ACTH 13.8 (7.2–63.3). Repeat CST showed a peak cortisol response of 24 ug/dL. Hydrocortisone was discontinued and the patient remained stable on subsequent follow-ups, without the need for further glucocorticoid replacement therapy. Thyroid lab abnormalities persisted after biotin cessation which led to the diagnosis of T3 thyrotoxicosis, the treatment of which caused resolution of the patient’s symptoms.

Discussion: The recommended daily intake of biotin for adults is 30 µg/d. Many over-the-counter products, specifically those marketed for hair, skin, and nail growth, contain biotin 100-fold higher than the recommended intake. Biotin interference with competitive immunoassays can cause falsely elevated hormone levels, whereas biotin interference with immunometric “sandwich” assays falsely lowers hormone levels. In our case, low ACTH was clinically misleading, prompting numerous unnecessary radiographic and laboratory testing and treatment with hydrocortisone. The US Food and Drug Administration issued a safety communication regarding biotin interference with laboratory tests. Education and communication between laboratorians, providers, and patients play an important role in investigating potential lab interference and the need for alternative lab assays for an accurate diagnosis. Patients should be asked to stop taking biotin supplements for at least 48 hours prior to specimen collection if possible.
Can Extra Adrenal Cortisol Secretion Occur in an Adrenalectomized Patient?
Authors: Iftikhar Sahar , Bingham Emma Margaret
Published: May 2021

Background: Established medical practice is that adrenalectomized patients require lifelong steroid replacement. We report a case which challenges that assumption. Clinical Case: A 38 year old female underwent transsphenoidal resection of a proven ACTH secreting pituitary adenoma. Post operatively her pituitary function was preserved, but due to residual tumour activity and the desire to preserve fertility, she had a bilateral adrenalectomy one year later and commenced hydrocortisone replacement. Subsequent pituitary imaging did not show recurrence of the tumour and her visual fields were stable, however her ACTH remained elevated at 100 and 130ng/L (09:00 <50 ng/L) despite steroid replacement.14 years after adrenalectomy she noticed weight gain and increased body hair. She also reported sometimes missing her hydrocortisone due to her busy job without ill effects. Her 9 am cortisol pre-hydrocortisone was elevated at 333 nmol/L (9am: 140–690 nmol/L) with ACTH of 203.0 ng/L (09:00 <50ng/L) She was able to suppress cortisol normally after a Dexamethasone suppression test. CT of her adrenals found no adrenal tissue. By now she had weaned herself off hydrocortisone, keeping an emergency supply. SST showed a cortisol of 320 nmol/L at 30 minutes, 360 nmol/L at 60 minutes with an elevated ACTH of 140 ng/L (09:00 <50 ng/L). Her weight gain and body hair growth stabilised. Discussion: We have demonstrated that this adrenalectomized patient has ACTH driven endogenous cortisol secretion which may be due to residual adrenal tissue due to seeding after surgery or the presence of steroid synthesis elsewhere. Extra adrenal sources for glucocorticoid production are known such as skin, gonads and thymus. However, the levels are insufficient to mount a significant stress response. There is evidence of adrenal regeneration in adrenalectomized animals. The regeneration is primarily of the adrenal cortex and does not involve the medulla. There has been one case report in literature of a 11 year old German boy who had adrenal regeneration detected on adrenal scintigraphy (Bilateral normal adrenal glands with normal activity) 13 years after adrenalectomy for Cushing’s disease.

References: Gotlieb N, Albaz E, Shaashua L, et al. Regeneration of Functional Adrenal Tissue Following Bilateral Adrenalectomy. Endocrinology. 2018;159(1):248–259. doi:10.1210/en.2017-00505

Taves MD, Gomez-Sanchez CE, Soma KK. Extra-adrenal glucocorticoids and mineralocorticoids: evidence for local synthesis, regulation, and function. Am J Physiol Endocrinol Metab. 2011;301(1):E11-E24. doi:10.1152/ajpendo.00100.2011
Catastrophic Presentation of a Ruptured Pheochromocytoma
Authors: Ibraheem Hamad Mohammad Khair Ahmad , Abdelrahman Salma Bashir , AlKhatib Mohammed , Obeidat Ibrahim , Mokhtar Marwa Gomaa , Alamer Zaina Abdelhalim , Al-Mohanadi Dabia Hamad
Published: May 2021

Background: Pheochromocytoma is a catecholamine-secreting tumor, encountered in less than 0.5% of patients with hypertension and around 4% of patients with adrenal incidentaloma.1 It classically presents with episodic headache, sweating, and hypertension but rarely can present with serious complications such as hypertensive, pheochromocytoma crisis, and hemorrhagic shock.

Clinical Case: We report a 49-year-old male patient with a history of hypertension for five years on Amlodipine but not compliant. Presented to the Emergency Department with sudden onset left severe flank pain associated with one episode of vomiting for six hours. Vital signs were stable, and basic labs were within normal. Bedside ultrasound couldn’t appreciate any abnormality due to obesity, urinary tract CT-scan showed a large heterogeneous non-enhancing mass, possibly hematoma arising from left adrenal gland. Afterward, his condition deteriorated rapidly, he became hypotensive, and hemoglobin level dropped from 14 to 8gm/dl within a few hours. He became agitated with a worsening level of consciousness, so he was admitted under the medical intensive care unit (MICU) and required intubation and started on mechanical ventilation. Abdominal CT-angiography was done to look for any active bleeding, showed re-demonstration of the same lesion in the left adrenal without contrast enhancement or extravasation. He underwent urgent explorative laparotomy that showed ruptured large left adrenal hematoma, which was entirely evacuated with the adrenal tissue, his vital signs were maintained stable during the surgery. Postoperative course showed uncontrolled blood pressure requiring three anti-hypertensive medications; otherwise, he had gradual improvement until successful weaning, and returned to his baseline. The histopathology result was suggestive of pheochromocytoma with extensive bleeding.

Conclusion: Ruptured pheochromocytoma is an extremely rare presentation of hemorrhagic shock and needs a high index of suspicion. In our patient, the lack of classical presentation and imaging features of pheochromocytoma combined with the condition rarity, made the diagnosis very challenging. Urgent surgical intervention may be warranted, and multidisciplinary perioperative preparation is the key to a favorable outcome.

References: 1 Bravo EL. Pheochromocytoma: new concepts and future trends. Kidney Int. 1991 Sep;40(3):544–56. doi: 10.1038/ki.1991.244. PMID: 1787652.
Classic CAH Presenting in Adulthood: Experience From a Tertiary Care Hospital in Eastern India
Authors: Mishra Ipsita , Narkar Rukma , Pathak Vaibhav , Choudhury Arun Kumar , Baliarsinha Anoj Kumar
Published: May 2021

Classic CAH presenting in adulthood: Experience from a tertiary care hospital in Eastern India: Congenital adrenal hyperplasia(CAH) is one of the most common genetic disorders transmitted as an autosomal recessive trait. Of the various forms CAH due to 21-hydroxylase deficiency is most common. Based on the clinical phenotype CAH can be classified as classic and non-classic form. It is very rare for classic CAH to present in adulthood. We describe 3 patients with classic CAH presenting in adulthood. Case 1: 21 year old female presented with complaint of not attaining menarche. She had features of virilisation t with a modified Ferriman Gallwey(FG) score of 18/36, pubic hair stage 4 and atrophied breasts. Genital examination revealed clitoromegaly (CI-100 mm2) with Prader stage 2. Biochemical evaluation revealed elevated levels of serum testosterone (257.2 ng/dl), 17-hydroxy progesterone(332 ng/ml), DHEAS(417 µg/dl) and PRA of 34ng/ml/hr. Case 2: 30 year old female presented with complaint of primary infertility for 5 years. She had history of delayed menarche at 20 years and oligomenorrheic cycles since last 10 years. On examination there was hirsutism with a modified FG score of 15/36, pubic hair stage 5 with atrophied breasts. Genital examination revealed symmetrical genitalia with nonpalpable gonads, clitiromegaly(CI=135mm2) and a single urogenital opening (Prader stage 3). Biochemical evaluation revealed elevated levels of serum testosterone (812ng/dl), 17-hydroxy progesterone (164.8 ng/ml), DHEAS (503 µg/dl) and PRA of 42ng/ml/hr. Case 3: 26 year old female presented with complaint of noticing excessive hair growth in androgen dependent areas. On examination there was short stature,modified FG score 16/36, pubic hair stage 5 with atrophied breasts. Genital examination revealed clitoromegaly (CI=75mm2) with Prader stage 2. Biochemical evaluation revealed elevated levels of serum testosterone (254.2 ng/dl), 17-hydroxy progesterone (351.8 ng/ml), DHEAS (296.2 µg/dl) and PRA of 30ng/ml/hr. Karyotype in all the three patients was 46,XX. All our patients had serum testosterone values in tumorous range, however imaging studies didnot reveal any evidence of malignancy in the adrenals except for occurrence of a single right adrenal nodule of size 2×2.1cm with precontrast HU of <10 and absolute contrast washout of >60% in case 2. Based on clinical and biochemical findings a diagnosis of classic CAH was made. They were started on corticosteroid and mineralocorticoid replacement. In all of the above three patients none of them had been evaluated for the presenting complaints prior to visiting our centre. Failure of implementation of neonatal screening for CAH in many centres in India and the social stigma associated with genital ambiguity are contributory to the delay in diagnosis of CAH.